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Sandeep Kunwar, M.D.Sandeep Kunwar, M.D.

Surgical Director, California Center for Pituitary DisordersSurgical Director, California Center for Pituitary DisordersAssociate Clinical Professor, University of California, San FranciscoAssociate Clinical Professor, University of California, San Francisco

Surgical Management of Cushing’s Disease in the Modern EraSurgical Management of Cushing’s Disease in the Modern EraCortisol Regulation

Cushing’s Syndrome – Excess Cortisol

� Truncal obesityTruncal obesityTruncal obesityTruncal obesity

� Decreased libidoDecreased libidoDecreased libidoDecreased libido

� Hypertension/DMHypertension/DMHypertension/DMHypertension/DM

� HirsutismHirsutismHirsutismHirsutism

� Plethora/Round FacePlethora/Round FacePlethora/Round FacePlethora/Round Face

� Thin skinThin skinThin skinThin skin

� WeaknessWeaknessWeaknessWeakness

� Growth failureGrowth failureGrowth failureGrowth failure

� Muscle weaknessMuscle weaknessMuscle weaknessMuscle weakness

� StriaeStriaeStriaeStriae

� AcneAcneAcneAcne

� Dorsal (and supraDorsal (and supraDorsal (and supraDorsal (and supra----clavicular) fat padclavicular) fat padclavicular) fat padclavicular) fat pad

� female baldingfemale baldingfemale baldingfemale balding

� menstrual changesmenstrual changesmenstrual changesmenstrual changes

� lethargy/depresssionlethargy/depresssionlethargy/depresssionlethargy/depresssion

� Osteopenia/osteoporosisOsteopenia/osteoporosisOsteopenia/osteoporosisOsteopenia/osteoporosis

� recurrent infectionsrecurrent infectionsrecurrent infectionsrecurrent infections

� Easy bruisingEasy bruisingEasy bruisingEasy bruising

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Cushing’s Syndrome: Major Causes

� Exogenous (iatrogenic)

� ACTH-dependent:

¬ Pituitary adenoma (Cushing’s diseaseCushing’s diseaseCushing’s diseaseCushing’s disease) 70%

¬ Ectopic ACTH Syndrome 15%

� ACTH-independent

¬ Adrenal adenoma

10%

¬ Adrenal carcinoma 5%

Diagnosis

� 24 hr urine free cortisol

� Overnight dexamethasone suppression test

� Midnight salivary cortisol

� Low dose dexamethasone suppression test

Midnight Salivary Cortisol

Putignano, P. et al. J Clin Endocrinol Metab 2003;88:4153-4157

Salivary cortisol

� Sensitivity: 92%

� Specificity: 95%

� False positives:

¬ Stress

¬ Sleep disturbances

¬ Sample contamination

Raff et al JCEM 83:2681, 1998

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Endogenous causes of Cushing’s Syndrome

ACTH dependent ACTH independent

Additional Work-up

� ACTH level

¬ <5 pg/ml (ACTH-independent)

- Adrenal CT

- Plasma DHEA-S

¬ ACTH normal or high (ACTH-dependent)

- High dose dexamethasone test

- MRI (dynamic sellar imaging)

- Inferior petrosal sinus sampling (IPSS)

MRI of Sella

� 1.5 or 3T magnet

� Coronal and Sagital thin cuts through sella

� T2 coronal images through sella

� Dynamic Imaging

¬ Timed coronal sequences after contrast administration

� Imaging must be reviewed by specialist or neurosurgeon with

experience in evaluating sellar MRI scans

56 yo male with a corticotrophic macroadenoma

Preop MRI Postop MRI

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37 yo female with Cushing’s disease, MRI read as negative

24hr UFC = 85 ug/d (nl < 50ug/d)

54 yo female with Cushing’s Disease

24hr UFC >1000ug/d (nl < 50 ug/d)

Inferior Petrosal Sinus Sampling

Determining source of ACTH

� Simultaneous measurement of blood from the cavernous sinus/inferior petrosal sinus and peripheral

blood

� Positive if central:peripheral ACTH level is >2 at baseline or >3 after CRH stimulation

� Important to review venous anatomy

27 yo female with Cushing’s disease

•MRI negative•IPSS positive,

•Strong left gradient (>10:1)•Symmetrical venous drainage

•Surgical exploration negative•Patient underwent hemihypophysectomy

•Postop Cortisol 1.4 ug/dl•Anterior lobe function preserved

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Cushing’s disease - Therapy

� Transsphenoidal surgery (complete exploration of gland)

¬ Adenomectomy

¬ Hemihypophysectomy

¬ Total hypophysectomy

� Radiosurgery/radiotherapy

� Cortisol synthesis inhibitors:

¬ Ketoconazole

¬ Metyrapone

¬ Mitotane

� Bilateral adrenalectomy

� 1910-1925 Cushing performed 231 transsphenoidal operations with a

mortality of 5.6%

� By 1929 Cushing was almost exclusively using the transfrontal approach

for pituitary surgery

� Transcranial route dominated in North America until 1965

History of transsphenoidal surgery - Cushing’s Contribution

Norman Dott

Rockefeller Fellow, 1923-1924

Neurosurgeon at the Royal Infirmary of Edinburgh

Continued performing TS surgery until 1962

Improved illumination with a modified speculum with lights

(0 mortality in 80 patients)

