Advances in Diagnosis and Management and Diagnosis in Advances Pituitary SATURDAY Francisco,Medicine San of School California of University Disorders forPituitary Center California the and Neurosurgery of Department October 21, 2017 San Francisco,San CA Square Union Marriott Disorders: Director, Minimally-Invasive Professor ofNeurologicalSurgery Manish K.Aghi,MD,PhD ORE CHAIRS COURSE Disorders at UCSF at Disorders forPituitary Director,Center CaliforniaSurgical Surgery; Neurological Professorof Associate Kunwar,Sandeep MD Skull

Base Surgery University of California of University San FranciscoSan Upcoming CME Courses

7th Annual UCSF Techniques in Complex Spine Surgery Friday, November 3 – Saturday, November 4, 2017 Vdara Hotel and MERIN – Las Vegas, Nevada

13th Annual UCSF Spine Symposium Friday, June 1 – Saturday, June 2, 2018 Parc 55 Hilton – San Francisco, California

Neurosurgery Update 2018 Thursday, August 2 – Saturday, August 4, 2018 Silverado Resort, Napa, California

All Courses Managed by: UCSF Office of Continuing Medical Education 3333 California Street, Room 450, San Francisco, CA 94118 For attendee information call: 415-476-4251 For exhibitor information: 415-476-4253 Visit the web site at https://cme.ucsf.edu The Department of Neurosurgery and the California Center for Pituitary Disorders University of California, San Francisco School of Medicine presents

Pituitary Disorders: Advances in Diagnosis and Management

October 21, 2017 Marriott Union Square San Francisco, California

Course Chairs

Manish Aghi, MD Sandeep Kunwar, MD University of California, San Francisco

University of California Acknowledgements

This CME activity was supported in part by educational grants from the following:

Corcept Therapeutics

Exhibitors

Ipsen

Pfizer

University of California, San Francisco Presents

Pituitary Disorders: Advances in Diagnosis and Management

The California Center for Pituitary Disorders within the Department of Neurosurgery at the University of California, San Francisco, presents its tenth annual course on Pituitary Disorders: Advances in Diagnosis and Management. This course will provide the latest updates and recent advances regarding pituitary tumors and related disorders. Endocrinologists, neurosurgeons, neurologists, primary care providers, trainees in these fields, nurse practitioners, physician’s assistants, and other allied health professionals can benefit from this program in diagnosis and management of pituitary tumors and disorders of pituitary function.

Educational Objectives

An attendee completing this course will be able to:  Differentiate the risks, benefits, and alternatives of pituitary surgery to patients with different disease states;  Perform clinical problem-solving to complex management of patients with acromegaly;  Interpret subtle radiographic clues to the differential diagnosis of pituitary disorders in practice;  Evaluate the genetic role of acromegaly and pituitary tumors and their implications on the role of medical therapy when discussing management with patients;  Use the caveats of treatment in practice to appropriately manage hyperprolactinemia;  Assess the potential for clinically silent pituitary adenomas to transition to functioning adenomas.

Accreditation

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this educational activity for a maximum of 7.75 AMA PRA Category 1 credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity meets the requirements under California Assembly Bill 1195, continuing education and cultural and linguistic competency.

Nurses For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 Credit™ issued by organizations accredited by the ACCME.

Physician Assistants AAPA accepts category 1 credit from AOACCME, prescribed credit from AAFP, and AMA PRA category 1 credit™ from organizations accredited by the ACCME.

Pharmacy The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 Credit™. General Information

Attendance Verification/ Sign-In Sheet Please remember to sign-in on the sign-in sheet when you check in at the UCSF Registration Desk on your first day. You only need to sign-in once for the course, when you first check in.

Speaker Survey- Electronic On Saturday morning, October 21st you will receive an email from [email protected] with a personalized link to access the Speaker Survey. Please make sure that you add this email to your safe senders list. This year the survey will be completed online for added convenience. If you did not receive the link, please see the UCSF Registration Desk. The Speaker Survey is to be completed in real time during the course and is separate from the Evaluation/CME Certificate.

Course Evaluation / CME Certificates In the afternoon on Saturday, October 21st, you will receive another email from [email protected] to complete your online Course Evaluation/ CME Certificate. The Qualtrics system will send you reminders to complete your Course Evaluation/ CME Certificate until you complete it.

Upon completing the Course Evaluation/ CME Certificate, your CME certificate will be automatically generated to print and/or email yourself a copy. For smartphone users, you may want to take a photo of your certificate as some settings prevent you from emailing the certificate.

The link will be available for 30 days after the last day of the course. However, after that date the link will expire and you will no longer be able to claim your credits online. You must then contact the Office of CME at [email protected] to receive your certificate and a $15 administrative fee may be applied.

Lunch A lunch buffet will be provided with your course tuition. Lunch is for attendees only.

Security We urge caution with regard to your personal belongings. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during lunch or breaks.

Exhibits Industry exhibits will be available in the Ballroom Foyer room during continental breakfast and breaks.

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000, and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government.

HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ .

As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services.

Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan.

A Recipient’s LEP plan likely will include translating vital documents and providing either on-site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending

on the emergent or non-emergent needs of the LEP individual, such as hiring bilingual staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations.

In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally-Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally-Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them.

The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled.

It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

Faculty List

Course Chairs

Manish K. Aghi, MD, PhD Professor of Neurological Surgery Director, Center for Minimally-Invasive Skull Base Surgery, UCSF

Sandeep Kunwar, MD Associate Professor of Neurological Surgery Director, California Center for Pituitary Disorders at UCSF

Special Guest Faculty

Lisa B. Nachtigall, MD Associate Professor of Medicine, Harvard Medical School Co-Director, Neuroendocrine Clinical Center, Massachusetts General Hospital Boston, MA

Course Faculty (all University of California San Francisco unless indicated)

Lewis S. Blevins, Jr, MD Professor of Medicine and of Neurological Surgery Medical Director, California Center for Pituitary Disorders at UCSF

Ivan H. El-Sayed, MD, FACS Professor, Division of Head and Neck Oncologic Surgery Co-Director, Minimally Invasive Skull Base Surgery Program Department of Otolaryngology-Head and Neck Surgery

Jorge D. Faccinetti, BA Managing Partner, IgniteThinking, LLC

José Gurrola II, MD Assistant Professor of Otolaryngology – Head and Neck Surgery

Arie Perry, MD Professor of Pathology and of Neurological Surgery Director of Neuropathology Director of Neuropathology Fellowship Training Program

J. Blake Tyrrell, MD Professor of Endocrinology and Metabolism

David M. Wilson, MD, PhD Associate Professor of Radiology Chief of VA Neuroradiology

DISCLOSURES

The following faculty speakers, moderators and planning committee members have disclosed NO financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Manish K. Aghi, MD, PhD Arie Perry, MD Lewis S. Blevins, Jr, MD Blake Tyrrell, MD Jorge D. Faccinetti, BA David M. Wilson, MD, PhD José Gurrola II, MD

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

Name Company Relationship Sandeep Kunwar, MD Nuvasive Holder of Intellectual Property Benvenue Rights Grant/Research Support SpineWave Consultant Holder of Intellectual Property Rights Ivan El-Sayed, MD Stryker Consultant Spiway Consultant Lisa B. Nachtigall, MD Ipsen Consultant Chiasma Grant/Research Support Novartis Honorarium Recipient Corcept Advisor or Reviewer Panel Member Consultant

This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced.

This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

Course Program SATURDAY, OCTOBER 21, 2017 7:30AM Registration and Continental Breakfast 8:00 Introduction (Pre-test) Manish K. Aghi, MD, PhD

8:15 Working Up a Pituitary Patient Before Sandeep Kunwar, MD Surgery

8:45 Endocrine Outcomes After Pituitary Surgery Manish K. Aghi, MD, PhD

9:15 Hypogonadotropic Hypogonadism and Lisa B. Nachtigall, MD Testosterone Replacement in Men

9:45 Diabetes Insipidus: Diagnosis and Lewis S. Blevins, Jr., MD Management

10:15 Coffee Break

10:30 The Pathology of Pituitary Tumors Arie Perry, MD

11:00 Role for Surgery in Patients Presenting with Sandeep Kunwar, MD Diabetes Insipidus

11:30 Advances in the Treatment of Acromegaly Lisa B. Nachtigall, MD

12:00 PM Lunch (included in attendee tuition fee)

1:00 Pituitary Imaging: You Make the Call David M. Wilson, MD, PhD

1:45 Types of Surgical Approaches for Pituitary Manish K. Aghi, MD, PhD; Patients Sandeep Kunwar, MD; José Gurrola II, MD; Ivan El-Sayed, MD

2:45 Update on Prolactinomas Blake Tyrrell, MD

3:15 Coffee Break

3:30 Update on Cushing’s Disease Blake Tyrrell, MD

4:00 From Rathke’s Cleft Cysts to Manish K. Aghi, MD, PhD Craniopharyngiomas: Pathologic Spectrum and Management Strategies

4:30 The Patient’s Journey Jorge D. Faccinetti, BA

4:45 Panel Discussion (Post-test) Manish K. Aghi, MD, PhD Sandeep Kunwar, MD 5:00 PM Adjourn

Working up a Pituitary Patient Before Surgery Disclosures

Sandeep Kunwar, M.D.

Surgical Director, California Center for Pituitary Disorders Associate Professor, University of California, San Francisco . Benvenue (consultant) Co-Director, Gamma Knife Program, Washington Hospital . Spineology (consultant) . SpineWave (royalty) . Nuvasive (royalty)

Pituitary Mass Lesions Sellar Anatomy Pituitary Origin . Pituitary adenoma . Rathke’s Cleft Cyst ¬ Progressive mass lesion . Pars Intermedia Cyst ¬ Does not grow . Craniopharyngioma . Pituicytoma ¬ Grade I astrocytoma of the posterior lobe . Pituitary hyperplasia . Pituitary venous engorgement Pituitary Mass Lesions Pituitary Mass Lesions Non-Pituitary Origin Non-Pituitary Origin

. Langerhan’s histiocytosis X . Meningioma (cavernous sinus, tuberculum sella) - Monoclonal macrophage tumor - TS meningioma often mistaken for pituitary adenoma - Assoc. with eosinophilic granulomatus disease - Cavernous sinus meningiomas can cause narrowing of the ICA . Lymphocytic hypophysitis - Firm, often vascular tumors - Third trimester of pregnancy . Metastatic - Posterior lobe (neuroinfundibulohypophysitis) - Breast . Sarcoid . Hemangioblastoma . Tuberculoma - Highly vascular tumor . Germ cell (posterior lobe) - Pediatric tumor presenting with DI . Lymphoma - Can mimic other lesions - Presents with cranial nerve palsy

Pituitary Mass Lesions Clinical History Non-Pituitary Origin . Other mass lesions ¬ Colloid Cyst . Menstrual/fertility history ¬ Arachnoid cyst ¬ Chordoma . Changes in libido - Presents with cranial nerve palsy ¬ Chondrosarcoma . Symptoms of hypersecretion ¬ Optic nerve glioma . Fatigue/weight changes ¬ Aneurysm . Height (children/young adults) . Hypothalamic masses - Craniopharyngioma . Polydipsia/nocturia - Hamartoma . Headaches - Glioma - pituicytoma Radiographic workup Endocrine Work Up

. Prolactin . MRI of sella with/without contrast . Testosterone (males) ¬ Dynamic imaging for small tumors or poorly defined tumors . TSH/Free T4 ¬ Identify stalk/normal gland ¬ Identify optic nerves/chiasm . AM Cortisol ¬ Cavernous sinus anatomy (invasion?) . GH/IGF-1 ¬ Presence of cyst . (24-UFC)

Preoperative Prolactin (ng/ml) in patients with Non- Causes of Hyperprolactinemia functioning Adenomas (EIA, n=548) Hypothalamic Drugs Tumors Dopamine receptor antagonist Percentiles Plot Sarcoid Inhibitors of dopamine synthesis 450 Radiation therapy and release 400 Estrogens 350 Pituitary Hormonally active tumors Neurogenic 300 Prolactinomas Chest wall/spinal cord lesions 250 200 Somatotroph adenomas Breast stimulation PRL TSH adenomas Suckling 150 Stalk Effect Physical Stress 100 Nonfunctioning adenomas 50 Rathke’s Cleft Cyst Others 0 Parasellar tumors Primary Hypothyroidism Stalk transection Renal Failure -50 0 20 40 60 80 100 Pregnancy Percentile Macroprolactinemia Idiopathic Prolactinomas vs NFA Expected Hormonal Changes

. Glandular compression . For macroprolactinomas (>1 cm) with ¬ GH deficiency no cystic component, Prl should be ¬ Hypogonadism >150 ¬ Hyperprolactinemia (stalk effect) . If prolactin is >200, diagnosis is a ¬ Hypothyroidism prolactinoma ¬ Hypocortisolism . Younger age = consider prolactinoma if . Dependent on tumor size and rate of size/prl relationship appropriate growth ¬ For prl 50-150 . Pituitary adenomas do not cause DI, even when very large

Vision Loss vs Size

100 . Opthamological Workup t ¬ For patients with suprasellar extension or 80 complaints of visiual changes 60 ¬ Humphreys Visual Field tests 40 (% of patients) Visual Impairmen 20

0 5-10 11-15 16-20 21-25 26-30 31-35 36-40 Size (mm) P<0.0001; Mann-Whitney Presentation of Pituitary Lesions Case Presentations

