Guidelines on the Management of Patients with Nonfunctioning Pituitary Adenomas
7. Management of Patients with Residual or Recurrent Nonfunctioning Pituitary Adenomas
Congress of Neurological Surgeons (CNS) and the Section on Tumors
Joint Guidelines Committee of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS)
Jason Sheehan, MD, PhD1, Cheng-Chia Lee, MD1, Mary E. Bodach, MLIS2, Luis M. Tumialan MD3, Nelson M. Oyesiku, MD, PhD4, Chirag G. Patil, MD5, Zachary Litvack, MD6, Gabriel Zada, MD7, Manish K. Aghi, MD, PhD8
1 Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA
2 Guidelines Department, Congress of Neurological Surgeons, Schaumburg, Illinois, USA
3 Barrow Neurological Institute, Phoenix, Arizona, USA
4 Department of Neurosurgery, Emory University, Atlanta, Georgia, USA
5 Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
6 Department of Neurosurgery, George Washington University, Washington, DC, USA
7 Department of Neurological Surgery, University of Southern California, Los Angeles, Los Angeles, California, USA
8 Department of Neurosurgery, University of California, San Francisco, San Francisco, California, USA
Jason Sheehan, MD, PhD
Department of Neurological Surgery University of Virginia
P.O. Box 800212
Charlottesville, VA 22908
Background: Despite the advancement of microsurgical and endoscopic techniques, some nonfunctioning pituitary adenomas (NFPAs) can be difficult to cure. Tumor recurrence or incomplete resection may occur in some patients with NFPAs, and management strategies for these NFPAs remain unclear.
Objective: To review the existing literature as it pertains to the management of post-surgical residual or recurrent NFPAs.
Methods: A systematic review of the treatment options for residual or recurrent NFPAs was performed. In this review, the authors critically evaluated the evidence to support the options of repeat microsurgical resection, stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), and fractionated radiation therapy (XRT).
Results: Forty-nine studies met the inclusion criteria for analysis: outcome of repeat surgical resection (n = 4), outcome of radiosurgery (ie, single session or hypofractionated SRS; n = 24), or fractionated radiotherapy (ie, conventional XRT, proton beam radiotherapy [PBRT], intensity modulated radiotherapy [IMRT], SRT; n = 21). No Class I evidence was available, 6 studies met criteria for Class II evidence, and other studies provided Class III evidence. A meta-analysis of 5 Class II studies with recurrence rates for both adjuvant radiation therapy and observation demonstrated that XRT for residual/recurrent NFPAs offered a lower rate of recurrence (odds ratio = 0.04; 95% confidence interval: 0.01-0.20; P < .0001). The analysis also demonstrated significant heterogeneity between the included studies (Chi2 = 20.70; P = .003; I2 = 81%).
Conclusion: Repeat resection, SRS, SRT, and XRT play a role in the management of patients with recurrent or residual NFPAs. SRS or some type of radiation therapy is typically performed for patients with residual tumor or tumor recurrence after resection.
Nonfunctioning pituitary adenoma, stereotactic radiosurgery, radiation therapy, systematic review, practice guidelines
NFPA = nonfunctioning pituitary adenoma, SRS = stereotactic radiosurgery, XRT = fractionated radiation therapy.
Should patients with recurrent or residual nonfunctioning pituitary adenomas (NFPAs) undergo stereotactic radiosurgery (SRS), fractionated radiation therapy (eg, XRT, fractionated stereotactic radiotherapy [SRT], or intensity modulated radiotherapy[IMRT]), or repeat resection?
These recommendations apply to adult patients with recurrent or residual nonfunctioning pituitary adenomas (NFPAs).
Level II Recommendations
- Radiosurgery and radiation therapy are recommended for treatment of residual or recurrent NFPAs to lower the risk of subsequent tumor progression.
- When no residual tumor is present or only a small intrasellar tumor exists postoperatively, serial neuroimaging studies are recommended.
- Radiosurgery using single-session doses of 12 or more Gy or radiation therapy with fractionated doses of 45 to 54 Gy is recommended for greater local tumor control rate of 90% or higher at 5 years after treatment.
