Podcast Summary: AACE Podcasts – Episode 53

Title: AACE Clinical Case Reports: Histopathologic Differences Between ACTH-Dependent and ACTH-Independent Adrenal Hyperplasia Causing Cushing Syndrome
Date: November 7, 2024
Host: Dr. Sina Jasim (AACE Clinical Case Reports Editor-in-Chief)
Guests:

• Dr. Amir Hamrahian, Endocrinologist and Adrenal Center Director, Johns Hopkins
• Dr. Ezra Barbon, Surgical Pathologist, Johns Hopkins
  Main Theme:
  A deep dive into two clinical cases highlighting the histopathological and diagnostic differences between ACTH-dependent and ACTH-independent adrenal hyperplasia in Cushing syndrome—emphasizing practical diagnosis, pathology, and manage­ment insights for clinicians.

Episode Overview

The episode explores two specific cases of Cushing syndrome—one ACTH-independent, one ACTH-dependent—focusing on their respective pathology findings, diagnostic approaches, and clinical management decisions. The discussion incorporates the latest thinking in nomenclature and highlights real-world patient journeys, challenges, and clinical decision-making.

Key Discussion Points and Insights

1. Guest Introductions and Expertise

• Dr. Hamrahian shares his background in adrenal disorders and how he established the Johns Hopkins Adrenal Center, emphasizing interdisciplinary collaboration (00:32–02:15).
• Dr. Barbon describes his role in surgical pathology and notes the “orphan” status of the adrenal among specialties, explaining his experience across varied organ systems (02:17–03:01).

2. Case Presentations

Case 1: ACTH-Independent Cushing Syndrome

• Patient: 64 years old, bilateral macronodular adrenal disease (larger on the left), initially declined for surgery due to cardiac risk (03:19–05:08).
• Treated with ketoconazole for six years; symptoms persisted and worsened, prompting re-evaluation.
• Ultimately underwent bilateral adrenalectomy with excellent outcomes: 80-pound weight loss and HbA1c drop from 8% to 6%.
• Dr. Hamrahian: "He has lost about 80 pounds since surgery and his A1C has got down from 8% to about 6%. So he has done very well after surgery." (04:34)

Case 2: ACTH-Dependent (Ectopic) Cushing Syndrome

• Patient with neuroendocrine tumor metastases, high cortisol (urine free cortisol >4,000 μg/day, elevated ACTH), weight loss—pointing to a malignant process (05:20–05:48).
• Emphasized need for swift action due to rapid clinical deterioration often seen with ectopic ACTH syndrome.

3. Diagnostic Approach to Cushing Syndrome (05:57–10:34)

• Discussion of stepwise testing: urine free cortisol, late-night salivary cortisol, 1 mg dexamethasone suppression test.
• For mild autonomous cortisol secretion, 1 mg dexamethasone suppression is preferred due to unreliability of other tests in this population.
• ACTH measurement distinguishes between ACTH-dependent/independent causes (less than 15 pg/ml suggests adrenal, above 20–25 pg/ml suggests ACTH-dependent).
• Imaging and stimulation tests (CRH, desmopressin) guide further localization.
• Dr. Hamrahian:
  "So, Cushing syndrome is generally divided to ACTH-dependent and ACTH-independent. Historically, about 70% from pituitary, 20% adrenal, 10% ectopic... There has been more attention nowadays to mild autonomous cortisol secretion." (06:27)

4. Adrenal Vein Sampling for Localization (10:37–13:31)

• Strategy depends on nodule size asymmetry and patient condition.
• Androstenedione and metanephrines help confirm sample adequacy.
• In patients with significant comorbidities, bilateral adrenalectomy might be favored over staged approach.
• Dr. Hamrahian:
  "In the case we discussed, the patient had much larger mass on the left side. However, the surgeon said, 'I have one shot at this patient... just take both adrenal glands out.'" (12:38)