. Optic nerve compression . 34 yo female pediatrician with miscarriage at 10 wks after spontaneous pregnancy . Work-up showed a prolactin level of 186 ng/dl . Repeat prolactin 3 months later was 154 ng/dl . MRI performed showing pituitary adenoma . Patient comes to discuss surgery vs. medical therapy

PMH/ROS Blood Work

. Menarche at age 13 . Additional lab work . Regular menses upto pregnancy ¬ TSH, Free T4-nl . No history of infertility, galactorrhea, ¬ GH-nl weight change, change in libido ¬ LH slightly low, FSH-nl . No allergies . MVI, no other medications Post Contrast MRI Scan

Dynamic MRI of the Sella Analysis . Clinical and MRI findings not consistent with laboratory findings ¬ Elevated prolactin without clinical symptoms ¬ MRI not conclusive ¬ Testing for Macroprolactin performed - showed 80% of prolactin was complexed - Free prolactin was 8.6 . Dx: Macroprolactinemia ¬ Believed to be caused by an antibody against prolactin ¬ Antibody/prolactin complex increases half- life of circulating hormone ¬ Complex not biologically active/bioavailable ¬ MRI normal in most cases Case Presentation 2

. 32 yo women, 33 wks pregnant with headaches and now blurry vision . Normal menses upto pregnancy . No history of infertility, spontaneous pregnancy . Labs – Prolactin >200

. Exam – VF-Superior quadrantanopsia

. MRI

Analysis

. MRI did not show expected findings of a macroadenoma ¬ Enlarged sella ¬ Absence of posterior lobe from chronic compression . Dx: Lymphocytic hypophysitis ¬ Started on steroids ¬ 4 days later, vision improved ¬ F/U MRI scan 1 month later, dramatic reduction in pituitary size Case 3

. 24 yo daughter of a neurologist presenting with severe headaches . MRI scan performed . Menses normal, hormonal w/u normal . Visual fields normal

Analysis Case Presentation

58 yo with bitemporal hemianopsia . Headaches were worse with exercise, improved with lying down . Dehydration worsened headaches . Dx: Spontaneous intracranial hypotension ¬ Can cause venous engorgement and pitutiary enlargement ¬ Diffuse dural enhancement ¬ “brain sag” . Patient was treated with a large volume epidural blood patch with 80% improvement of symptoms. Diagnosis: Tuberculum sella meningioma Cavernous sinus meningioma

of ICA

Postop MRI, visual fields improved at 6 month f/u

Stalk Lesion Stalk Lesion

•26 yo with HA’s •Pituitary function intact 46 yo male •No DI presenting with DI and hypogonadism

Diagnosis – hypothalamic lipoma Diagnosis: Langerhans Histiocytosis X Stalk and Gland lesion Diagnosis?

•58 yo woman presents with DI and panhypoptuitarism

•Prior resection of a pituitary adenoma 12 years ago Craniopharyngioma Apoplexy

Diagnosis: Lymphocytic hypophysitis

Epidermoid Cyst

Pituitary Apoplexy Pituitary Apoplexy (Infarction)

. Hemorrhage or Infarction of a pituitary tumor . Increased sellar pressure leads to absence of contrast enhancement . Often associated with sphenoid sinus inflamation Postop MRI Epidermoid Cyst - MRI

Epidermoid Cyst- DWI Epidermoid Cyst-Postop MRI Postoperative MRI – Pituitary Pituitary Adenoma (typical) Adenoma

Partial hypopituitarism, no DI

Dx - Pituicytoma Postop: Pituicytoma

Vision loss Panhypopituitarism No DI

Stalk is anteriorly displaced and midline

Stalk is anteriorly displaced and midline Case Presentation Surgical Considerations

52 yo with panhypopituitarism . Assess MRI for: ¬ Carotid anatomy ¬ Cavernous sinus anatomy ¬ Tumor anatomy

Diagnosis: Pituicytoma

64 yo man with headaches and hypogonadism Carotid Anatomy

Ectatic right ICA Ectatic R ICA, tumor cyst shows a fluid/fluid level 51 yo male with acromegaly Postop MRI scan

Inter-carotid distance = 4mm Postop GH: 0.8

Endonasal Transsphenoidal Resection of Cavernous Sinus Invasion? Giant Adenoma

Preop 3 mo postop . Cavernous sinus invasion is the main reason for incomplete resection of pituitary tumors . When tumor extends lateral to carotid artery, the diagnosis is made . In all other cases, visualization/inspection of the cavernous sinus wall is important to achieve optimum results ? Invasion into right cavernous sinus Pituitary adenoma causing acromegaly and visual loss Pitutiary Adenoma Anatomy

Pre-Op MRI ? Right cavernous sinus invasion Variations in tumor anatomy my warrant an extended approach

1 Year Post-Op MRI GH 1.1 IGF-1 nl

Unusual Tumor Anatomy Extended Transsphenoidal Approach with Suprasellar Tumor Endoscope assist

40 yo female with bitemporal hemianopsia, normal pituitary function Postop – Extended endoscopic Giant Adenoma (5.5 cm) approach

72 yo male with bitemporal vision loss, headache, panhypopituitarism

Lessons learned Lessons learned

. 1000 consecutive endonasal . Diagnosis (cont’d) transsphenoidal surgeries from 2000-2008 ¬ Epidermoid Cyst – 4 . Diagnosis ¬ Optic nerve tumor – 4 ¬ Metastatic tumors - 4 ¬ Pituitary Adenoma – 778 ¬ Lymphocytic hypophysitis – 3 ¬ Rathke’s Cleft Cyst – 134 ¬ Germ cell tumor - 3 ¬ Craniopharyngioma – 28 ¬ Colloid Cyst – 2 ¬ Chordoma – 11 ¬ Hypothalamic mass – 2 ¬ CSF leak repair – 11 ¬ Plasmacytoma – 1 ¬ Meningioma – 6 ¬ Cholesterol granuloma – 1 ¬ Langerhans – 4 ¬ Hemangioblastoma – 1 ¬ Arachnoid Cyst – 4 Conclusions: Acknowledgements

Department of Neurosurgery . Patterns for presentation are important Manish Aghi Division of Neuropathology to recognize for pituitary pathology Arie Perry Phillip Theodosopolous Andrew Bollen . Consider all possible diagnoses if the Lewis Blevins Tarik Tihan clinical or radiographic presentation does not fit the “picture” Division of Endocrinology . Complete workup includes Lewis Blevins ¬ MRI scan Blake Tyrell ¬ Anterior lobe hormonal workup ¬ Visual field testing (if suprasellar extension Division of Neuroradiology present) William Dillon Chris Hess Functional Outcomes after Disclosures Pituitary Tumor Surgery None Manish K. Aghi, M.D., Ph.D. Professor California Center for Pituitary Disorders Director, Center for Minimally Invasive Skull Base Surgery

Department of Neurological Surgery University of California, San Francisco (UCSF) Saturday, October 21, 2017 8:45 –9:15 am

Overview

1. Introduction 1. Introduction 2. Visual Outcomes after Pituitary Surgery 2. Visual Outcomes after Pituitary Surgery 3. Endocrine Outcomes after Pituitary Surgery 3. Endocrine Outcomes after Pituitary Surgery 4. Headache Outcomes after Pituitary Surgery 4. Headache Outcomes after Pituitary Surgery

Page 1 Focus of my neurosurgical research team Case breakdown by pathology (Five year at UCSF interval)

• In 2007, we established the California Center for Pituitary Disorders (CCPD) at UCSF, integrating neurosurgical and Miscellaneous 150 neuroendocrine care Craniopharyngioma 50

Rathke’s Cleft Cysts 124

Endocrine Inactive 381

Endocrine Active 340

0 100 200 300 400 • Five years later, the completion of 1015 transsphenoidal Number of cases surgeries at the center offered a nice benchmark for evaluation of functional outcomes after pituitary surgery.

Main symptoms of pituitary tumors

1. Vision loss – mass 1. Introduction effect on the overlying 2. Visual Outcomes after Pituitary Surgery optic chiasm 3. Endocrine Outcomes after Pituitary Surgery 2. Hypopituitarism – 4. Headache Outcomes after Pituitary Surgery mass effect on the surrounding pituitary gland 3. Headache – from mass effect on the dura

Example - how a pituitary adenoma could cause symptoms

Page 2 Visual symptoms by pituitary pathology Visual symptoms caused by pituitary tumors based on patient anatomy (theory) 1. Chiasm over 2. Chiasm over 3. Chiasm over Frequency of visual symptoms by pathology at UCSF tuberculum (prefixed) diaphragm dorsum (postfixed) 50.0% % of 40.0% patients 30.0% with visual 20.0% symptoms 10.0% % of 10% 80% 10% patients 0.0% Endocrine- Endocrine- Rathke’s Cranio- Other Tumor Contralateral Bitemporal Monocular active inactive cleft pharyngioma visual hemianopsia hemianopsia deficit cyst adenomas adenomas symptoms

Visual symptoms caused by pituitary Example of monocular deficit from tumors (reality) nonfunctional adenoma • 48 year old male on coumadin for pacemaker • From January 2003 to Visual deficits observed in UCSF July 2012, 967 adenoma patient cohort (n=967) • status post transsphenoidal resection of nonfunctional nonfunctional adenomas Deficit Share of patients adenoma at outside hospital resected at UCSF Bitemporal 49% • referred to us for radiosurgery for residual tumor in left • 492 (51%) presented hemianopsia cavernous sinus. with visual symptoms Monocular 31% • reoperation due to persistent left eye monocular deficit. • Median duration of Quandrantopia in 20% vision loss prior to one eye combined surgery was 6.5 months with quadrantopia or hemianopia in the other eye

Page 3 Rectifying monocular deficits can require Vision Improvement after Surgery for slightly more lateral exposure nonfunctional adenomas Analysis of postoperative visual improvement after surgery for nonfunctional adenoma patients with preop visual deficits at UCSF 2007-2012: • 77% had some postoperative improvement in vision • 37% had postoperative return to baseline vision • Multivariate analysis revealed increased age and increased duration of visual symptoms before surgery to decrease chance of return to baseline vision after surgery.

Source: Journal of Neurosurgery 116: 283, 2011

Delay in Diagnosing Nonsecretory Adenomas Race and age both increase duration of visual Lowers Chance of Surgery Correcting Vision symptoms, reducing postop improvement

• Elderly patients tend to have a greater delay from onset of visual symptoms to adenoma diagnosis (over 6 months compared to 2 months in younger patients). 100 • Elderly patients often due to not seeking care or being diagnosed with other conditions (cataracts, retinopathy, glaucoma). • Unfortunately elderly patients with prolonged duration of visual symptoms are 10 unlikely to return to baseline vision after surgery (months) 60% Duration of 1

Percent of symptoms visual patients Source: JNS 116: 283, 2011 with 40% 0.1 postop 20s-30s 20s-30s 40s-50s 40s-50s 60s-70s 60s-70s return to 20% Caucasian non- Caucasian non- Caucasian non- baseline Duration n=6 Caucasian Caucasian n=12 Caucasian over 6 months n=10 vision 0% of visual n=12 n=22 n=13 Age 20s- Age 40s- 6 or fewer months symptoms Age/Race Group 30s Age 60s- 50s 70s Age at diagnosis Source: Journal of Neurosurgery 116: 283, 2011

Page 4 Apoplexy has less postop visual improvement and associated socioeconomic risk factors

• The extreme form of vision loss in adenoma patients is apoplexy. • Apoplexy lowers chances of 1. Introduction postoperative visual improvement 2. Visual Outcomes after Pituitary Surgery (81% in non-apoplexy cases, 3. Endocrine Outcomes after Pituitary Surgery 53% in apoplexy cases at UCSF 2003-2012). 4. Headache Outcomes after Pituitary Surgery • Apoplexy patients were more likely to lack insurance and primary care and in retrospect had symptoms that could have led to the diagnosis of adenoma before apoplexy if they had access to care. Source: Journal of Neurosurgery 119: 1432, 2013

Hypopituitarism assessment and confirmation Predicting incidence of deficits by axis based of central (pituitary) source on anatomy/susceptibility

Hypothalamic Some theorize that differential robustness of cells in the hormones normal pituitary gland leads to a growing adenoma causing endocrine deficits in the following sequence: (1) growth hormone, (2) LH/FSH, (3) thyroid, and (4) cortisol.

Anterior pituitary hormones

Downstream organ Nature Reviews Cancer 4: 285, 2004 hormones

Need to confirm deficiency in downstream hormone and the pituitary hormone to confirm that the deficiency is central (pituitary) rather than at the level of the downstream gland (thyroid, adrenal, etc.)

Page 5 Variables associated with Preoperative Hypopituitarism by Axis –Real Incidences Pituitary Deficits • Rates of preoperative central hormonal deficits at UCSF 2007-2012 for • Patients with preoperative endocrine deficit(s) 1015 cases, 305 nonfunctional adenomas. Every patient had some endocrine evaluation but some patients had incomplete evaluations: were

50% – older (mean age=60 vs. 54 years; P=0.004) – More male (64% male vs. 36% female; P=0.0005), 40% All cases Nonfunctional adenomas – Had larger NFAs (mean diameter=2.4 cm vs. 2.1 cm; 30% P=0.02) 20% • Effect of size on specific axes: size correlated 10% with male/female hypogonadism but not with low 0% Male reproductive Female reproductive Growth hormone Cortisol Thyroid axis thyroid, GH/IGF-1, or cortisol.