Level III Recommendations
- Assessment of NFPA proliferative index and ACTH staining to identify silent corticotrophic adenomas are recommended for providing guidance regarding the risk of adenoma progression and the benefit of earlier adjuvant radiation.
- Repeat resection is recommended for the treatment of symptomatic recurrent or residual NFPAs.
- Radiosurgery or radiation therapy for NFPAs is recommended when residual/recurrent sellar or parasellar tumor exists and the risk of a repeat resection is high.
Pituitary adenomas are relatively common tumors, and, in fact, they are found in 10%-27% of the general population.1,2 Nonfunctioning pituitary adenomas (NFPAs) do not secrete a pituitary hormone, but they may exhibit immunohistochemical positivity for one or more hormones. NFPAs comprise approximately one-third of all pituitary adenomas. Most NFPAs exhibit symptoms as a result of mass effect on adjacent structures such as the optic apparatus, the normal pituitary gland or stalk, or cranial nerves traversing the cavernous sinus. Historically, many NFPAs are diagnosed as macroadenomas. However, in part with the increasing access to neuroimaging modalities such as MRI, nonfunctioning ones can also be found incidentally and diagnosed as microadenomas.
Pituitary adenomas represent challenging clinical entities that neurosurgeons must contend with. Surgical resection, typically through a transsphenoidal corridor, is the upfront treatment for NFPAs. However, some NFPAs can be difficult to cure with surgery alone. Tumor recurrence or incomplete resection can occur in many pituitary adenoma patients. Nearly a century ago, Harvey Cushing realized the limitations of microsurgical approaches for treating pituitary adenomas. Cushing and his colleagues used a radium bomb to deliver a single-session, focused radiation to treat pituitary adenomas.3,4 Henceforth, neurosurgeons and radiation oncologists have employed repeat resection or ionizing radiation to treat selected patients with recurrent or residual pituitary adenomas.
Authors perform a systematic review of the treatment options for residual or recurrent NFPAs. In this review, authors critically evaluate the evidence to support the options of repeat microsurgical resection, stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), and fractionated radiation therapy (XRT). In addition, authors provide guidelines for the use of the approaches in the management of recurrent or residual NFPAs. These guidelines are based upon the evidence currently available in the published literature.
The evidence-based clinical practice guideline task force members and the Tumor Section of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological (CNS) conducted a systematic review of the literature relevant to the management of NFPAs. Additional details of the systematic review are provided below and within the introduction and methodology chapter of the guideline.
Disclaimer of Liability
This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. The presentations are designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in its development are not meant to replace the individualized care and treatment advice from a patient’s physician(s). If medical advice or assistance is required, the services of a physician should be sought. The recommendations contained in this guideline may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in this guideline must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.
Potential Conflicts of Interest
All NFPA Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Committee (JGC). The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs.
The task force collaborated with a medical librarian to search for articles published from January 1, 1966, to October 1, 2014. Authors searched 2 electronic databases, PubMed and The Cochrane Central Register of Controlled Trials. Strategies for searching electronic databases were constructed by the evidence-based clinical practice guideline taskforce members and the medical librarian, using previously published search strategies to identify relevant studies (Appendix A).5-12 The Cochrane Library was searched for all NFPA articles. There were no specific Cochrane reviews for pituitary adenomas. Therefore, all appropriate references were found in the aforementioned PubMed search.
Statistical Analyses of Pooled Data
To compare the tumor control rates between patients who underwent adjuvant radiation therapy and patients who were treated conservatively, the pooled data were analyzed using Review Manager version 5.2.8 (The Nordic Cochrane Centre; The Cochrane Collaboration, 2012). The tumor control rates were extracted for the patients who underwent SRS, SRT, and XRT as adjuvant treatment, and for patients who chose observation. Studies with tumor control rates of NFA comparing adjuvant SRS and observation were included in the meta-analysis. Odds ratios for individual studies and the sum of the included studies were computed using the Mantel-Haenszel test.