5. Pathology and Histopathologic Differences (14:01–17:53)

Case 1: Nodular Adrenal Cortical Disease

• Bilateral multinodular glands composed of multiple small rounded nodules—formerly called “adrenal cortical hyperplasia.”
• Molecular findings show these are clonal (benign neoplasms with sometimes separate mutations), prompting a shift in terminology from “hyperplasia” to “nodular adrenal cortical disease.”
• Hyperplasia implies a reversible, stimulus-driven process—not accurate for autonomous neoplastic nodules.
• Dr. Barbon:
  "There's been a shift... from 'hyperplasia' to 'nodular adrenal cortical disease' because hyperplasia doesn't reflect the clonal, neoplastic nature." (15:05)

Case 2: True Cortical Hyperplasia

• Adrenal glands thickened homogeneously, without nodularity; a physiologic response to exogenous ACTH from tumor.
• Histology is smooth and diffusely thickened—classic for ACTH-dependent (ectopic) Cushing syndrome.
• Dr. Barbon:
  "This is a rare example of true cortical hyperplasia... It is as smooth as can be, but just too thick... this is exactly normal response to exogenous ACTH." (16:40)

6. Management Decisions: Medical vs. Surgical (17:53–21:20)

• Decision for surgery vs. medical therapy is highly individualized, depending on:
  • Patient's clinical status
  • Side and size asymmetry of adrenal tumors
  • Disease severity (mild vs. overt Cushing)
  • Comorbidities and follow-up reliability
• Surgical intervention is more aggressive and may be life-saving in severe or rapidly progressing cases.
• There are nuanced thresholds for medical management versus surgery, and sometimes observation.
• Dr. Hamrahian:
  "If there is a significant asymmetry in adrenal nodules, argue for surgery on the larger one. For similar sizes and mild secretion, rarely would I consider bilateral adrenalectomy." (18:38)

7. Teaching Points and Clinical Relevance (21:20–23:50)

• Rapid intervention is crucial in ectopic ACTH syndrome with severe symptoms—bilateral adrenalectomy can be life-saving.
• Prolonged medical management in suboptimal surgical candidates may lead to subpar outcomes.
• Even with best practices, risk of adrenal crisis remains; education and careful patient selection are key.
• Dr. Hamrahian:
  "When you have a patient with significantly metastatic ectopic ACTH syndrome, don’t waste too much time; go for bilateral adrenalectomy, it can be life-saving." (21:58)
  "Whatever you do with medical therapy, you will not achieve a state of eu-cortisol for most patients." (23:08)

Notable Quotes and Memorable Moments

• On nomenclature change (Dr. Barbon, 15:05):
  “There's been a shift... from 'hyperplasia' to 'nodular adrenal cortical disease' because hyperplasia doesn't reflect the clonal, neoplastic nature.”

• On urgent intervention (Dr. Hamrahian, 21:58):
  “When you have a patient with significantly metastatic disease with a malignancy and ectopic ACTH syndrome, don’t waste too much time. Go for bilateral adrenalectomy—it can be life-saving.”

• On bilateral adrenalectomy decision (Dr. Hamrahian, 12:38):
  “The surgeon told me, ‘Amir, I have one shot at this patient... just take both adrenal glands out.’”

• On pathology difference (Dr. Barbon, 16:40):
  “This is a rare example of true cortical hyperplasia... completely smooth and just too thick. This is exactly the normal response to exogenous ACTH.”

Timestamps for Key Segments

• 00:32 – Expert Introductions / Background
• 03:19 – Case 1 (ACTH-Independent) Overview
• 05:20 – Case 2 (Ectopic ACTH) Description
• 06:27 – Diagnostic Approach and Test Choices
• 10:37 – Adrenal Vein Sampling: Indications, Technique
• 14:01 – Pathology: Old vs. New Terminology
• 17:53 – Surgery vs. Medical Therapy Decision-Making
• 21:20 – Teaching Points, Urgency in Ectopic Cases
• 23:41 – Final Thoughts and Sign-Off

Final Thoughts

This episode delivers a rich, case-based exploration of Cushing syndrome, integrating up-to-date medical, surgical, and pathologic knowledge, and offering pearls for clinicians managing challenging adrenal cases. The discussion is practical, candid, and clinical, with real-world insights on timing, terminology, and patient safety.

For more in-depth learning or to submit your own case:
Visit AACE Clinical Case Report