• Comparison to Nomikos et al. (Acta Neurochir 146:27, 2004): 721 nonfunctional adenomas with full preop lab panels – 35% adrenocortical, 77% gonadal, 19% thyroid.

Improvement/Normalization of Endocrine New Endocrine Deficits after Surgery by Deficits after Nonfunctional Adenoma Surgery axis

49% 50% Improvement at 6 weeks 50% 45% Normalization at 6 weeks 38% 36% Normalization at 6 months 40% 40% 35% 30% 30% 28% 30% 26% 30% 25% 22% 19% 20% 20% 14% 3% 4% 6% of patients 10% 3% Percentage 15% 1% 9% of patients 8% Percentage 10% 5% 3% 0% 5% 0% Central Male Low Growth Female Central Hypo- Hypothyroid Hypogonadism Hormone (GH, Hypogonadism adrenalism 0% (TSH, T4, T3) (FSH, LH, IGF1) (FSH, LH, (ACTH, Cortisol) Central Hypothyroid Male Hypogonadism Low Growth Female Central Hypo- testosterone) amenorrhea) (TSH, T4, T3) (FSH, LH, Hormone (GH, IGF1) Hypogonadism (FSH, adrenalism (ACTH, testosterone) LH, estradiol) Cortisol) Hormone Axis Hormone Axis • No variables predicted development of new deficits • Difference between nonfunctional adenomas vs. other sellar tumors: • Comparison to largest previous study (Webb et al.; JCEM delayed improvement unique to nonfunctional adenomas 84: 3696, 1999): 56 NFAs – 25% new hypoadrenalism, 16% new reproductive, 14% new GH, 10% new TSH

Page 6 Threshold for Surgical Correction of Multivariate Analysis –Factors Predicting Pituitary Deficits Endocrine Improvement after NFA surgery • Male reproductive and thyroid axes were the two axes • Lower threshold beyond which surgical correction was most commonly impaired and most likely to get better. not witnessed • For these 2 axes, younger age and less severe deficit – TSH < 0.03 mlU/mL (normal at UCSF is above 0.45 mIU/mL) predicted normalization (P<0.05) – Testosterone < 2.0 ng/dL (normal at UCSF is above 141 ng/dL) – Cortisol < 1 g/dL (normal at UCSF is above 4 g/dL) • No variables predicted normalization in other axes: – IGF‐1 < 35 g/dL (normal at UCSF above 64 for females, – Female Reproductive Axis above 87 for males) – Cortisol –IGF-1

Preoperative and postoperative gland Preoperative and postoperative gland volume volume

• Measurements of normal pituitary gland volume reveal that • Patients who do not exhibit postoperative endocrine most patients experience postoperative expansion of gland improvement exhibit lower preoperative gland volume than those who go onto exhibit endocrine improvement (P<0.01). 1 Gland Preop 0.8 volume Postop (cm3) 0.6 0.4

0.2

0 No endocrine Endocrine improvement improvement postop postop No preop deficit Preop deficit

Page 7 Headaches • Preoperative presentation with headache at UCSF 2007‐2012: 1. Introduction Headache Presentation 2. Visual Outcomes after Pituitary Surgery 35% 3. Endocrine Outcomes after Pituitary Surgery 30%

4. Headache Outcomes after Pituitary Surgery 25%

20%

15%

10%

Percent of Patients 5%

0% HA as a Sx HA Chief Complaint HA only

Rates of headaches as a complaint Multivariate Analysis ‐ factors associated with versus sole complaint per pathology headache in pituitary tumor patients

• Factors associated with headache as a complaint Preoperative Headache Rates – Diagnosis (P=0.01) • Most commonly with Rathke’s Cleft Cysts Misc. • Endocrine-inactive adenomas least common Endocrine (-) Adenomas – Younger Age (P=0.001) – Female Gender (P=0.002) Endocrine (+) Adenoma – Recurrent Lesions (P=0.04) Craniopharyngioma • Factors not associated with headache as a complaint – Lesion size Rathke’s cleft cysts – Suprasellar extension Apoplexy – Hypopituitarism

0% 10% 20% 30% 40% 50% 60%

Page 8 Headache in pituitary adenoma Rates of headache improvement after pituitary patients surgery for all patients with headache • High independent incidences of headaches and pituitary tumors • Headache in adenoma patients does not become in the general population means that failure of headache to more common with increasing size (unlike vision improve postop could mean failure to resolve mass effect or loss and hypopituitarism) headache unrelated to tumor. • For all pathologies combined at UCSF 2007-2012, headache improvement recorded at 6 weeks and 6 months postop 100.0% 80.0% 80.0% Percent 70.0% headache of 60.0% less than 1 cm % of patients 60.0% ≥ 1 cm but < 2 cm headache as chief complaint patients 40.0% ≥ 2 cm but < 3 cm with 50.0% ≥ 3 cm headache 40.0% 20.0% improvement 30.0% 0.0% VISION LOSS HYPOPIT HEADACHE 20.0% Symptom 10.0% 0.0% 6 weeks postop 6 months postop

Multivariate Analysis for Headache Mechanism of Headache from Pituitary Improvement Tumors –is it sellar pressure? • Factors associated with improvement Two patients with suprasellar Rathke’s cleft cysts and headache – Gross total resection (GTR) P=0.04 – Younger Age P=0.03 Headache better Headache not better postop postop

• Factors not associated with improvement – Duration & location of HA – Gender – Pathology – Lesion size

Page 9 Measuring sellar pressure and correlating Conclusions with headache

• A bolt (ICP monitor) placed into the dura can be used to measure • Vision (absolute indication for surgery by Society guidelines) intrasellar pressure, which is elevated in patients with headache – Return to baseline vision unlikely if • Patients over age 60 AND • visual symptoms have been present longer than 6 months. • Endocrine (relative indication for surgery by Society guidelines) – Thyroid and male reproductive function most commonly affected axes by nonfunctional adenomas and most likely to improve

Source: JCEM 85: 1789, 2000 – Thyroid/male reproductive improvement unlikely if We are working to: • Older patients • confirm that intrasellar pressure is particularly elevated in • More severe deficits • Smaller preoperative gland volume. patients whose headaches improve with surgery • Headache (not mentioned in endocrine society guidelines for NFAs) • identify imaging biomarkers of sellar pressure so that we – More common in younger patients with Rathke’s cleft cysts can better predict from MRI whether the headache is – Less likely to improve in being caused by the sellar lesion or is unrelated. • older patients

Acknowledgements

• Lewis Blevins, MD Jeffrey Wagner, BS • Sandeep Kunwar, MD Arman Jahangiri, BS

Page 10 9:15AM- 9:45AM Hypogonadotropic Hypogonadism and Testosterone Replacement in Men Lisa B. Nachtigall, MD NOTES

First clear description of Diabetes Insipidus in 1792 Diabetes Insipidus A French woman had suffered from “a burning thirst” since birth. Lewis S. Blevins, Jr., M.D. At the age of three she consumed two buckets of water per day. She ran away from home because of “the ill treatment this disposition occasioned her to experience from her parents”. When examined in Paris in 1791 she was in good health and had given birth to ten children. She continued to drink great quantities of water. The other patient was an English laborer who after a long febrile disease developed thirst and polyuria at the age of 31. Twenty-four years later he was still drinking 20–25 l per day but otherwise in perfect health. It is difficult to doubt that both patients suffered from diabetes insipidus— though less clear of which type.

Lindholm Pituitary 7: 33–38, 2004

Medical facts and observations. London. 1792;2:73–101

Neurohypophysis Relationship between Plasma Osmolarity and AVP

AVP secreting neurons in SON and PVN

Osmo- and thirst receptors/centers in anterior hypothalamus

Ascending pathways from ANS and brainstem

Terminal boutons in neurohypophysis

© Astellas Alterations in AVP secretion AVP Receptors Receptor Location Effect V1A Vascular smooth Vasoconstriction, muscle, platelets platelet aggregation

V1B Anterior pituitary ACTH release

V2 Renal collecting duct Free water absorption

Aquaporins Relationship between Urine Osmolarity and AVP

© Astellas Diabetes Insipidus AVP Dynamics Polyuria • Passage of large quantities of dilute urine due to absence of vasopressin or lack of its action

• Urine specific gravity usually <1.005

• Polyuria defined as 30 mL urine per kg body weight in 24h

• UOP >300 mL/h over 2-3 consecutive hrs in hospitalized patient at-risk for DI is suggestive

• Broad DDx including DM, renal disease, solute load, excessive intake of oral fluids, overzealous administration of IV fluids, post surgery for Acromegaly, therapy with vaptans, etc.

Diabetes Insipidus Thirst Polydipsia • Water intake due to a combination of factors • Thirst is logarithmic o Social • Usually begins at a pOsm higher than the set point o Cultural for AVP secretion o Solute load • Defense against dehydration o Volume status • Serum sodium and pOsm usually “normal” and at o Psychological thirst set point if patient able to respond to thirst • Polydipsia in DI is a measure of the response to thirst due to increased pOsm and volume depletion • Concern in patients with: • Patients often prefer iced water, take water everywhere, o Adipsia always know where to get it…. “water dogs” o Altered sensorium • Beware of those with Psychogenic Polydipsia who can o Restrained nearly mimic DI Neurogenic Diabetes Insipidus Diabetes Insipidus Causes • Central or “neurogenic” • Transsphenoidal surgery 5-30% depending on many factors • ACA aneurysms/bleeds • Suprasellar lesions • Nephrogenic o Craniopharyngioma o Pilocytic astrocytoma • Infiltrative disorders o Langerhans Cell Histiocytosis o Sarcoidosis • Inflammatory disorders • Metastases • Head trauma • Heritable disorders

Diabetes Insipidus Diabetes Insipidus Suspicion and Diagnosis Acute Management • Intake and Output relative to body weight • Encourage PO intake to drink to thirst • Use GI tract access via tube if possible • Urine specific gravity • IVF ½ NS or D5W at 150-200 mL/hr for a few liters if • Serum or urine glucose if Ur spgr is not low needed • Serum sodium • AVP sc 3-5 U q4-6 hrs PRN • Intranasal dDAVP 10 mcg PRN • Clinical history and imaging characteristics • sc dDAVP 0.5-2 mcg PRN • Observation • Trial of therapy • Re-dose when needed • Water deprivation test Diabetes Insipidus Diabetes Insipidus Chronic Management Patient Resources • Intranasal dDAVP 10-20 mcg qd-bid PRN • dDAVP 0.05-0.2 mg PO qD-tid PRN • Drink to thirst • Awareness of I/O, body weight http://www.pituitaryworldnews.org/wp- • Subsequent dosing based on need at least once to content/uploads/2017/02/Brochure_Diabetes-insipidus-1.pdf twice per week • Avoidance of situations that lead to water intoxication http://www.pituitaryworldnews.org/diabetes-insipidus-our-survey- • Periodic withholding of therapy as DI sometimes report-is-in/ improves • Water Rx for those with adipsic hypernatremia • Careful control of rate of rise in patients with hyponatremia

Water is a marvelous life sustaining and yet simple molecule that must be offered tremendous respect for it can be a very dangerous thing in many different ways. DISCLOSURES (Arie Perry, MD)

• I have no financial relationships to disclose. PITUITARY/SELLAR - and - REGION PATHOLOGY • I will not discuss off label use or investigational use in my presentation Arie Perry, M.D. Director, Neuropathology

School of Medicine

ADENOHYPOPHYSEAL DEVELOPMENT

Corticotroph Somatotroph ACTH GH *Tpit

GH Oral Rathke pouch *Pit-1 Somatotroph ERMammo- ER Lactotroph ACT endoderm Stem cell Stem cell somatotroph PRL GH PRL repressor *SF-1 TEF ER GH repressor FSH Gonadotroph Thyrotroph LH TSH

*Diagnostically useful transcription factors Modified from: Asa SL, Ezzat S. Annu Rev Pathol Mech Dis 2009:4:97-126 PITUITARY ADENOMA CONCEPTS PITUITARY APOPLEXY • Common: ~17% incidence; ~15% of symptomatic intracranial tumors • Microadenomas (<1 cm) usually functional, especially corticotroph adenomas • Macroadenomas (>1 cm) often present with bitemporal hemianopsia or hypopituitarism • Medical therapies (e.g. bromocriptine, cabergoline, octreotide, pegvisomant, etc.)