Under the assumptions of possible clinical diversity among the included studies, the random effects model was implemented in the analyses for this review. Study heterogeneity was detected using the chi-square and I2 test statistics. In general, a small number of studies in the analyses lower the power of the chi-square test. Therefore, both a chi-square value within the 10% (P < .10) and a I2 value exceeding 50% were required for significance.
RESULTS AND DISCUSSION
The search resulted in 95 articles, and 46 were excluded based on the inclusion and exclusion criteria mentioned above according to the title and abstract. The remaining 49 articles were included, and these were as follows: outcome of repeat surgical resection (n = 4), outcome of radiosurgery (ie, single-session or hypofractionated stereotactic radiosurgery [SRS]) (n = 24), or fractionated radiotherapy (ie, stereotactic radiotherapy [SRT], conventional fractionated radiotherapy [XRT]) (n = 21) (Figure 1). This review highlights the most important contributions on the treatment efficacy in residual/recurrent NFPA of surgical approaches, on radiosurgery, and on studies aimed at the identification of new markers in relation to tumor behavior or response to treatment.
Although a few studies have assessed the long-term results of surgery alone as a definitive treatment for NFPAs, the recurrence after initial resection has been noted to be as high as 44%-75% within a 10-year period of time after resection.13-16 Those with cavernous sinus invasion, larger tumor remnant, and extrasellar location (ie, cavernous sinus invasion) were more likely to exhibit tumor regrowth. Factors portending a more favorable chance of tumor control were those with a smaller tumor remnant and older age.17-20 Therefore, for the residual NFAs that were tending to grow, the adjuvant treatment was suggested, either repeated surgery SRS or radiation therapy.
Four studies of repeat resection met inclusion for this guidelines project (Table 1). Of these studies, all represented retrospective, class III evidence.21-24 In a study by Cappabianca et al,21 repeat resection was carried out with an endoscopic, transsphenoidal approach. Gross total resection was achieved in 2 of 6 patients; no hypopituitarism or other complications were noted. In another larger study, Cavallo et al22 performed repeat endoscopic resection via a transsphenoidal approach, and they achieved gross total resection of 62%. Prior microsurgical resection portended a greater chance of gross total resection, whereas prior endoscopic resection was related to a lower rate of gross total resection. In the largest of the studies by Chang et al,23 visual deterioration was seen in 5%, permanent diabetes insipidus in 1.2%, transient diabetes insipidus in 4.9%, meningitis in 2.5%, postoperative hematoma in 2.5%, and perioperative mortality in 1.2%.
Thus, repeat resection for an NFPA would seem reasonable for those with larger, symptomatic residual or recurrent tumors (ie, optic compressive neuropathy, other cranial nerve dysfunction, or hydrocephalus). The use of specific surgical approaches depends on the location of a residual/recurrent tumor. A lesion invading the cavernous sinus, suprasellar region, or even the hypothalamus is usually more difficult to treat via surgical resection, although some neurosurgeons have great experience in pterional, subfrontal, or interhemispherical approaches. There is insufficient evidence in the literature to recommend one particular surgical technique (ie, endoscopic versus microscopic) for those requiring repeat resection. While most recent publications are focused on comparing the conventional microsurgical approach to the endoscopic approach, the evidence does not show that the endoscopic TSS approach for residual/recurrent NFPA is superior to the microscopic TSS approach in terms of the rate of gross total resection or the endocrinological outcome, although the endoscopic approach did reduce hospital stay (class III evidence), perioperative morbidity (lumbar drains or labial complications), and patient discomfort as compared to the microscopic approach. However, there is one report that suggests that the application of a different approach than the one used in the initial resection may be helpful for gross total resection of residual/recurrent NFPA.22 Similarly, a few studies demonstrated some advanced surgical techniques such as intraoperative optic nerve identification, intraoperative MRI,25-27 or with pituitary transposition to reduce the rate of incomplete resection.28
Although there is no direct comparison, second transsphenoidal approaches appear to convey higher complication rates, varying from 1%-22%.17, 21-24 The complications include hypopituitarism (<5%), cerebrospinal fluid (CSF) leakage (1.5%-2.5%), postoperative hyponatremia (3.7%), transient or permanent diabetes insipidus (<5%), visual deterioration (<5%), meningitis (2.5%), hematoma on the tumor bed (1.7%), epistaxis, sinusitis, and anesthetic risks. Incomplete resection or failure to identify the remaining adenoma secondary to obscured anatomy can also occur during repeat resection.
