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Surgical Management of Cushing’s Disease: Recurrence After Early Remission

Baha M Arafah, MD

Case Western Reserve University

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Diagnosis and Management of Cushing’s Syndrome

• Continues to be challenging• Can be a humbling experience• Requires integration of all available data and

great attention to details• One can not take short cuts

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ACTH-Secreting Pituitary TumorsManagement

• Primary Treatment of the tumor– Surgery: Best option

– Radiation: effective; slow onset; – Medical therapy of the tumor itself: Not very

effective in most patients; reserved for those poor surgical candidates/ recurrence, large tumors

• Lower glucocorticoid production– Surgical adrenalectomy– Medical therapy:

• Decrease GC synthesis• Block GC action

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ACTH-Secreting Pituitary Adenomas

Assessment of Surgical Adenomectomy Outcome• Immediate Evaluation: Development of ACTH deficiency• Subsequent assessment:

– Clinical and biochemical remission• Long-term management:

– Taper hydrocortisone gradually– Most patients stop hydrocortisone in 6-12 months– Testing after discontinuation of glucocorticoids to confirm NL

HPA function– Subsequent follow up/ testing is necessary– Possible recurrence

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ACTH-Secreting Pituitary Adenomas

• Success of Surgical adenomectomy depends on– Correct diagnosis – Expertise / experience– Tumor size and / or extension

• Assessment of Surgical Outcome– Clinical remission: takes several months– Immediate development of ACTH deficiency

• Is this a reliable indicator? • Evaluation can be confounded by peri-operative GC use

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Peri-Operative Management

• Literature Review• Inconsistent Approach

– Give GC peri-operatively• Change to dexamethasone, measure serum cortisol• CRH test (while on dexamethasone)• Withhold GC at 2, 6 , or 12 weeks and measure serum cortisol

– Withhold GC• Measure serum cortisol• Give GC to those whose serum cortisol levels are “low” • Give GC to patients with symptoms of AI• Is it safe?

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Management of Patients with ACTH-Secreting Pituitary AdenomasOur Peri-operative Management

• No GC are administered before or during surgery• Cortisol & ACTH levels are measured every 4-6 hours post-operatively • Patients are monitored for signs/ symptoms of AI• GC are administered if and when either one of the following happens

• Patient has symptoms• Serum cortisol < 3 mcg/dL

• Advantages of this approach:

• Provides immediate and Long-term assessment of function

• Ability to get reliable peri-operative data that can predict future recurrence

Neurosurg Focus 2015JCEM 2013, 98: 1458-65. JCEM 2018; 103:477-485

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The Ideal Patient

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Peri-operative HPA Function: The Reality

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Peri-operative HPA Function: The Reality

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Peri-operative HPA Function: The Reality

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Nadir Serum Cortisol of ≤ 3 ug/dL

N=66

Nadir Serum Cortisol of ≥ 4 ug/dL

N=13

P Value:

Age 39.8±12.3 39.3±8.5 0.67

Gender: Females: males 46:20 8:5 0.28

Tumor size(cm) 0.79±0.52 1.48 ± 0.72* 0.01

Pre-operative Data

ACTH (ng/L)Cortisol (ug/dL)DHEA (ng/ml)

DHEA-S (ug/dL)

80.2± 66.829.9± 12.37.7± 5.0

151.9± 57.1

89.9± 45.730.6± 6.4

9.0 4.8171.6±39.3

0.930.970.140.11

Pre- and Post-Operative Clinical and Biochemical Characteristicsin 79 Patients with Cushing’s disease stratified according

to their Nadir Postoperative Serum Cortisol Levels

JCEM 2013, 98: 1458-65.JCEM 2018; 103:477-485

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Peri-operative HPA Function: The Reality

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Time to Reach Serum Cortisol of < 3 ug/dL

Mean/ median : 33 hours

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Recurrence of Cushing’s Disease

• Does it happen after initial remission? – Depends how remission was defined

• How often? 10-30 % • Why ?• Can we predict who will have recurrence?

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Clinical Outcome in Patients with Nadir Serum Cortisol of <3 ug/dL

n=66Number of

Patients%

Clinical Remission

66/66 100%

Need for GC 66/66 100%

Recurrence 11/66 17%

Time of Recurrence

34-66 months

JCEM 2013, 98: 1458-65.JCEM 2018; 103:477-485

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JCEM 2013, 98: 1458-65.JCEM 2018; 103:477-485

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Patients Who Had Sustained Remission

(N=55)

Patients with Recurrence

(N=11)

P Value: Sustained Remission VS Recurrence

Age 39.8±12.3 39.3±8.5 0.67

Gender: Females: males 39:16 7:4 0.42

Tumor size(cm) 0.74±0.62 1.18 ± 0.72* 0.02

Pre-operative Data

ACTH (ng/L)Cortisol (ug/dL)DHEA (ng/ml)

DHEA-S (ug/dL)

81.2± 66.830.5± 12.37.9± 5.0

155.9± 58.2

79.9± 38.730.6± 6.4

9.2 4.8175.6±37.3

0.930.970.440.11

Levels at The 36 Post-operative Hours

Cortisol (ug/dL)ACTH (ng/ml)DHEA (ng/ml)

DHEA-S (ug/dL)

2.9± 2.212.1± 5.41.2± 1.1

48.9 ±38.2

3.4± 1.733± 7.13.8± 1.7

143.9± 45.2

0.52<0.0010.005

<0.001

Pre- and Post-Operative Clinical and Biochemical Characteristics in Patients who had a Post-Operative

Nadir Serum Cortisol of ≤ 3 ug/dL

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No Recurrence Recurrence

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No Recurrence Recurrence

P=0.28

JCEM 2013, 98: 1458-65.JCEM 2018; 103:477-485

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JCEM 2013, 98: 1458-65.JCEM 2018; 103:477-485

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What Went Wrong?

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First surgery

Second surgery

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ACTH-Secreting Pituitary AdenomasSummary

1. Avoiding the routine use of glucocorticoids during and immediately after adenomectomy is a safe and valuable approach as it provides important clinical data that can affect immediate management as well as help predict long-term benefit

2. Despite low serum cortisol levels of < 3 ug/dl, plasma ACTH in the immediate peri-op period in patients who had recurrences were not low

3. The most likely explanation for the persistence of ACTH secretion in the peri-op period is the presence of residual tumor

4. Measurements of plasma ACTH & cortisol levels in the immediate post op period are valuable in defining immediate and long-term benefit from adenomectomy

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Thank You