Reticulin

School of Medicine School of Medicine

PITUITARY ADENOMA CLASSIFICATION PITUITARY ADENOMA Endocrine Manifestations • GH: Acromegaly/gigantism • PRL: Amenorrhea/galactorrhea (women) Hypogonadism or no symptoms (men) • ACTH: Cushing’s Disease • LH/FSH: Hypogonadism or no symptoms • TSH: Hyperthyroidism or no symptoms • Alpha subunit: no symptoms • Non-functioning adenomas account for ~30% • Diabetes insipidus: rare (probably not adenoma)

School of Medicine SILENT ADENOMAS

• Adenomas that produce IHC detectable hormones, but are clinically non-functional • Produce, but don’t secrete? • Majority of gonadotroph adenomas are technically “silent adenomas” • Silent corticotroph adenomas types 1 and 2 − Produce POMC, but not functional ACTH • Pit-1 family plurihormonal (silent subtype 3)

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NORMAL VS. PITUITARY ADENOMA PATHOLOGY WORKUP (UCSF underlined)

• Routine Cytology/Histology • Histochemical stains: reticulin, PAS • Hormone immunostains: ACTH, GH, PRL, FSH, LH, TSH, SSTR2a* (*for acromegaly) • Non-hormone immunostains: Cytokeratin CAM 5.2, Ki-67, p53, synaptophysin • Transcription factor IHC: Tpit, PIT-1, SF-1 • Electron microscopy • Far fewer null cell adenomas now School of Medicine School of Medicine NORMAL VS. PITUITARY ADENOMA NORMAL VS. PITUITARY ADENOMA

Reticulin

School of Medicine School of Medicine

CLINICOPATH CLASSIFICATION WHO 2017 CLASSIFICATION • Lactotroph: more aggressive in men* • Pituitary adenoma (~95%) • Corticotroph: Cushing, Nelson*, Crooke cell*, Silent* • Somatotroph: sparsely* vs. densely granulated • Atypical pituitary adenoma (~5%) • Combined Lactotroph/Somatotroph +/- TSH: Mixed GH/PRL, Mammosomatotroph (rare), Acidophil Stem Cell (rare)*, − Increased mitotic activity Remove in 2017 WHO Plurihormonal PIT-1 positive adenoma (rare; previously known Endocrine Tumors − Ki-67 LI >3% as silent subtype 3)* • Gonadotroph − p53 immunoreactivity • Thyrotroph (rare) • Plurihormonal*: immunostaining for developmentally or • Pituitary carcinoma (<1%) physiologically-unrelated hormones (rare) − Craniospinal and/or systemic metastases • Null cell: hormone and transcription factors negative (rare)

School of Medicine School of Medicine *More aggressive subtype LACTOTROPH (PRL) ADENOMAS

• A.k.a. “prolactinoma” (25% of adenomas) • 2/3rd macro-, 1/3rd micro-adenoma (female) • More aggressive in men • Mostly sparsely granulated (99%) • Less often resected due to dopamine agonist Rx (bromocriptine, cabergoline) • Fibrosis and decreased cytoplasm in treated adenomas • PIT-1 family School of Medicine PRL

SOMATOTROPH (GH) ADENOMAS

• Acromegaly more common than gigantism • Densely granulated (DG; 5% of all adenomas), tend to be sensitive to somatostatin analogs • Sparsely granulated (SG; 5%); more aggressive and more likely to respond to GHR antagonists • EM: large granules (DG) and/or fibrous bodies (SG) • PIT-1 family

School of Medicine Post dopamine agonist DENSELY GRANULATED GH ADENOMA SPARSELY GRANULATED GH ADENOMA

GH CK

MIXED GH‐PRL ADENOMA COMBINED GH-PRL ADENOMAS

• Mixed GH and PRL adenomas (2 cell types) • Mammosomatotroph adenoma (1 cell type with both GH and PRL features) − Requires EM or dual color IHC for diagnosis • Acidophil stem cell adenoma − Aggressive, invasive macroadenomas − More often presents with mild PRL increase clinically, while the GH is silent but detectable with IHC − Requires EM or AMA IHC for diagnosis • Plurihormonal Pit-1 adenoma (GH, PRL, TSH): silent or active

School of Medicine MIXED GH‐PRL ADENOMA MIXED GH‐PRL ADENOMA

GH PRL PIT-1

MIXED GH‐PRL ADENOMA CORTICOTROPH (ACTH) ADENOMAS

• Cushing disease: 10% of all adenomas • 87% microadenomas • PAS and ACTH+; Crooke’s hyaline in non- neoplastic corticotrophs • Nelson disease: 2%; highly aggressive due to loss of feedback inhibition • Silent: 3%; more aggressive; no Crooke’s hyaline • Crooke’s adenoma (<1%); aggressive • New Rx: pasireotide (somatostatin analog) • Tpit family (but no reliable IHC antibodies)

School of Medicine SSTR2a CORTICOTROPH ADENOMA CROOKE’S HYALIN

CK ACTH

School of Medicine PAS

GONADOTROPH ADENOMA GONADOTROPH ADENOMA

• 10-15% of adenomas, but likely higher now • Mostly indolent tumors of older adults • Ribbon-like, papillary, pseudorosetted • May be oncocytic • Scattered FSH and LH positive cells • Many prior “null cell” adenomas are now reclassified as gonadotroph based on transcription factor expression • SF-1 family School of Medicine LH SF-1

THYROTROPH ADENOMA PITUITARY CARCINOMA Rare (~1%): Hypothyroidism > hyperthyroidism; Mostly invasive macroadenomas; often spindled • Rare (<1% of pituitary tumors) • Many arise from classical or ‘worrisome’ adenomas, some in setting of Nelson syndrome • Most are hormonally active: PRL or ACTH • Defined by craniospinal or systemic metastases • Extremely difficult to treat and typically fatal in < 1 year

School of Medicine School of Medicine CRANIOPHARYNGIOMA (WHO GRADE I)

• Children/young adults • Suprasellar or suprasellar/intrasellar • Present with hypopituitarism, visual deficits, and sometimes DI • Adamantinomatous and papillary types • Frequently recur • Morbidity common: visual loss, panhypopituitarism, etc.

School of Medicine

ADAMANTINOMATOUS CRANIOPHARYNGIOMA CRANIOPHARYNGIOMA

School of Medicine ADAMANTINOMATOUS CRANIOPHARYNGIOMA ADAMANTINOMATOUS CRANIOPHARYNGIOMA

Beta catenin

PAPILLARY CRANIOPHARYNGIOMA PAPILLARY CRANIOPHARYNGIOMA PAPILLARY CRANIOPHARYNGIOMA RATHKE’S CLEFT CYST

• Common incidental autopsy finding • Developmental cyst arising from remnants of Rathke’s epithelium • Resembles ciliated respiratory epithelium with columnar and scattered Goblet cells • Occasional squamous metaplasia raises DDx with papillary craniopharyngioma but BRAF V600E negative

School of Medicine BRAF-V600E Beta catenin

RATHKE’S CLEFT CYST PITUICYTOMA

• Benign tumor of posterior pituitary • Overlap with granular cell tumor and spindle cell oncocytoma • Origin thought to be pituicytes • Variably GFAP and S-100+ • TTF1+

School of Medicine PITUICYTOMA PITUICYTOMA

GFAP S100 TTF1

GRANULAR CELL TUMOR GRANULAR CELL TUMOR

Smear Alpha-AT AMA SPINDLE CELL ONCOCYTOMA

TTF1

PITUICYTOMA

AMA TTF1 Pituitary Adenoma PITUITARY ADENOMA SONG Music to Danny’s Song by Kenny Loggins, Lyrics by Arie Perry, MD Patient presents to you with bitemporal hemianopsia, prolonged amenorrhea, and galactorrhea MR imaging reveals a sellar neoplasm, pushing up the optic chiasm, from prolactin forming cytoplasm Chorus: Pituitary adenoma, with your disrupted reticulin stroma You’ve lost the microacinar pattern of the normal gland Your cells appear so monomorphic, with nuclei so round and perfect And salt and pepper nuclear chromatin In Cushing’s syndrome, the adenoma’s often very small The neurosurgeon’s who you better call, don’t you know he’ll try to get it all Excess ACTH causes cortisol to spin, out of control but feeding back again Corticotrophs build up Crooke’s hyaline (Chorus) Somatotrophic tumors lead to acromegaly, or gigantism more rarely, in patients exposed before puberty Gonadotrophs present most commonly in elderly, with few hormonal symptoms typically So macroadenoma’s what you see (Chorus) Though most pituitary adenomas are benign, patients often suffer endocrine, Manifestations that are scarcely fine Atypical adenomas may be challenging, carcinoma’s the malignant king Better treatment’s what we strive to bring (Chorus)

School of Medicine School of Medicine 11:00AM- 11:30AM Role for Surgery in Patients Presenting with Diabetes Insipidus Sandeep Kunwar, MD NOTES

Conflict of Interest Disclosure Lisa Nachtigall, MD Advances in the Treatment of Acromegaly Ipsen, Novartis: Consultation Ipsen, Chiasma: Grant Support

Lisa Nachtigall, MD Co-Director, Neuroendocrine & Pituitary Tumor Clinical Center Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Acromegaly: Familial Syndromes Causes of Acromegaly MEN-1 – MEN1 gene – Pituitary tumors, hyperparathyroidism and pancreatic tumors GH EXCESS Carney’s Complex > 95 % GH secreting pituitary adenoma – Mutations in the PRKAR1A gene: type 1 alpha regulatory subunit < 1.0 % ectopic GH secreting tumor (R1alpha) of cAMP-dep protein kinase – spotty skin pigmentation, hormone excess & myxomas – acromegaly, thyroid & testicular tumors, & (ACTH)-independent GHRH EXCESS Cushing’s/primary pigmented nodular adrenocortical < 1% hypothalamic GHRH McCune Albright hamartoma, glioma, gangliocytoma, etc – GNAS1gene mutation results in an abnormal version of the G protein causing somatotroph hyperplasia that causes the adenylate cyclase enzyme to be constitutively activated – fibrous dysplasia, café au lait, precocious puberty, Cushing’s & thyroid dz < 1% ectopic GHRH AIP Mutations carcinoid, islet cell Ca, pheo – Aryl hydrocarbon interacting protein, on 11q13.3, involved in tumor suppression – mutations predispose to adenoma (mostly GH and/or PRL secreting)

Lytras et al Neuroendocrinology 2006 Horvath et al Rev Endocr Metab Disord 2 Familial Isolated Diagnosis of Acromegaly: Facial Features Pituitary Adenomas 18 % of FIPA due to aryl hydrocarbon interacting protein (AIP) 11q13.3, which predisposes to adenoma

< 30 % family members with AIPmut developed clinical disease

Hernández-Ramírez L et al J Clin Endocrinol Metab 2015 Daly AF et al J Clin Endoocrinol Metab 2007 Daly AF et al J Clin Endoocrinol Metab 2010 1876-1916 1887-1914 Tichomirowa M et al Eur J Endocrinol 2011 For this and all other photos, patients have granted permission to share these images W.W. de Herder (personal collection)

Prevalence of Clinical Signs and Symptoms Random GH Measurements Result in False- Positive and False-Negative Diagnoses Acral enlargement and/or coarse features Sweating Menstrual disorder 15 90 Headache Healthy Adult Acromegaly Arthritis Carpal tunnel syndrome 10 60 Diabetes or impaired glucose tolerance ng/mL Impaired potency and/or libido ng/mL 5 30 Hypertension Visual field defect Obstructive sleep apnea 0 0 Galactorrhea 0 400 800 1200 1600 0 400 800 1200 1600 Coronary artery disease Time (min) Time (min) 0 20 40 60 80 100 % Patients With Complications GH and IGFI levels vary with method used Clemmons DR, et al. J Clin Endocrinol Metab. 2003;88(10):4759-4767. Adapted from Giustina A, Veldhuis JD. Endocr Rev. 1998;19(6):717-797. Hypertension and Cerebrovascular events Diagnosis of Acromegaly heart disease and headache

Inability to suppress serum GH during an Acromegaly oral glucose tolerance test (OGTT) to less Co-morbidities than 1 ng/ml Sleep apnea

Elevated serum IGF-I levels

– Age - matched normal range required Arthritis

Insulin-resistant diabetes

Acromegaly Significantly Impacts Long-term Mortality Improves Survival With Normal IGF-1 Levels After Surgery 1.0 1.0 General population Normal IGF-1 0.9 All acromegaly 0.8 Elevated IGF-1 0.8 Acromegaly + diabetes Cox model 0.7 0.6 Acromegaly + predicted cardiac disease survival 0.6 0.4 Patient in remission 0.5 0.2 Patient not in remission 0.4 0 5 10 15 20 25 0 5 10 15 20 Length of Survival (years) Years after surgery

Adapted from Rajasoorya C et al Clin Endocrinol 1994 Swearingen B et al J Clin Endocrinol Metab 1998 Probability of Survival According to Serum GH Concentrations Acromegaly: Therapy

1 • Surgical 0.8 GH<1 mcg/L • Medical New Zealand 0.6 population • Radiation GH<2 mcg/L 0.4

Survival (%) Survival GH<5 mcg/L 0.2 GH>5 mcg/L 0 0 5 10 15 20 25 30 Time (yrs)

Holdaway IM et al J Clin Endocrinol Metab 2004

Surgical Debulking Enhances Efficacy 1,2,3 of SSA Therapy Options for Medical Therapy 90 1st 80 2nd 70  Somatostatin Analogs 60 – octreotide 50 40 – lanreotide 30 – pasireotide IGF-1 for Age (%) Age IGF-1 for 20 Prevalence of Normal Prevalence of 10  Dopamine agonists 0 Microadenomas Enclosed Extrasellar Invasive – bromocriptine macro macro macro X Prevalence of normal IGF-I levels during the first and – cabergoline second courses of SSA treatment in relation to tumor size.  GH receptor (GHR) antagonists