Stereotactic Radiosurgery for Residual/Recurrent Nonfunctioning Pituitary Adenomas
In 1951, Lars Leksell, a neurosurgeon, devised the concept of SRS. He described SRS as the “closed skull destruction of an intracranial target using ionizing radiation.”29 Seventeen years later, Leksell treated the first pituitary adenoma patient using the Gamma Knife.
SRS delivers a precisely focused and high dose of ionizing radiation to the target while sparing surrounding structures of appreciable radiation. Radiosurgery is usually delivered in a single session, but it may be delivered in up to 5 sessions (ie, fractions) in recent SRS models.30 For cobalt-based SRS devices such as the Gamma Knife, the steepest gradient index is achieved around the 50% isodose line, whereas for linear accelerators (LINACs)-based radiosurgical systems, it is usually achieved at an 80% to 90% isodose line. As such, a radiosurgical dose plan with the Gamma Knife will have more heterogeneity within the target volume than a LINAC-based treatment. A margin dose of 12 to 20 Gy is frequently used for single-session radiosurgery of NFPAs.
For treating NFPAs, careful attention to the neuro-anatomy is important, and this holds true for both radiosurgery and fractionated radiation therapy. Accurate contouring of the target and adjacent critical structures is required. In order to develop an accurate dose plan, a patient undergoes at least one type of stereotactic neuroimaging. For pituitary adenoma patients, this is most frequently a stereotactic MRI and/or CT. During radiosurgical delivery, semi-rigid or rigid target immobilization of the patient’s cranium is utilized. Patients are immobilized using rigid frames fixed to the skull or other immobilization such as thermoplastic masks or bite blocks. Each immobilization device has a stereotactic coordinate system. Radiosurgery is image guided, and it reliably confers sub-millimeter accuracy for intracranial targets. With the use of onboard imaging systems (eg, cone beam CT or orthogonal X-rays) or patient movement detection systems (eg, systems with vacuum detection for patient motion or infrared tracking), patient tracking and compensation for errors (eg, set-up error, patient movement, etc) can be made. The literature review revealed the routine use of commercially available radiosurgical delivery devices including the Gamma Knife (Elekta AB, Crawley, United Kingdom), modified linear accelerators (LINACs) such as Novalis (Brainlab, Munich, Germany) and Cyberknife (Accuray, Sunnyvale, California), and proton beam units.
Regarding outcome of SRS for recurrent or residual NFAs, we identified 24 studies that met the predefined study criteria. Of these, 2 studies were Class II evidence,31,32 whereas the remaining represented Class III evidence (Table 2).33-54
Overall, tumor control of NFPAs with SRS varied from 83% to 100% (Table 2). In a case-controlled (ie, Level Class II) study by Picozzi et al,31 5-year progression-free survival in radiosurgically managed NFA patients was 89.8% compared to 51.1% in untreated NFA patients. In the largest study to date, Sheehan et al33 demonstrated progression-free survival at 3, 5, 8, and 10 years of 98%, 95%, 91%, and 85%, respectively. Those with a smaller adenoma volume were more likely to exhibit post-SRS tumor control, whereas those with suprasellar extension were less likely to do so. Other studies, including those from Park et al,36 Starke et al,34 and Gopalan et al,38 demonstrate the diminished effectiveness of radiosurgical tumor control for larger-volume adenomas. In addition, lower radiosurgical margin dose, particularly below 12 Gy, appears to confer a lower rate of long-term tumor control.44,45,50 While most of the radiosurgical literature was composed of Gamma Knife-based series, several linear accelerator-based radiosurgical series afforded a high rate of NFA control.35,37
For complication after SRS, hypopituitarism is the most frequently occurring unintended side effect of radiosurgery for an NFA. Rates of hypopituitarism ranged from 0% to 39% in the identified series (Table 2). The second most common side effect from radiosurgery is a cranial neuropathy. Optic nerve dysfunction varied from 0% to 12.8%. Other deficits involving cranial nerves III, IV, and VI varied from 0% to 13.7% (Table 2). In the identified studies, no cases of radiation-induced neoplasia or cerebral ischemia were noted from SRS of an NFPA.
