Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for the Role of Imaging for Patients With Functioning Pituitary Adenomas

NEUROSURGERY, 2025

Sponsored by: Congress of Neurological Surgeons (CNS) and the AANS/CNS Section on Tumors

Endorsement: Reviewed for evidence-based integrity and endorsed by the Congress of Neurological Surgeons (CNS), American Association of Neurological Surgeons (AANS)

Authors: 

Jacqueline C. Junn, MD¹; Kalmon D. Post, MD²; Manish K. Aghi, MD, PhD, MAS³; Gabriel Zada, MD⁴; Daniel Prevedello, MD⁵; Bradley Delman, MD⁶; Puneet Belani, MD⁶; D. Ryan Ormond, MD, PhD⁷; Isabelle M Germano, MD, MBA²

Departmental and institutional affiliations:

1.         Department of Radiology, Emory University, Atlanta, Georgia

2.         Department of Neurosurgery, Ichan School of Medicine at Mount Sinai, New York, New York

3.         Department of Neurological Surgery, University of California San Francisco, San Francisco, California

4.         Department of Neurosurgery, Keck Medicine at University of Southern California, Los Angeles, California

5.         Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio

6.         Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York

7.         Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado

Corresponding Author contact information:

Isabelle M. Germano, MD, MBA

Department of Neurosurgery, Ichan School of Medicine at Mount Sinai

Keywords: functioning pituitary adenoma, radiosurgery, stereotactic fractionated radiotherapy

Conflicts of Interest

All Guideline Task Force members were required to disclose all potential conflicts of interest (COIs) prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. 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.

Funding 

These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.

The AANS/ CNS Section on Tumors funded the cost of publication for the supplement. 

Abbreviations

Conflicts of Interest (COI)

Functioning pituitary adenomas (FPA)

Magnetic resonance images (MRI)

Adrenocorticotrophic hormone (ACTH)

Secreting ACTH syndrome (EAS).

Positron emission tomography (PET)

Positron emission tomography (PET-CT)

Polyethylene glycol (PEG).

Corticotropin-releasing hormone (CRH)

Inferior petrosal sinus sampling (IPSS)

Bilateral inferior petrosal sinus sampling (BIPSS)

Zurich Pituitary Score (ZPS)

Three dimensional (3D)

Contrast-enhanced Constructive Interference In Steady State (CE-CISS)

Fluid-Attenuated Inversion Recovery after contrast enhancement (CE-FLAIR).

Contrast enhanced-T1 weighted images (CE-T1 WI).

Internal carotid artery (ICA)

Gradient Echo (GRE)

Disclosures

See Supplemental Digital Content 5: Appendix V for a complete list of disclosures.

ABSTRACT

Background: Patients with functioning pituitary adenomas (FPA) present a diagnostic challenge with identification of microadenomas and/or invasion of the cavernous sinus.

Objective: This study aims at providing evidence-based recommendations on the use of imaging to facilitate an accurate diagnosis.

Methods: PubMed and Embase were searched from the inception of the database to June 8, 2021, using search terms and search strategies to identify pertinent abstracts. These were then screened using published exclusion/inclusion criteria to identify full-text review articles. Evidence tables were constructed using data from full-text reviews, and recommendations were made.

Results: Of the total 8,685 identified abstracts pertinent to this topic, 138 full papers met the eligibility criteria. Of these, 18 met the inclusion criteria and were included in the evidence tables. Class III evidence supported 4 Level III recommendations for adult patients with FPA.

Conclusion: This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to imaging. The Congress of Neurosurgeons will continue to pursue timely updates and to further improve the care of patients with diagnosis.

RECOMMENDATIONS

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary adenomas (FPA)

Key Question 1: In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary adenomas, does assessment with magnetic resonance images (MRI) or endocrine assessment alone provide a more accurate confirmation and localization of the pituitary tumor?

Recommendation, Level III: In adult patients with endocrinological suspicion of FPA, assessment with MRI is suggested as it provides a more accurate confirmation of the pituitary tumor than endocrine assessment alone. In patients with endocrinologocially suspected ectopic adrenocorticotrophic hormone (ACTH) syndrome (EAS), computed tomography (CT) of the abdomen/pelvis rather than pituitary MRI is suggested.

Target Population: Adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPAs with MR images negative for tumor

Key Question 2: In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, does bilateral inferior petrosal sinus sampling (BIPSS) provide a more accurate assessment of tumor location than exploratory surgery alone?

Recommendation, Level III: In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, BIPSS is suggested as a diagnostic benefit.

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas.

Key Question 3: In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas, does positron emission tomography computed tomography (PET-CT) using radioactive metabolic tracers, such as [18]fluoro-2-deoxy-D-glucose (18F-FDG), 68Gallium-DOTATATE (68Gad), and 11C-methionine (11C-met) provide a more accurate tumor localization compared to MRI alone?

Recommendation, Level III:  In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas with negative MRI PET using radioactive metabolic tracers is suggested as a diagnostic benefit.

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of FPA

Key Question 4: In adult patients with signs/symptoms and endocrine evaluation suggestive of FPA, do MRI grading systems and/or sellar imaging protocols developed since 2015 result in better prediction of post-operative biochemical control and/or complete tumor resection compared to no grading system and/or no new imaging protocols?