1 • Colao A et al J Clin Endocrinol Metab. 2006 (LAN + OCT) 2 – pegvisomant • Petrossians P et al Eur J Endocrinol. 2005 (LAN + OCT) 3 • Karavitaki N et al Clin Endocrinol (Oxf) 2007 (LAN only) Serum IGF-I Levels on Cabergoline Dopamine Agonists pre-cabergoline on cabergoline Most effective for min elevated IGF-1, 1200 1/3 nl IGF-1 using monotherapy, assoc with PRL In combination therapy 1/2 nl IGF-1 when added to SA Efficacy independent of PRL level or tumor staining – Cabergoline 0.5 mg po q week 1000 concern re valvular effects in acromegaly given higher CVD in these patients but 2012 study was – (may need up to 3.5 mg per negative Serum 800 IGFI week) (ng/ml) 600

400

200 Patients

Abs J et al J Clin Endocrinol Metab 1998 Sandert L et al J Clin Endocrinol Metab 2011 Maione L et al Clin Endocrinol Metab 2012

Somatostatin Receptor Subtype Expression in Somatostatin Analog (SSA) Therapy Human GH Tumors and Drug Susceptibility pasireotide 30 times lanreotide Octreotide and octreotide – LAR IM 10, 20, 30, 40 mg/month 1/3 times – OCT SC 100-500 μg TID 5 times Lanreotide sc – Autogel 60, 90,120 mg/month (up to Q 8 weeks) 39 times – SR 30 mg Q 7-14 days (not available in US)

Affinity for Pasireotide IM 20, 40, 60 mg/month receptor

Danila DC et al J Clin Endocrinol Metab 2001 SSA Therapy: Side Effects SSA Therapy: Efficacy

Gastrointestinal (diarrhea, nausea, abdominal pain) • Controls GH or IGF-I in 50-66 % Early, 49% Persistent, <10% – but studies vary greatly: 20%-80% depending Biliary tract abnormalities on patients and study design All types, 50% New gallstones, 15% (4–22%) • When used as secondary therapy, tumor Abnormalities of glucose metabolism shrinkage occurs in about 30% of patients Hypoglycemia, 2% Hyperglycemia, 7–15%

• Tumor shrinkage in most patients is Injection site pain, 24% (4–31%) between 20% and 50% Transient hair loss, 3–6%

Hypothyroidism, 2% Freda P J Clin Endocrinol Metab 2002 Malmed S et al Pituitary 2010 Abu Dabrh et al J Clin Endocrinol Metab 2014 Freda PU J Clin Endocrinol Metab 2002

Preop Treatment with Somatostatin Analogs Preop Treatment with Somatostatin Analogs • Retrospective studies show mixed results Study 2: • 2 randomized prospective studies show benefit • N=49 pretreatment (PT): 49 % cure Study 1: • N=49 direct surgery: 9 % cure N=26 pretreatment (PT): 50 % cure • LAN 30 mg/1-2 wks x 4 month N=25 direct surgery: 16 % cure • Cure based on IGF-1 only LAR 20mg/month x 6 month • Evaluated for cure 4 months • caveats postoperatively – Baseline lower IGF-1 in PT group – Only 3 months postop (SA may maintain effect) • caveat – Not significant when GH level plus IGF-1 levels – Unusually low surgical cure rate used Carlsen S et al J Clin Endocrinol Metab 2008 Mao ZG et al Eur J Endocrinol 2010 *Fouqner SL et al Eur J Endocrinol 2014 Pasireotide LAR vs. Octreotide LAR: hyperglycemia related Prevalence of Normal IGF-1 and GH<2.5: adverse event according to baseline glucose status Pasireotide LAR vs Octreotide LAR

Baseline Pasireotide Pasireotide Octreotide 20- pasireotide Glucose 40 mg (n=63) 60mg (n=62) 30 mg (n=66) Status octreotide Diabetic 71% 70% 22% Prediabetic 70% 50% 56% Normal 38% 46% none

All Surgery De Novo

Colao A et al. J Clin Endocrinol Metab 2014 Coloa A et al J Clin Endocrinol Metab 2014

Pasireotide LAR vs. Octreotide LAR or Lanreotide in uncontrolled patients: phase 3 study results Primary Medical Therapy for Acromegaly

somatostatin Pas 40mg Pas 60mg Lan/LAR • Should be considered if surgery is analog contraindicated or refused % Normal IGF-1 15 20 0* and GH % 33 31 14* • Maybe appropriate for hyperglycemia – Inaccessible, invasive tumors % DM 21 26 8 * – Tumors unlikely to be surgically curable – Tumors not compressing optic chiasm

pas =pasireotide LAR Lan= lanreotide LAR= octreotide LAR *p<.05

Gadelha MR et al Lancet Diabetes Endocrinol 2014 Model for GH Receptor Activation by GH Medical Therapy Targets of the GH/IGFI Pathway

GH-secreting Tumor • SSAs SSA GHRH – SSA receptor ligands – + – Directly inhibit GH secretion – Indirectly inhibit IGF-I secretion SSA DA Agonist GH • DA Agonists

– D2 receptor X – Directly inhibit GH secretion GH – Indirectly inhibit IGF-I secretion IGF-I X • GHR Antagonist GHR Antagonist – Does not suppress GH secretion 1. GH binds to the extracellular domain – Directly inhibits IGF-I secretion 2. Within the pre-existing homodimer one GHR Subunit rotates relative to the other Increased Somatic 3. This reorientation results in transmission through the transmembrane domain Growth & Metabolic 4. This causes repositioning of TKs bound to cytoplasmic domain Dysfunction 5. Distance between the box 1 motifs increases, fundamental to activation of JAK2 Adapted from Thorner et al Brooks AJ Nature Reviews Endocrinology 2010

GHR Antagonist Elevates GH Levels GH receptor (GHR) Antagonist Dosing and Administration • Pegvisomant

(20 mg/day) 6-Month 12-Month 18-Month 1000 Cohort Cohort Cohort 50 ( GH Serum – 90% of patients (n=131) (n=90) (n=39)

g/L) Supplied as  attained 40 normalized IGF-I 750

 – 10,15,20,25,30 mg SC daily – Increased 30 g/L) 500 GH levels Serum IGF-I( 20 – Investigational evidence for – 2 pts had tumor 250 growth 10 efficacy of weekly use

– N=160 0 0

006 66120 12 18 – May be used as first line Months Months Months therapy

Van der Lely AJ et al Lancet 2001 Pegvisomant: Effect on Tumor Size Pegvisomant: Adverse Events

AE, n SAE, n • N = 61 on pegvisomant 5-30 mg/day (%) (%) – 3 tumors with significant increase Injection site reactions (erythema, swelling, 17(7.4) – lipohypertrophy) – All tumor growth in 1st year Elevated liver enzymes 9 (3.9) 12 (5.2) – All were assoc with DC of SSA Increase of pituitary tumor volume – 12 (5.2) – None were assoc with symptoms Headache 4 (1.7) – • N = 936 from global surveillance study Adverse events (AEs) and serious adverse events (SAEs) – 3.2 % had significant increase by MRI with an incidence > 1%, n=229). at mean of 2 year follow up (in subset with central MRI reports) Buhk J et al J Clin Endocrinol 2010 Schreiber I et al Eur J Endocrinol 2007 Bonert VS et al J Clin Endocrinol Metab 2008 Van Der Lily AJ et al J Clin Endocrinol Metab 2012

Pegvisomant Plus SSA: Efficacy Radiosurgery for Acromegaly

Gamma Gamma Gamma Proton Knifec Knife Knife Beam Pollock Jagannathan Lee Petit N 46 95 136 22 Follow up 22-168 18-168 12 -191 30-178 time (mos) Median or 36 24 28 42 mean time to (50 %) (53 %) (64%) (59 %) NL IGF-1 New 33 34 31 38 hormonal loss (%) Absence of GH suppressive meds at RT correlated with remission IGF-I concentration in serum of 31 patients with acromegaly Pollock et al J Neurosurg 2007 before (*) and after ({circ}) 138 (35-149) wk of combined therapy Jagannathan et al J Neurosurgery 2008 Lee C et al 2014 Neggers, S et al J Clin Endocrinol Metab 2007 Petit JH et al Endocr Pract 2007 Acromegaly: An Endocrine Society Clinical Practice Guideline Management of Acromegaly: Summary Points

Preoperative SSA Management of acromegaly Goals TranssphenoidalTranssphenoidal surgery surgery Considerations – IGF-I normal, OGTT suppression of GH <1 μg/L (most(most patients) patients) . If majority of tumour unresectable and no chiasmal compression – Control tumor . Poor surgical candidate Persistent disease Remission (incomplete surgery) Surgical debulking Surgery remains first-line management

Medications Medical Therapy . Annual IGF-1 and random GH • Dopamine agonists, somatostatin analogs and GH receptor SSA DA . Consider OGTT Pegvisomant (for most) (mild disease) antagonist • Primary medical therapy may be used for invasive tumors, which . Partial clinical and biochemical response to maximal MRI (if clinical or are unlikely to be completely resected, if chiasmal compression is doses biochemical signs of not present. • Consider combination therapy of above drugs recurrence) . No clinical and biochemical response • Consider alternative monotherapy Radiation Therapy: stereotactic or fractionated for uncontrolled Radiation therapy may be tumors or GH/IGF-1, if meds fail, not tolerated or inaccessible. considered at any point following Ineffective or intolerable medications incomplete surgery Consider SRT (conventional radiation if not Katznelson L et al. J Clin Endocrinol Metab 2014 candidate) DA, dopamine agonist; OGTT, oral glucose tolerance test;SRT, stereotactic radiotherapy; SSA, somatostatin analogues

Investigational Therapy: oral octreotide acetate (OOA); a phase III, global, multicenter, open- Oral Octreotide label study: Methods

• N= 155 subjects controlled (defined as IGF-I levels <1.3 ULN, and 2hr integrated GH <2.5 • 65% obtained IGF-1 < 1.3 × ULN and GH ng/mL, on 3 months of IM SSA < 2.5 ng/mL at 7 months • switched to OOA dose 40-80mg BID. • 85 % of subjects initially controlled • dose adjustment was followed by a fixed dose maintained this response up to 13 months. phase for up to 7 months of OOA • safety profile consistent with approved • controlled patients were then offered an somatostatin analogs additional 6-month extension

Melmed S et al J Clin Endocrinol Metab 2015 Melmed et al J Clin Endocrinol Metab 2015 Supplement

Selective Estrogen Receptor Estrogen and Selective Estrogen Modulator Clomiphene Improves Receptor Modulators in Acromegaly IGF1 in Men with Acromegaly Prospective Study 2015: • Meta-analysis 2014 • 16 men: clomiphene 50 mg/day as adjuvant • Mostly small observational studies therapy for 3 months • Estrogen therapy • Serum IGF-1 levels decreased by 41% – greatest decrease in IGF-1 in women – (mean ± SD, 424 ± 108 to 250 ± 83 ng/mL; P • SERMs (tamoxifen and raloxifene) < .0004), – less effective than estrogen and more • 44% (seven of 16) achieved normal IGF-1 effective in women than men levels

Stone J et al Pituitary 2014

Duarte F et al J clin endocrinol and Metab 2015 GH Replacement in Patients with Changes in IGFI & GH levels during the 1st GHD and History of Acromegaly trimester pregnancy in acromegaly (N=12) • GH replacement improved body composition & cv risk markers & QOL • Safety of GH replacement in this population has not been established • Long-term data (from KIMS) suggest possible increase in CV mortality (but not all cause mortality) – Caution advised in prescribing GH to such patients, especially those with increased cv risk

Miller KK. et al., J Clin Endocrinol Metab, 2010 Tritos NA et al J Clin Endocrinol Metab 2014 Caron P et al J Clin Endocrinol Metab 2010

Acromegaly Therapy During Acromegaly and Pregnancy Pregnancy

• DA’s and SA cross the placenta- but safety • GH excess may improve with high E2 evidence in several studies • Risk of gestational DM (4/64) & HTN (8/64) • Octreotide? assoc with microsomia; try to assoc with poor control GH/IGF1 use short acting preconception and stop • Rare tumor enlargement in macros 3/27 • Pegvisomant only reported in 2 cases • GH-suppressive therapy can be safely withdrawn after conception in most

Cheng S et al Clin Endocrinol 2012 Caron P et al J Clin Endocrinol Metab 2010 Brian SR et al J Clin Endocrinol Metab 2007 Discrepant IGF-1 and GH after Surgical Therapy of Acromegaly

• Post op IGF-1 nadir may take 3 month • Assay challenges may play a role • Consider other factors that affect IGF-1 • Clinical signs, sxs, and complications of acromegaly need to be closely evaluated to determine if medical therapy is indicated for cases with discordant levels Midline masses and Sella Midline masses and sella: Location, location, location… • Topic #1: What is the location? David M. Wilson UCSF Department of Neuroradiology

• Sella- Big 4 lesions and pitfalls.

UCSF University of California, San Francisco

Midline masses and Sella Differential Diagnosis: Essentials

• Most likely diagnosis • Topic #1: What is the location?

• Most dangerous diagnosis

• Sella- Big 4 lesions and pitfalls. • Feigning erudition (appearing smart) Case #1 Case #2

Case #3 Case #4 Location, location, location. The point…

• To determine the identity of a midline mass, you must determine its location.

• Additional imaging features are often needed to determine the location!