Fractionated Radiation Therapy for Residual/Recurrent Nonfunctioning Pituitary Adenomas
Conventional fractionated radiation therapy includes various types, such as conventional fractionated radiotherapy (XRT), charged particle (most frequently proton [PBRT] or carbon ion) radiotherapy, intensity modulated radiotherapy (IMRT), and stereotactic radiotherapy (SRT). Radiotherapy has been utilized for decades to treat patients with NFPAs. Four-field techniques for the skull base used anterior-posterior and lateral opposing fields. The technique of radiation therapy has undergone substantial technological leaps over the past decade. As such, a four-field approach has been supplanted by techniques such as 3-dimensional conformal radiation therapy and intensity-modulated therapy. During radiation therapy, the patient’s head is usually immobilized in a tight-fitting mask. Common fractioned doses to pituitary adenomas are 45 to 54 Gy at 1.8 to 2 Gy per fraction per day. Four to 5 fractions are delivered per week over the time span of 5 to 6 weeks.
Utilizing the aforementioned search criteria, we identified 20 XRT/SRT studies that met inclusion criteria (Table 3). Of these studies, 4 studies represent Class II evidence,55-58 while the remaining studies represent Class III evidence.37,59-74
In the studies, tumor control following XRT or SRT varied from 74% to 100% (Table 3). In one large and long-term study comprising 120 patients with a mean follow-up of 108 months, progression-free survival was noted to be 87.5%, 77.6%, and 64.7% at 10, 20, and 30 years after XRT, respectively.68 In a study by Woollons et al,58 in 72 patients with a mean follow-up of 64 months and representing Class II evidence, radiation therapy resulted in tumor control in 74% of patients as compared to 54% in pituitary adenoma patients not treated with XRT. In another study by Park et al,57 early XRT resulted in an improvement in tumor control as compared to observation alone.
For the complications after XRT and SRT, immediate side effects may include nausea and some fatigue. These symptoms are usually mild, but they may last 1 to 2 months after radiation treatment. Hair loss at the entry sites, decreased taste, and diminished olfaction can also occur after XRT and SRT. Similar to SRS, the most common side effect after XRT and SRT is radiation-induced hypopituitarism. Hypopituitarism in the studies that met inclusion criteria ranged from 0% to 88% (Table 3). Using conventional dose and fractionation schemes, the rate of radiation-induced damage to the visual pathways with XRT is 1% to 5% (Table 3). Rare instances of radiation-induced tumor formation (eg, parasellar fibrosarcomas), cerebral ischemia from carotid stenosis, and neuropsychological or cognitive changes have also been described. The risk of cognitive changes is an important area for future investigation, ideally comparing XRT to SRS, as outlined at the end of this manuscript. Cerebrovascular complications following radiation therapy were noted to be 4.5% in the series by Langsenlehner et al.61 In Breen’s series of 120 patients previously noted, radiation-induced neoplasia occurred in 1.7% of patients.68
Comparing Repeat Resection, Stereotactic Radiosurgery, and Radiation Therapy
There is no Class I comparison of repeat resection, XRT, and SRS for recurrent/residual NFPAs. Resection is typically utilized in those with larger adenomas for whom relief of mass effect is desired. Patient preference and fitness for a repeat surgery will also naturally impact the decision to proceed with a repeat resection.