Recommendation, Level III: In adult patients with signs/symptoms and endocrine evaluation suggestive of FPA, MRI grading systems and/or newer sellar imaging is suggested to further predict postoperative biochemical control and/or complete tumor resection.

INTRODUCTION

Multiple disciplines are involved in managing adult patients with FPA in various clinical settings. As these patients are within a multifaceted system and approach, a clinical guideline is needed to provide treatment for these patients with appropriate information and a decision-making process. This guideline provides an educational tool for physicians with diagnostic and treatment decisions for more streamlined and improved care of FPA patients.

Pituitary adenomas or pituitary neuroendocrine tumors are considered primary tumors in the pituitary gland¹. Pituitary adenomas are the most common intracranial neoplasms. Functioning pituitary adenoma (FPA) accounts for approximately two-thirds of adenomas and they most commonly occur as micro-adenomas, less than 10mm in size.^2,3 Diagnostic challenges for these tumors include confirmation and location of the tumor within the sellar region.

The aim of these guidelines was to provide an evidence-based approach on how best to use imaging techniques to diagnose and localize FPA using four key questions: 1. The role of MR images in diagnosing this disease compared to endocrine evaluation alone; 2. In those cases where the MR images fail to disclose the tumor, the aim is to provide evidence of the role of other testing; 3. In those cases where the MR images fail to disclose the tumor, provide imaging modalities to further the diagnostic yield; 4. To provide evidence of improved diagnostic yield of new MR techniques and/or MRI-based score systems to further the FPA diagnosis.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guidelines relevant to treating adult patients with FPA. Through objective evaluation of the evidence and transparency in making these recommendations, an evidence-based clinical practice guideline was developed for diagnosing and treating adult patients with FPA. The Guidelines Task Force used DistillerSR (which utilizes artificial intelligence) to cull, narrow and aid its review of the relevant literature.  All abstracts were reviewed and relevant full text articles were retrieved and graded (by individuals of the guideline task force).  

These guidelines are designed for educational purposes to assist practitioners in their clinical decision-making processes. Additional information about the methods utilized in this systematic review is provided below.

The task force members identified search terms/parameters, and a medical librarian implemented the literature search, consistent with the literature search protocol, using the National Library of Medicine/PubMed database and Embase for the period from 1946 (inception of the database) to June 8, 2021, using the search strategies provided in Supplemental Digital Content 1: Appendix I.

RESULTS

The literature search yielded 8,685 abstracts.  Task force members reviewed all abstracts generated from the literature search and removed duplicates and/or abstracts only. From the remaining 5,660 abstracts, the task force selected 138 full-text articles for full-text review.  Of these, 18 met the inclusion criteria outlined in the evidence tables. The extracted evidence-based data was Class III evidence supporting four Level III recommendations for adult patients with FPA. 1. In adult patients with endocrinological suspicion of FPA, assessment with MRI is suggested as it provides a more accurate confirmation of the pituitary tumor than endocrine assessment alone; 2. In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, bilateral inferior petrosal sinus sampling (BIPSS) is suggested as a diagnostic benefit; 3. In adult patients with suspected FPA micro-adenomas micro-adenomas with negative MRI PET-CT using radioactive metabolic tracers is suggested as a diagnostic benefit;4. MRI grading systems and/or newer sellar imaging is suggested to further predict post-operative biochemical control and/or complete tumor resection.

CONCLUSIONS

This guideline provides evidence-based recommendations for the imaging diagnosis of patients with FPA. While this guideline consisted of a thorough literature review and review by experts across neurosurgery oncology, neuro-radiology, and endocrinology disciplines, the studies included in this study were all done retrospectively. In addition, these studies were largely conducted at single institutions with limited numbers of patients. Thus, future research should incorporate prospective studies, ideally with standardized imaging sequences.

Over the years, machine learning has emerged as the next medical frontier, including imaging. Artificial intelligence (AI) and machine learning (ML) have catapulted for quantitative analysis to evaluate patients with pituitary adenomas. Mainly, radiomics and ML have been the focus of early diagnosis/screening, tumor grading, differential diagnosis, predicting outcomes, and determining the adenoma subtypes/assessing tumor consistency.^32-35 As this field is evolving, most likely new paradigms will become available to increase diagnostic accuracy.

Cavernous sinus invasion has also been a topic of interest in AI and ML studies. Even though these ML-based radiomic studies have shown high accuracy, they are still retrospective studies that need further evaluation to eliminate bias. Further research focused on providing prospective data is needed.

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. Each chapter is 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 their 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 competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

Acknowledgments

                    The guidelines task force would like to acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Review Committee, as well as the contributions of Trish Rehring, MPH, Director for Evidence-Based Practice Initiatives for the CNS, and Janet Waters, MLS, BSN, RN, for assistance with the literature searches. Throughout the review process, the reviewers and authors were blinded from one another. At this time, the guidelines task force would like to acknowledge the following individual peer reviewers for their contributions: Brandon Lucke-Wold, MD, Koji Ebersole, MD, Andrew Carlson, MD, MS, Andrew Ryu, MD

Vincent Alentado, MD and Jeffrey Olson MD.

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