• Understand the clinical impact! Jermaine (Flight of the Conchords)

Guide to Midline Masses Guide to Midline Masses

1. Normal Anatomy 1. Normal Anatomy

2. Softballs 2. Softballs

3. Challenges… 3. Challenges…

4. Conclusions 4. Conclusions 1. Normal Anatomy 1. Normal Anatomy

Planum Sphenoidale/ Tuberculum Olfactory Groove Sellae

1. Normal Anatomy 1. Normal Anatomy

Dorsum Sellae Meningioma Clivus Chordoma, Metastases, Chondrosarcoma, NPC 1. Normal Anatomy 1. Normal Anatomy

Macroadenoma, Rathke’s Cyst Sella Optic chiasm

1. Normal Anatomy 1. Normal Anatomy

Hypothalamic Hamartoma/ Hypothalamus/ Tectum Tectal Glioma Glioma Tuber cinereum 1. Normal Anatomy 1. Normal Anatomy

Pineoblastoma, Pineocytoma, Pineal Gland Germ Cell Tumor, Pineal Cyst Corpus Callosum GBM, Lymphoma, Demyelinating

Guide to Midline Masses

1. Normal Anatomy

• If the exact anatomic location can be 2. Softballs identified, the diagnosis (or differential) is straightforward. 3. Challenges…

4. Conclusions Case #1

Pituitary Macroadenoma

Case #1 Case #2

Tectal glioma Hypothalamic hamartoma Case #3 Guide to Midline Masses

1. Normal Anatomy

2. Softballs

3. Challenges…

4. Conclusions

Pineoblastoma

Sellar/ suprasellar lesions Challenges arise if… • S Sella/paraselar tumor (adenoma) • A Aneurysm • T Teratoma/ germ-cell tumor • You do not know the location. • C Craniopharyngioma • H Hypothalamic glioma/ histiocytosis • M Meningioma/ metastasis • The lesion is an oddball. • O Optic glioma • E Epidermoid/ dermoid & EG • The lesion is promiscuous. This differential implies that you do not know the location! Sellar? How do you determine the location?

• Lesion characteristics

• Additional planes/ modalities

Location?

• Avidly enhancing • Dural tail • Hyperostosis (CT…)

Hypothalamic/ Optic Tract Glioma (Consider Cranio) Falcotentorial Meningioma Location?

GBM

Oddball… Promiscuous…

Pituitary abscess Lipoma Case #4

Dermoid, epidermoid Tectal lipoma

Guide to Midline Masses Conclusions- midline masses

1. Normal Anatomy • Know the location. 2. Softballs • If you don’t know the location, figure it 3. Challenges… out. • Consider the most harmful diagnosis. 4. Conclusions • Surgeons… Midline masses and Sella Sella: The big 4:

• Macroadenoma • Topic #1: What is the location?

• Rathke’s cleft cyst

• Craniopharyngioma • Sella- Big 4 lesions and pitfalls.

• Meningioma

OUTLINE OUTLINE

1. Normal anatomy & imaging 1. Normal anatomy & imaging

2. Adenoma and pitfalls 2. Adenoma and pitfalls

3. Cystic lesions 3. Cystic lesions Pituitary gland- structure DURA

• Meningeal and periosteal layers • Continuous with dura along planum sphenoidale & clivus

www.autismpedia.org/wiki/images/e/e5/Pituitary.jpg Capero A et al, Neurosurgery 2008; 62: 717-23

DURA UCSF Sella MRI protocol

• Thin single layer along medial cavernous sinus • Double layer along lateral cavernous sinus

• Sagittal & coronal pregad T1 - 12 minutes TR=600ms, TE=min, NEX=3, 2.7 mm no skip • Coronal fatsat T2 FSE - 4 minutes microadenoma TR=3000ms,TE=102ms, ETL=16, NEX=3, 2.0 mm no skip • Dynamic gad T1- 45 second intervals TR=600ms, TE=17 ms, ETL=8, NEX=2, 2 mm no skip (5 slices) • Sagittal & coronal gad T1 - 12 minutes TR=800ms,TE=min,NEX=3, 2.7 mm no skip hemorrhage • Coronal GRE - 6 minutes TR=787ms, TE=25ms,NEX=2, 3 mm no skip

Capero A et al, Neurosurgery 2008; 62: 717-23 Adenoma: Dynamic Gad T1

0 s

45 s 45 sec90 sec 135 sec

Dynamic enhancement • Onset: ~36 sec • Higher time resolution but generally noisier • Peak signal: 1.2 - 2.2 min 90s • Estimated 10% increase* in sensitivity • Washout: 2.7 - 5 min

*Bartynski W et al, AJNR 1997; 18: 965-72

OUTLINE Microadenoma • Endocrine dysfunction or incidental • Arise within the adenohypophysis • < 10 mm diameter 1. Normal anatomy & imaging • “Picoadenoma” (< 3 mm) diagnostic challenge • Rarely ectopic outside of pituitary fossa 2. Adenoma and pitfalls

3. Cystic lesions ??

Adenoma: T1 signal Adenoma: Enhancement

• Usually same or slightly lower signal than gland • Almost all lower signal than enhanced gland • High T1 signal if hemorrhagic (typical of prolactinoma) • May have higher signal after 30-45” delay • Contour deformity +/-

Macroadenoma

• Vision changes, hypopituitarism • > 10 mm • “Giant” adenoma if > 4 cm • May grow in any of 6 directions Superiorly (suprasellar) - 80% of cases Laterally (cavenous sinuses) Adenoma: T2 signal Anteriorly & inferiorly (sphenoid) Posteriorly (clivus) • Usually same or slightly higher than gland (“soft”) • Important observations • Less commonly lower than gland (“firm”) Hemorrhage • Higher T2 = higher secretion Optic chiasm T2 signal 80% PRL tumors have high T2 signal Cavernous sinus invasion 40-60% GH tumors have low T2 signal T1 Signal T2 Signal

• Heterogeneous, typically ~ gray matter • Highly variable - often heterogeneous, cysts and necrosis • High T1 signal implies hemorrhage or another lesion • Hemorrhage Can have any T2 signal Fluid levels helpful feature for diagnosis If hemorrhage suspected, confirm with GRE or CT

Suprasellar extension

Enhancement

• Mild to avid enhancement typical • Rarely hypoenhancing (thyrotropin secreting) • Look for enhancing gland (preserved surgically) • Speculative role of diaphragmatic hiatus Macroadenoma: Cavernous invasion

Best signs of involvement •Involvement > 2/3 circumference (PPV 100%) • 6-10% of adenomas •Carotid sulcus venous compartment (PPV 95%) • Biologically more aggressive tumors • Medial sinus has only 1 layer of dura •Lateral to lateral intercarotid line (PPV 85%) • Clinical symptoms late • Suspect when prolactin > 1000 ng/mL

Cottier J-P et al, Radiology 2000; 215: 463-69

Pitfalls…

Best signs of NO involvement (all have NPV 100%) •Involvement of < 1/4 circumference •Gland between tumor, cavernous sinus •Medial venous compartment preserved • 22 year-old woman, severely hypothyroid •Medial to medial intercarotid line • Diagnosis: pituitary hyperplasia

Cottier J-P et al, Radiology 2000; 215: 463-69 Pitfalls… Pitfalls…

• 58 year-old woman, hyperprolactinemia • Diagnosis: Tuberculum sellae meningioma Optic/ hypothalamic glioma

OUTLINE

1. Normal anatomy & imaging

2. Adenoma and pitfalls

3. Cystic lesions

RATHKE CLEFT CYST

• Incidental (13-22% of autopsy and MRI) or symptomatic • Non-neoplastic, single cell layered cyst arising from remnants of embryonic Rathke’s cleft • Natural history also slow enlargment with time RCC Two types

2/3 1/3 RATHKE CLEFT CYST • Well-defined round or ovoid, thin rim enhancement • Intrasellar (40%) and/or suprasellar (60%) T1 bright, T2 variable T1 dark, T2 bright • Between anterior and intermediate lobes (pars intermedia) •“Machine oil” cyst • Fluid like CSF • Stalk typically midline • More often symptomatic

Case: 37F panhypopit, polydipsia, vision changes RCC: Useful Diagnostic Features

• Arise out of pars intermedia • Midline or near midline • No displacement of stalk • Anterior to stalk if suprasellar • “Simple” single intensity The big third- Craniopharyngioma

• Histologic continuum with RCC

• Childhood type Adamantinomatous histology Poor prognosis (frequently recur)

ABSCESS • Adult type Papillary squamous epithelium • Primary (in normal gland) or secondary (in pre-exisiting adenoma or Rathke’s cyst) Good prognosis (rarely recur) • Present like other cystic tumors, fever & meningismus rare • Mixed type • Source of infection hematogeous or via sphenoid sinus Behave like adamantinomatous • Only 50% grow organisms, gram+ & gram- equally common

Adamantinomatous Craniopharynioma Adamantinomatous Craniopharynioma

• Locations: 75% suprasellar 21% supra- and intrasellar 4% intrasellar only

• Intrinsic T1 & T2 signal varies with contents of cysts (bright T1 cysts are typical)

• “Complex” signal typical

• Rule of 9’s • Rule of 9’s 90% mixed solid & cystic 90% mixed solid & cystic 90% enhance 90% enhance 90% calcify 90% calcify Case: 9 year-old with visual disturbances

Diagnosis: Craniopharyngioma

Papillary Craniopharynioma CYSTIC ADENOMA

• Surrounded by pituitary gland • Predominantly solid • More frequently off midline (PRL) • Cysts (if present) hypointense • Variable signal intensity • Spherical geometry typical • Evolve over time if hemorrhagic • May bloom on GRE Question #1: Which of the following pineal tumors Question #1: Which of the following pineal tumors has the lowest rate of spinal metastases? has the lowest rate of spinal metastases?

A. Endodermal sinus tumor A. Endodermal sinus tumor B. Germinoma B. Germinoma C. Pineocytoma C. Pineocytoma D. Pineoblastoma D. Pineoblastoma

Ito et al. Pathol Int 1995 45(6): 463 Roberts et al. Am J Roentgenol 2006 186(3 supp): S224-6. Onesti et al. Clin Neurol Neurosurg 2012 114(7): 1081-5.

Question #2: Which of the following has been reported Question #2: Which of the following has been reported in conjunction with NF1? in conjunction with NF1?

A. Tectal glioma A. Tectal glioma B. Craniopharyngioma B. Craniopharyngioma C. Hypothalamic hamartoma C. Hypothalamic hamartoma D. Pineoblastoma D. Pineoblastoma

Pollack et al. Neurology 1996 46(6): 1652-60 Chen et al. Oncogene 2013 (epub ahead of print) Crouse et al. Curr Top Dev Biol 2011 94: 283-308 Question #3: Which of the following are common Question #3: Which of the following are common treatments for hypothalamic hamartoma? treatments for hypothalamic hamartoma?

A. Chemotherapy A. Chemotherapy B. Stereotactic radiosurgery B. Stereotactic radiosurgery C. Endoscopic surgery C. Endoscopic surgery D. B and C D. B and C E. A and B E. A and B

Wethe et al. Neurology 2013 81(12): 1044-50. Mittal et al. Neurosurg Focus 2013 34(6): E7. Choi et al. Adv Tech Stand Neurosurg 2012 39: 117-30.

Question #4: Which of the following cell markers is Question #4: Which of the following cell markers is 100% sensitive for choriocarcinoma? 100% sensitive for choriocarcinoma?

A. AFP A. AFP B. hCG B. hCG C. LDH C. LDH D. CA-125 D. CA-125 E. CEA E. CEA

Jorsal et al. Acta Oncol 2012 51(1): 3-9. Kyritsis J Neurooncol 2010 96(2): 143-9. Chieffi et al. J Endocrinol Invest 35(11): 1015-20. Question #5: The following statement about papillary Question #5: The following statement about papillary craniopharyngioma is correct: craniopharyngioma is correct:

A. Seen almost exclusively in adults A. Seen almost exclusively in adults B. Calcification in 90% B. Calcification in 90% C. Higher incidence in females C. Higher incidence in females D. Commonly cystic D. Commonly cystic E. Consists of reticular endothelial cells E. Consists of reticular endothelial cells

Sartoretti-Schefer et al. AJNR 1997 18(1): 77-87 Eldevik et al. AJNR 1996 17(8): 1427-39

THANK YOU! [email protected] u “Prolactin is the sed rate of the endocrinologist”

Wm Doughaday BLAKE TYRRELL OCT 2017

 42 yo woman • 1996-Infertility,irregular menses -PRL 30-40,TSH increased -RX’d with T4 • 1998-PRL 27.1 ng/ml (3-19),TSH 2.81 -IVF-FTND • 2001-IVF-FTND-twins • 2002-Amenorrhea,TSH 8.58 -T4 dose adjusted • 2005-Amenorrhea continues -PRL 83.1,TSH 2.65

NOW WHAT ?? PRL Secreting Tumor vs Nonfunctional Macroadenoma With Stalk Compression

1.Physiologic 1.PHYSIOLOGIC 2.Miscellaneous  Pregnancy/Postpartum  3.Drug Induced Breast Feeding 4.Neurogenic 2. MISCELLANEOUS 5.Hypothalamic-Pituitary Lesions  Renal Failure  Primary Hypothyroidism  Idiopathic/Pituitary Hyperplasia  Macroprolactinemia 3.DRUG INDUCED 4.NEUROGENIC Estrogen/OCP’s Tricyclics • Breast Stimulation Metoclopramide MAOinhibitors • Local Breast Disease Cimetidine Phenothiazines • Chest Wall Injury/Trauma Verapamil Pimozide • Spinal Cord Lesions Cocaine Haloperidol Opiates Resperidone Molindone Olanzapine