Meta-analysis from 5 Class II studies with recurrence rates for both adjuvant radiation therapy and observation demonstrated that fractionated radiation therapy for residual/recurrent NFA offered a lower rate of recurrence (OR = 0.04; 95% CI: 0.01-0.20; P < .0001). The analysis also demonstrated significant heterogeneity between the included studies (Chi2 = 20.70; P = .003; I2 = 81%). The result of the meta-analysis was demonstrated in Figure 2.
In terms of specific radiation treatment modalities, clinicians must select the approach (SRS, IMRT, PBRT, SRT, or XRT) that permits a highly targeted irradiation of the NFPA while still achieving a dose considered tolerable to adjacent critical structures based upon radiotoxicity guidelines such as the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) studies.75
For patients with residual or recurrent NFPA, long-term tumor control can be achieved with radiation, with modalities including SRS, SRT, IMRT, PBRT, or XRT. For those with a known residual adenoma, radiographic signs of progression make for a more compelling reason to intercede and retreat the adenoma. Radiographic signs of progression in the setting of younger patients or patients with symptoms attributable to progression should be considered even more strongly for intervention.
Delayed hypopituitarism is the most common complication after SRS, SRT, IMRT, PBRT, or XRT. Other serious complications after SRS, SRT, IMRT, PBRT, and XRT are rare. Patients with residual or recurrent NFPAs undergoing repeat resection, SRS, SRT, IMRT, PBRT, or XRT should have long-term follow-up.
- The timing of SRS or XRT after prior resection warrants further investigation.
- While radiosurgery and radiation therapy are seldom used as an upfront treatment for patients with NFPAs, there are favorable but limited reports of initial SRS as a management for NFPAs. Further evaluation of this treatment approach is warranted.
- Similarly, the role of multisession (ie, hypofractionated) radiosurgery for NFPAs, particularly those exhibiting larger volumes or in close proximity to critical structures, has been explored in limited publications. Optimal dose and fractionation schemes, particularly for SRS of NFPAs, should be explored.
- The neurocognitive effects of SRS and XRT in pituitary adenoma patients warrants further study with the use of validated neurocognitive tests and appropriate assessment intervals.
Disclosure of Funding
These evidence-based clinical practice guidelines were funded exclusively by the CNS and the Tumor Section of the CNS and the AANS, which received no funding from outside commercial sources to support the development of this document.
The authors acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Committee for their review, comments, and suggestions throughout peer review, and Pamela Shaw, MSLIS, MS, for assistance with the literature searches. Also, the authors acknowledge the following individual peer reviewers for their contributions: Sepideh Amin-Hanjani, MD, Kathryn Holloway, MD, Odette Harris, MD, Brad Zacharia, MD, Daniel Hoh, MD, Isabelle Germano, MD, Martina Stippler, MD, Kimon Bekelis, MD, Christopher Winfree, MD and William Mack, MD. Lastly, and most significantly, the authors would like to acknowledge Edward Laws, MD, for serving as an advisor on this nonfunctioning adenoma guidelines project and providing comprehensive critical appraisal.
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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1. Pituitary Neoplasms [Mesh] OR Adenoma [Mesh] OR Adenoma, Chromophobe [Mesh]
2. (microadenoma*[Title/Abstract] OR adenoma*[Title/Abstract] OR macroadenoma*[Title/Abstract] OR incidentaloma*[Title/Abstract] OR chromophobe*[Title/Abstract] OR transsphenoidal*[Title/Abstract])
3. (pituitary[Title/Abstract] OR hypophyse*[Title/Abstract] OR sellar[Title/Abstract] OR transsphenoidal[Title/Abstract])
4. #1 OR (#2 AND #3)
5. (residual[Title/Abstract] OR recurr*[Title/Abstract])
6. #4 AND #5
7. NOT Comment[pt] NOT Letter[pt] Limit to English, Humans, publication date to 10/01/2014
1. MeSH descriptor Pituitary Neoplasms
2. MeSH descriptor Adenoma
3. 1 and 2
4. ((pituitary OR hypophyse* OR sellar) NEAR/4 (microadenoma* OR adenoma* OR macroadenoma* OR incidentaloma* or chromophobe*)):ti,ab,kw
5. 3 or 4 and (asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
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