Gerard Guiot

Neurosurgeon at the Hospital Foch

Performed TS surgery from 1956-1981 (over 1000 cases)

Introduced televised fluoroscopy

Changed the position to semisitting

Combined surgery with postoperative radiation therapy

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Jules Hardy

Worked as a fellow with Guiot

Continued to use fluoroscopy but added preoperative angiography and intraoperative pneumoencephalography

Introduced the use of the operating microscope and developed specialized instruments

1968, he introduced the concept of microadenomas

Transsphenoidal Procedures

� Sublabial (incision under the lip) transsphenoidal

� Transseptal (incision in the nose) transsphenoidal

� Microscopic endonasal transsphenoidal with endoscope assist

� Endoscopic endonasal transsphenoidal

Direct endonasal transsphenoidal approach used since 2000

� Griffith and Veerapen described a direct transnasal approach

to the sphenoid sinus (JNS, Jan, 1987)

� No submucosal septal dissection

� Mucosal incision made along rostrum

� No need for nasal packing

Endonasal transsphenoidal approach

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Second Modification:

Endoscopic Endonasal Transsphenoidal

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Case example:32 yo female with Cushing’s disease and a 6 mm adenoma

Postoperative cortisol: 0.9 ng/ml

Postoperative Management

� Cortisol level obtained the day after surgery

� Patients are maintained on low dose steroids and then monitored by the

endocrinologist afterwards

� Patients cured of their Cushing’s may require 6-12 months of cortisol

replacement

¬ ACTH axis suppressed in gland (6 months)

¬ CRH axis suppressed in hypothalamus (12 months)

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Transsphenoidal Surgery for Cushing’s Disease

Personal Series: 2000-2010

� 113 pts with Cushing’s disease

¬ 26 pts recurrent tumors

- 7 from UCSF

- 19 from outside hospitals

¬ 15 patients with macroadenomas (13%)

Outcomes

� 68 consecutive patients studied

¬ 84% had immediate postoperative cortisol levels <2 ug/dl

¬ 90% required postoperative cortisol replacement therapy >6 months

¬ Microadenomas and prolonged cortisol replacement therapy

correlated with sustained remission/cure

Copyright ©1999 The Endocrine Society

Kunwar, S. et al. J Clin Endocrinol Metab 1999;84:4385-4389

Pediatric Pituitary AdenomasPediatric Pituitary Adenomas

Relationship between age and pathologyRelationship between age and pathology

Preop 1 year postop

7 yo boy with Cushing’s disease

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45 yo male with Cushing’s Disease

Preop 6 months Postop

Preop 6 months Postop

Gamma Knife® surgery

PERFEXION

Outpatient procedure

Submillimeter accuracy

Most conformal therapy

possible

Utilizes 200 to >1000 beams

� Kobayashi et. al. (J Neurosurg, Dec. 2002)

¬ 25 patients with persistent Cushing’s disease

- Mean F/U = 63 months (30-109 months)

- Mean max dose = 49.4 Gy (30-100 Gy)

- Mean margin dose = 28.7 Gy (15-70 Gy)

- Mean no. of isocenters = 3.8 (1-11)

- Mean prescription isodose = 61.5% (50-90%)

- Mean volume = 3.24 cc

¬ 100% tumor volume control

¬ 35% of patients had normalization of hormones (median 18 months)

¬ 85% of patients had improvement of hormone levels

¬ Treatment dose related to effect (improved response with max dose >55 Gy and/or margin

dose >40Gy (p<0.01))

Gamma Knife Radiosurgery - Outcome

Recurrent/Residual Corticotroph Adenoma

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Pre-GKRS 6 months Post-GKRS

Gamma Knife Radiosurgery

28 yo woman with recurrent Cushing’s disease with a Macroadenoma

Combined surgery then radiosurgery treatment

Gamma Knife Radiosurgery

28 yo woman with mulitple recurrent Cushing’s disease with a Macroadenoma

Combined surgery then radiosurgery treatment

Pre-GKRS6 months Post-GKRS –cortisol normal on ketoconazole

Persistent Cushing’s Disease

� Repeat imaging studies

¬ Consider repeat surgery

¬ Gamma knife Radiosurgery

¬ 3-D conformal radiotherapy

� If not tumor can be identified/hypercortisolemia persists

¬ Laparoscopic bilateral adrenalectomy

Nelson’s Syndrome

� Rapid enlargement of a pituitary adenoma following bilateral

adrenalectomy

� Lack of negative feedback from cortisol

¬ Mass effects

¬ Increased production ACTH

¬ Increased production melanocyte stimulating hormone.

- Muscle weakness

- Hyperpigmentation

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Acknowledgements - CCPD

Department of Neurosurgery

Manish Aghi

Gwen Stanhope

Anna Frankfurt

Charles B. Wilson

NeuroEndocrinology

Lewis Blevins

Blake Tyrell

Division of Neuroradiology

William Dillon

Christopher Hess

Division of NeuropathologyAndrew BollenTarik TihanArie Perry

Radiation OncologyPenny SneedMichael McDermott