 Galactorrhea and/or Amenorrhea in women 5.HYPOTHALAMIC-PITUITARY LESIONS  Unexplained Hypogonadism/Infertility in men • Prolactinoma  Suspected Pituitary/Hypothalamic Dysfunction • Other Pituitary Adenomas • Pituitary Stalk Compression/Section • Hypothalamic Lesions • Empty Sella Syndrome  Confirm Elevated Level  Clinical Features  Drug/Medication HX  Diagnosis  Pregnancy Test (Women)  Therapy  Testosterone Level (Men)  Questions  Thyroid FX: TSH  Think about Macroprolactinemia  MRI

 Galactorrhea Women Men • Women >80%  Mean age(yrs) 28 43 • Men <10%  Abn menses 99 --  Early Endocrine Symptoms  Galactorrhea 81 6 • Women-Oligo/Amenorrhea/Infertility  Decreased libido 14 71 • Men-Decreased Libido/Infertility  Visual defect 10 38  Late Local Symptoms  Microadenoma 64 9 • Headache  • Visual Field Defect Macroadenoma 36 91 • Hypopituitarism *From Molitch and Reichlin, 1980 (Age in yrs, all others as %)  Exclude Other Causes  MICROADENOMAS  Persisting Hyperprolactinemia • Dopamine Agonists -Bromocriptine/Cabergoline PRL Level(ng/ml) • Microadenoma 20-100 Transsphenoidal Surgery Probable Adenoma 100-200 Definite Adenoma >200*  MACROADENOMAS • Dopamine Agonists -Bromocriptine/Cabergoline  Abnormal MRI** • Surgery/Dopamine Agonists/Radiotherapy *Levels may be higher with pregnancy and resperidone ** Caution re: false positives

 MICROADENOMAS • PRL OR gonadal FX normal in 80-90% • PRL normal in 60-70%

 MACROADENOMAS • PRL normal in 50-70% • Tumor size reduction in 70% (>25%)

 Molitch and Reichlin 1980  ADVANTAGES  Long Acting Dopamine Agonist • Non-invasive  • Reasonable success rates Usual Doses~0.25-0.5 mg twice a week • Avoids surgery  Usual Dose Range~0.25 mg once a week to 1.0mg twice a week  DISADVANTAGES  • BID dosing Intolerance Rare • Intolerance (5-12%)  Resistance Rare • Resistance (9%)

 MICROADENOMAS  Ono et al. JCEM 2008,93:4721 • PRL Normal In >90% • N=150 (Women 122/Men 28) (Age 33.4+9.7) • Micro 93, Macro 57 (10>3cm)  MACROADENOMAS • Prior Bromocriptine* 90/150 (60%) • PRL Normal In 70-80%* • Prior TS surgery 47/150 (31%) • Tumor Size Decrease In >70%* • Basal PRL 570+141ng/ml (53-14,416 ng/ml)

*PRL levels and tumor size continue to decrease *Intolerant or resistant with longer therapy  N=150 (Micro 93/Macro 57)  ADVANTAGES ◦ Mean basal PRL 570+141ng/ml (range 53-14,416) • More effective and better tolerated than bromocriptine ◦ Monthly dose escalation • Intolerance and resistance are rare  Normal PRL @ 1year—149/150 (99.3%)  Dose Range (0.5-12mg/wk) ◦ 84% Normal @ 3mg/wk ◦ 92% Normal @ 6mg/wk ◦ 97% Normal @ 9mg/wk Ono et al. JCEM 2008,93:4721

 Pregnancy ?? PERCENT  Life long therapy ??  Microadenomas <2  Cardiac damage ????  Macroadenomas(untreated) 23  Macroadenomas(post-surgery) 3

Endo Metab Clin NA 35:99,2006  There is no increased risk of fetal loss or fetal abnormalities  Microadenomas when dopamine agonists are used to restore fertility • RX with cabergoline until cycles normalize  Experience is greater with bromocriptine than with • With first missed period obtain HCG cabergoline • If positive D/C RX • (Follow prolactin Q 6 weeks) • (Follow visual fields)

 N Macroadenomas . Macroadenomas* • Prior surgery effectively reduces the risk of tumor expansion  Conception with bromocriptine 86  VFD during pregnancy 20(23%) • There are limited data on risk after tumor suppression with dopamine  RX’d with surgery 4  RX’d with bromocriptine 15 agonists  Successful outcome 20

. Macroadenomas  Continuous bromocriptine** 29  VFD during pregnancy 2  Successful outcome 29

* Endo Metab Clin NA 35:99, 2006

**Fertil Steril 41:793,1984,Am J ObGyn 146:935,1983. 7/29 patients probably had non-functioning adenomas (Baseline PRL<200ng/ml)  Macroadenomas (N=29)*  Macroadenomas (N=29)* • Dose escalation PRE POST • Conception when menses resumed x3 months & tumor <1cm in height • Prolactin (ng/ml ) 348+152 6.0+3.6 • Cabergoline dose mg/wk(range) 3.59+2.77 (2-9) • Tumor height(mm) 12.7+1.4 11 not seen Range (mm) 10.6-16.4 18 were <1cm *Ono et al. JCEM 95:2672,2010 • Time to tumor shrinkage—6-24 months • Pregnancy—27 pts had 30 pregnancies with no symptoms of tumor expansion

*Ono et al. JCEM 95:2672,2010

 Macroadenomas:Options  WORST CASE=TUMOR ENLARGEMENT • Suppress tumor with cabergoline to normalize menses and prolactin • Usually in 2nd or 3rd trimester with headache and visual defect and shrink tumor to <1cm (6-24months). Then D/C at conception and • MRI (non-contrast) to define size follow • Bromocriptine is effective in most (N=15) • (Continuous bromocriptine: there are no data on cabergoline) • Cabergoline is also effective (N=11) • (Surgery prior to conception) • Deliver early if fetus viable • Transsphenoidal surgery if medical therapy fails  Is Life Long Therapy Required ??  Following 2-4 YRS of therapy ~30% can be withdrawn and remain normoprolactinemic  Best outcomes-1) NTH*, 2) Microadenomas, 3)post therapy PRL<5 and residual tumor <3mm, 4) longer duration of therapy

 CAUTION: current studies are poor and include many patients without adenomas

* Nontumoral hyperprolactinemia

 STRATEGY  Patients treated with cabergoline or pergolide for • NTH-RX 1 year and withdraw Parkinson’s are at increased risk of cardiac valve damage • Micro-RX 3 years and withdraw and the risk is dose related • Macro-RX 3-5 years, reassess PRL level and tumor size and consider  Average dose of cabergoline was 3.6 mg per day=25.2mg withdrawal per week*

 Usual doses of cabergoline for prolactinomas are 0.25-2.0 mg per week

 * NEJM 356:29,2007  STRATEGY  NONINVASIVE ADENOMAS • Use lowest possible dose • Microadenomas-initial success in 91% • Withdraw RX as soon as possible • Macroadenomas-initial success in 80-88% • If long term RX is required, baseline and follow up cardiac evaluation • Complications in 1-2% should be performed • Recurrence varies with the surgeon  INVASIVE ADENOMAS • Initial success in <50% • Complications increase with tumor size • Recurrence in 20-30%

* Tyrrell et al, Neurosurg 44:254,1999

Don’t forget the “Hook Effect” CUSHING’S SYNDROME (CS)

• DIAGNOSIS • DDX OF ACTH‐INDEPENDENT AND ACTH‐ DEPENDENT CUSHING’S DISEASE CAUSES • DDX OF PITUITARY (CD) AND ECTOPIC CAUSES OF ACTH‐ BLAKE TYRRELL DEPENDENT CS OCTOBER 2017

CS: DIAGNOSIS CS: DIAGNOSIS

DO NOT USE • Overnight Dexamethasone suppression (ONDST 1 mg) • Tests which are not useful • Any test beginning with “17” • AM, 4PM, or random serum cortisol • Late evening salivary cortisol (LNSC) • Tests which are not practical • Midnight serum cortisol • 24h urine cortisol (U Cort) • Six day DST • Tests for DDX • Localizing procedures CS:DIAGNOSIS CS:DIAGNOSIS FALSE POSITIVE RESPONSES* FALSE NEGATIVE RESPONSES* • False + (Pseudo Cushing’s syndrome) • False negative responses • Acute illness/hospitalization – Mild Cushing’s • Severe stress – Episodic /Cyclic Cushing’s (RARE) • Morbid obesity • Sleep apnea • Depression/Anxiety *Regardless of test used • Alcohol excess • Anorexia nervosa

* Regardless of test used

CS:ONDST(1mg) CS:ONDST(1mg)

• DEX 1mg at 2300H • Advantages • Serum cortisol at 8:00 AM (LC/MS/MS) – A normal response excludes CS with 97‐98% accuracy • Disadvantages (false +) • Normal response‐AM cortisol < 1.8mcg/dl (50 nmol/l) – Pseudocushing’s • Sens‐‐‐97‐100% – Estrogen/tamoxifen increase CBG • Spec‐‐‐80‐100% – Accelerated DEX metabolism‐phenytoin, phenobarbital, rifampin, carbamazapine – Renal failure • Disadvantages (false‐) – Delayed DEX metabolism (<1%) CS:LNSC Raff H and Findling JW

• Collect 2 samples at 2300H on consecutive days • Normal values – ELISA/EIA‐‐‐<4.3 nmol/l – LC/MS/MS‐‐‐<2.5‐2.8 nmol/l • Sensitivity‐‐‐92% • Specificity‐‐‐96%

CS:LNSC—A WORD OF CAUTION CS:LNSC

• Advantages • Liu et al * – Male veterans with DM2 – Ease of collection/multiple specimens – LNSC SPEC(%) • All subjects 80 – Many pts with pseudo Cushing’s maintain normal diurnal variation • DM/HTN/AGE>60 60 – Two normal values exclude Cushing’s • Baid et al ** – Obese subjects • Disadvantages(false+) – LNSC • By RIA 84 – Pseudocushing’s • By LC/MS/MS 92 – Altered sleep/wake cycles * Clin Endocrinol 63:642,2005 – A WORD OF CAUTION ** JCEM 94:3857,2009 CS:URINE CORTISOL(U Cort) CS:UC

• Collect two 24H urines (or 4??) • Advantages • Assay by LC/MS/MS – Estimates 24H excretion – Not increased in moderate obesity • Normal range 4‐50 mcg/24H • Disadvantages • Sens‐‐‐76‐100% – Requires 24H collection • Spec‐‐‐81‐100% – Many patients with pseudocushing’s have mild to moderate increases in UC – False + with high urine volume – False ‐ in renal failure

CS:DIAGNOSIS CS: DIAGNOSIS JCEM 100:3856,2015 (38CS,99non) OTHER TESTS Sens Spec LR‐ LR+ • Two day low‐dose DST • DST 1mg • <50 nmol/l 100 91.9 12.4 DEX 0.5mg Q6H x 48H (OR 1.0 mg Q12H) <138 nmol/L 86.8 96.7 0.14 28.7 • Collect AM serum cortisol at 48H • Normal response—serum cortisol <1.8mcg/dl • LNSC • Useful in pts with mildly abnormal results of other tests <14.5 nmol/L 84.2 88.9 0.18 7.6

• UCORT (LC/MS/MS) <170 nmol/24h 97.4 90.9 0.03 10.8 CS:DIAGNOSTIC STRATEGY CS:ETIOLOGY AND DDX

• Choose conditions/assay • ACTH‐dependent Percent • Perform ONDST(1MG) or LNSC or U CORT – Pituitary (Cushing’s disease) 75 – Ectopic ACTH syndrome 10 • If normal CS very unlikely – Ectopic CRH <1 • If abnormal confirm with 2nd test • If equivocal consider two day LDDST and/or follow over time • ACTH‐independent – Adrenal adenoma 10 – Adrenal carcinoma 5 – PPNAD & AIMAH <1

CS:DDX ACTH DEPENDENT VS DDX:PITUITARY(CD)VS ECTOPIC ACTH INDEPENDENT • Measure ACTH by IRMA or ICMA assay • THE PROBLEM • Pituitary adenomas average 5mm in diameter • These assays reliably detect suppressed • Many ACTH‐secreting carcinoids are <10mm • Routine MRI positive in 42*‐50% of pts with CD levels ie < 5 pg/ml • MRI positive in 10% of normals • • STRATEGY ACTH <5 pg/ml=ACTH independent (image the adrenals) • Do Dynamic MRI‐‐Positive or suspicious in 83%** • ACTH >10 pg/ml =ACTH dependent • If MRI negative, equivocal or if high suspicion for ectopic ACTH syndrome proceed to inferior petrosal sinus sampling (IPSS). • IPSS:positive for CD if central/peripheral ACTH ratio >2 OR >3 after CR

*NIH‐JCEM 98:2285,2013 (501 PATIENTS) **UCSF‐J Neurooncol 16:693,2014 Cavernous/Inferior Petrosal Sinus Sampling CUSHING’S MICROADENOMA IPSS

Oldfield et al 1985

IPSS:TUMOR LATERALIZATION INFERIOR PETROSAL SINUS SAMPLING (IPSS)

• Newell‐Price et al* • Overall diagnostic accuracy‐‐‐62%*‐69%** – 21 series, 646 subjects – 96% success in canulating bilateral sinuses – Sensitivity‐‐96% – Specificity‐‐100% • 15/28(54%) cured by hemihypophysectomy – Lateralization (diagnostic accuracy‐‐78%) based on lateralization data.* • UCSF‐Liu C et al** – N=95, all with non‐diagnostic MRI, sampled CS and IPS with and without CRH – Sensitivity 100% ,specificity 100% *UCSF‐ Clin Endo 61:478,2004(N=95) – Lateralization (diagnostic accuracy‐‐ 62 %) **NIH‐ JCEM 98:2285,2013(N=501) *Endo Rev 19:647,1998. **Clin Endo 61:478,2004 CD: TRANSSPHENOIDAL SURGERY (TSS) CD: INDICATIONS FOR PITUITARY EXPLORATION OUTCOME & RECURRENCE • ACTH dependent hypercortisolism • MGH (1978‐1996)* NO % • Positive pituitary MRI (lesion>5mm) – Remission 137/161 85** – Recurrence 10/136 7 OR • Positive central venous sampling • UCSF (1975‐1998)*** – Remission 236/289 82 – Recurrence 13/150 9

*Ann Intern Med 130:821,1999 , ** 28 pts had more than 1 operation. *** JCEM 89:6348,2004

CD:MORTALITY CD:THERAPY

NO SMR • Transsphenoidal surgery(TSS) • MGH • Remission:70‐85%* • Therapy of persisting or recurrent disease – Deaths 6/159 0.98 • Repeat TSS • Radiotherapy • UCSF • Medical RX – Deaths 29/248 • Bilateral adrenalectomy – Remission 1.2 *If your remission rate is 50%, you have either the wrong diagnosis or the – Persisting disease 2.8 wrong surgeon CD:REPEAT TSS* CD:RADIOTHERAPY*

% • • Conventional Remission 168/246(68%) • Remission 46‐84 (Range 37‐87%) • Hypopit 10‐76 • Tumor control 93‐100 • Gamma knife(SRS) • Relapse 22/123(18%) • Remission 10‐83 (Range 0‐35%) • Hypopit 5‐66 • Tumor control 85‐100 *Arq Bras Endocrinol Metab 51:1373,2007, *Can J Neurol Sci 38:12,2011 (11 series,246 patients) Pituitary 17:60,2014

CS:MEDICAL THERAPY CD:CABERGOLINE

• Inhibit ACTH secretion Dose (mg/wk) U Cort normal • Cabergoline • Pasireotide (new somatostatin analog) • Study #1* 1‐7 (median 3.5) 8/20(40%) • Cyproheptadine ,bromocriptine ,older somatostatin analogs and sodium valproate are not effective 24 months • Inhibit cortisol secretion • Study #2** 0.5‐6 (mean 2.1) 9/30(30%) • Ketoconazole • Metyrapone 12‐60 months • Mitotane (mean 37) • Etomidate (IV only) • Glucocorticoid receptor antagonist *JCEM 94:223,2009 • Mefipristone **Eur J Endocrinol 136:709,2010 CD:PASIREOTIDE CD:KETOCONAZOLE NEJM 366:914,2012 JCEM 99:1623,2014 600 mcg* 900 mcg* All pts Dose U Cort normal • U Cort normal (mean:mg/day) • At 6 mos 12/82 21/80 33/162 • Pre Surgery 755+284 19/39(49%) (15%) (26%) (20%) (4.1+4.1 mos) • At 12 mos 5/39 10/39 15/78 • Post TSS or XRT 780+292 78/158(49%) (13%) (26%) (19%) (24.8+33.6 mos) • Adverse effects‐diarrhea 58%, nausea 52%, • Long term 33/51(65%) DM/hyperglycemia 73%,new diabetic RX 46% (24‐135 mos) • Adverse effects‐intolerance 21%,elevated LFT’s 16%,markedly *600 or 900 mcg SQ BID elevated LFT’s 3%, AI 5%

CD:MIFEPRISTONE CD:COMBINATION MEDICAL THERAPY* JCEM 97:2039,2012 • Glucocorticoid antagonist‐can’t follow cortisol UCORT normal • 50 pts treated for 6 mos(dose 732+366 mg/day) • Cabergoline/ketoconazole 25/32 (78%) • C‐DM‐‐decreased aucGTT >25% 15/25(60%) • Pasireotide/cabergoline/ • C‐HT‐‐‐decreased DBP >5mm HG 8/21(38%) • WT decreased 5.7+7.4 % ketoconazole 13/17 (76%) • Adverse effects—Nausea 48%,fatigue 48%,headache • Octreotide LAR/ketoconazole 3/4 (75%) 44%,hypokalemia 34%,HTN 24%. *Pituitary 18:253,2015 Arthralgia,vomiting,edema,dizziness,anorexia in 20‐30%. AI‐N=2 CD:LAPAROSCOPIC BILATERAL ADRENALECTOMY CD:CONCLUSIONS

• Consider in • TSS is the primary therapy of choice, however, there are no • Young patients clear guideline as to how to proceed when patients fail TSS. • Those who fail TSS,XRT and medical RX • Advantages • Rapidly corrects hypercortisolism with low morbidity/mortality • Should reverse excess mortality • Low recurrence rate • Disadvantages • Permanent AI • Risk of Nelson’s syndrome From Rathke’s Cleft Cysts to Craniopharyngiomas: Pathologic Disclosures Spectrum and Management Strategies • None

Manish K. Aghi, MD, PhD San Francisco, CA Maydan Endowed Professor Department of Neurological Surgery Saturday, October 21, 2017 Director 4:00 –4:30 pm Center for Minimally Invasive Skull Base Surgery University of California San Francisco

Overview Normal pituitary development • The hypophysis is an amalgam of two tissues. Early in 1. Pituitary development gestation (3-4 weeks), a finger of ectoderm called Rathke's 2. Rathke’s cleft cysts vs. Craniopharyngioma – pouch grows up from the stomodeum (roof of the mouth), eventually developing into the anterior pituitary or histology and genetic origin adenohypophysis. 3. Rathke’s cleft cyst – management and risk • At the same time, another finger of ectodermal tissue factors for recurrence evaginates from the diencephalon of the developing brain, 4. Craniopharyngioma – management and risk becoming the posterior pituitary or neurohypophysis. factors for recurrence • Ultimately, the two tissues grow into one another and become tightly apposed, but their structure remains 5. Cases distinctly different. Rathke’s Cleft Cysts vs. Spectrum Part One – The Craniopharyngioma Epithelial Pathologic Spectrum • Rathke’s cleft cysts (RCCs) are benign cystic Rathke Rathke Craniopharyngioma lesions of the sellar region which arise from the Single layer Squamous Stratified squamous embryonic remnants of Rathke’s pouch of ciliated – Typically, they are lined by a single layer of ciliated cuboidal or metaplasia. epithelium cuboidal or columnar epithelium. columnar epithelium. • Craniopharyngiomas originate from the ectopic embryonic remnants of the craniopharyngeal duct which connects the stomodeum with the Rathke’s pouch. – The papillary subtype, usually found in adults, is characterized by stratified squamous epithelium – the adamantinomatous subtype, more common in children, typically has stratified squamous epithelial nests separated by stellate reticulum.

Distinct genetic origins Rathke’s Cleft Cysts • Incidence – 13-22% of autopsies • Could craniopharyngiomas ever arise from • Symptoms – headache (60%) most common; 35- Rathke’s with squamous metaplasia? 50% hormonal dysfunction; 20-50% visual • Seems unlikely because distinct clonal mutations disturbance have been identified in CTNNB1 (β-catenin) in •MRI – nearly all adamantinomatous 1. T1 dark, T2 bright – fluid like CSF craniopharyngiomas and in BRAF in all papillary 2. T1 bright, T2 variable – fluid is mucus, higher rate of craniopharyngiomas, while no mutations have presenting with h/a (100%) or gland dysfunction (40%); higher rate of postop DI than adenomas been found in the cellular lining of a Rathke’s cleft 3. Stalk often midline cyst. Rathke’s cleft cyst – when to Rathke’s Cleft Cysts – Factors treat? Predicting Recurrence Changes in incidentoloma size in 236 patients followed • Radical resection of whole wall with no impact over 2.3 to 9 years in 9 published series 1990-2006 on recurrence, but increases postop DI from 9% to 42% • Fat graft increases recurrence rate ↑ SIZE ↓ SIZE NO CHANGE • Squamous metaplasia increases recurrence 19% MICROADENOMAS 10% 6% 84% 42% MACROADENOMAS 20% 11% 69% 39% RATHKE’S CYST 5% 16% 78%

Source: JNS 102: 189, 2005

Rathke’s Cleft Cysts – Factors Rathke’s Cleft Cysts – Factors Predicting Recurrence: Predicting Recurrence: Suprasellar Superinfection • UCSF experience: – Intraop suspicion of infection enough to elevate recurrence rate

Source: Neurosurgery 69: 1058, 2011

Source: Neurosurgery 67: 762, 2010 Rathke’s Cleft Cysts – Factors Spectrum Part Two – The Predicting Recurrence: Suprasellar Radiographic Spectrum • Is the suprasellar Rathke an intermediate step on a spectrum towards craniopharyngioma? • Rathke’s pouch gives rise to the pars tuberalis in the suprasellar cistern, the likely origin of suprasellar Rathke’s cleft cysts, a distinct origin from that of craniopharyngiomas • UCSF experience: o unlike sellar Rathke’s cleft cysts, a radiographic GTR with full wall excision can be achieved for suprasellar Rathke’s cleft cysts without increased DI risk o Radiographic GTR of suprasellar Rathke’s leads to the same 8% recurrence risk seen with sellar Rathke’s, and far less than the 15-20% recurence rate after GTR of craniopharyngioma

Source: Neurosurgery 69: 1058, 2011

Craniopharyngiomas – surgical Craniopharyngiomas approaches • UCSF experience: 83 patients 1986-2010 (23 • Expanded endoscopic approaches have allowed wide access transsphenoidal, 60 craniotomy) to the suprasellar cistern, reducing but not eliminating the indications for craniotomy for craniopharyngioma.

Source: Journal of Clinical Neuroscience 21: 1558, 2014 Source: JNS 124: 627, 2016 Case #1

• 73 year old female with 3 months of headache and visual impairment • Bitemporal hemiamopsia with 20/100 vision centrally

Cases – suprasellar pathology

Case #1 Case #1

Postop: No postop relief Postop relief Vision normalized Postop imaging = no residual Case #2 Case #2 • 79 year old female with severe headache and fluctuating Mineralized suprasellar cyst intimately attached to stalk visual deficit No postop relief Postop relief

Case #2 Case #3 39 year old male with 4 months of headaches, vision loss (L>R), memory impairment, and loss of libido. Case #3 Case #3

Conclusions The future is now • The histologic and radiographic overlap of Rathke’s cleft cysts and craniopharyngiomas is not indicative of a continuous spectrum because of their distinct tissue origins and distinct genetics. • Incidentally found Rathke’s cleft cysts wthout mass effect can be observed but radiographic overlap with craniopharyngioma underscores the importance of making sure patient is not lost to follow up. • Numerous factors can increase Rathke’s cleft cyst recurrence rates, but overall recurrence rate is low with pro-active strategies (attempting GTR for suprasellar Rathke’s, being cognizant of infected Rathke’s) • ALLIANCE sponsored clinical trial of BRAF • STR and lack of radiation in setting of STR increase inhibitor for recurrent papillary craniopharyngioma recurrence. craniopharyngioma opening later this month. Acknowledgements • Lewis Blevins • Ivan El-Sayed • Sandeep Kunwar • Philip Theodosopolous • Michael W. McDermott A bit about myself

The Patient’s Journey  My background

 Professional background Jorge D Faccinetti Chairman and CEO Pituitary World News  My work

My journey to diagnosis The Diagnosis

 Looking back at the early signs  Hip replacement pre-op meeting  The dentist  Hypertension  …and by the way “  High blood sugars  Growing  The pain: joints, bones, and muscles “I THINK YOU HAVE ACROMEGALY”  The hips Some visuals My work now

 Pituitary World News

 A joint effort to increase awareness of pituitary disease so more people are diagnosed properly and 1986 1971 1973 early  Awareness/Information/education  Public policy  QOL

 Here’s a look

2010 two months 1995 Recent before surgery

Disclosures

Nothing to disclose

Thank you University of California San Francisco 10/13/2017 MNS18002: Pituitary Disorders

UCSF OCME Registrant List Page 1 of 1

Name City, State 1Citron John T. MD Oakland, CA 2Gerber Imichael Lee Md Reno, NV 3Grua James R MD Salt Lake City, UT 4Hasinski Stefan Md Phoenix, AZ 5Kahn Condren Stacey Md Vancouver, WA 6Kissel Phillip Md San Luis Obispo, CA 7Linfoot John A. MD Lafayette, CA 8McFarland Bentson H. MD, PhD Portland, OR 9Meyer Edward J. MD Fremont, CA 10Plimpton Timothy Stanley Md Sacramento, CA 11Quirk Christopher Quirk Ardross, WA., Australia 12Rosen Norman J Md Lafayette, CA 13Sajjadi Hamed MD San Jose, CA 14Smith Craig S. MD Elk Grove, CA 15Srinivasan Lakshmi MD Fremont, CA 16Tykodi Gunjan Md Bellevue, WA 17Uihlein Alexander Vogel MD Ross, CA 18Wille Mark T. MD Lafayette, CA

Total Number of Attendees for MNS18002: 18 University of California San Francisco