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Cushings cases

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Cushings cases

  1. 1. Cushing’s Syndrome A few illustrative cases Lewis S. Blevins, Jr., M.D. Director, California Center for Pituitary Disorders at UCSF San Francisco, CA
  2. 2. Case 1 A 36 year old woman Chief complaints of brain fog and an unspecified weight gain Exam showed classical cushingoid features 24h UFC 174 mcg 1mg DST cortisol 14 mcg/dL ACTH 41 pg/mL MRI illustrated 1cm left-sided pituitary macroadenoma
  3. 3. Case 1 A 36 year old woman
  4. 4. Case 1 A 36 year old woman Gross total resection of an ACTH-immunopositive tumor Postoperative serum cortisol 1 mcg/dL Required steroid supplementation for 2 years until recovery of HPA function proved by low-dose ACTH stimulated cortisol 21 mcg/dL Lost 45 pounds in one year Initial recovery 24h UFC 18 mcg Lost to follow-up for 2 years
  5. 5. Case 1 A 36 year old woman Presented for follow-up with complaints of insomnia, weight gain No cushingoid features on examination 24h UFC 41 mcg 1mg DST 14 mcg/dL
  6. 6. Case 1 A 36 year old woman
  7. 7. Cushing’s Disease Surgical Results FirstAuthor n Cure (%) Recurrence (%)Mean f/u (m) Invitti 288 69 17 Bochicchio 668 76 13 46 Blevins 96 85 16 49 Sonino 103 77 26 72 Mampalam 216 79 5 46 Swearingen 161 85 7 24 Nakane 100 92 9 39 Hammer 289 82 9 131
  8. 8. Cushing’s Disease Surgical Results: Macroadenomas Author n Cure (%) Recurrence (%) f/u (m) Blevins 21 67 36 62 Swearingen De Tomassi 17 37 65 68 18 12 104 42
  9. 9. Cushing’s Disease Causes of Surgical Failures • Incomplete or failed tumor resection • Invasive disease • 8% of microadenomas • 62% macroadenomas • “Negative” MRI • 26% failure vs. 13% • “Negative” histopathology • 47% failure vs. 17% Scheithauer et al. J Neurosurg 65:733-744, 1986. Bochicchio et al. JCEM 80:3114-3120,1995.
  10. 10. Cushing’s Disease Causes of Surgical Failures • Incorrect preoperative diagnosis • Syndrome of ectopic ACTH hypersecretion • Underreported, 2-5% • Ectopic pituitary adenoma • Cavernous sinus, suprasellar, stalk adenoma • Corticotroph hyperplasia • ~4% of pituitary-dependent cases of Cushing’s • Pseudo-Cushings • Factitious
  11. 11. Cushing’s Disease Identification of Surgical Failures • Elevated postoperative cortisol levels • Recurrence in 4% of patients with undetectable levels • Relapse in only 24% with normal cortisol levels • 6-12 week postoperative levels better predictors • No glucocorticoid substitution required • Lack of diurnal variation in cortisol secretion Toms et al. JCEM 76:291-294,1993
  12. 12. Cortisol Secretion Health and Disease
  13. 13. Cushing’s Disease Identification of Surgical Failures Estrada et al. JCEM 86:5695-5699,2001
  14. 14. Cushing’s Disease Identification of Surgical Failures • Estrada et al. JCEM 86:5695-5699,2001 3% 50% 65%
  15. 15. Salivary Cortisol Profile
  16. 16. Case 1 A 36 year old woman 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 8 AM Afternoon Late Night Salivary Cortisol Profile Case 1 Normal patient
  17. 17. Case 2 A 46 year old woman Chief complaints of headaches and visual disturbances PMH of a “pituitary tumor” dating back 12 years with no intervention CT suggested empty sella MRI suggested arachnoid cyst prompting the referral
  18. 18. Case 2. A 46 year old woman
  19. 19. Case 2 A 46 year old woman • Empty Sella Syndrome • Primary- incompetent diaphragma sellae • Secondary- some other cause • Apoplexy or necrosis of a macroadenoma • Surgery for a macroadenoma • Lymphocytic hypophysitis • Sheehan’s syndrome • Pseudotumor cerebrii • Others • The findings of an expanded sella and the hypoenhancing lesion suggest she had a macroadenoma of some type that underwent necrosis/apoplexy
  20. 20. Case 2 A 46 year old woman IGF-1 20 ng/mL suggested GH deficiency PRL 7.8 ng/mL suggested no evidence for PRL secretion from the lesion TFT’s normal ACTH 10 pg/mL and cortisol 12 mcg/dL Recommended GH replacement and annual follow up One year later there were no changes then patient lost to follow up
  21. 21. Case 2 A 46 year old woman Presented to PCP 2 years later with complaints of abdominal bloating, weight gain, insomnia, fatigue. CT Abdomen to evaluate abdominal bloating revealed 2.6 cm L-sided adrenal adenoma Was told to schedule follow up to evaluate adrenal mass
  22. 22. Case 2 A 46 year old woman
  23. 23. Case 2 A 46 year old woman • Laboratory investigations showed • Random Cortisol 23 mcg/dL • Random ACTH 73 pg/mL • 1mg DST cortisol 3.7 mcg/dL • Normal PRA and Aldosterone • 24h UFC 110 mcg
  24. 24. Case 2 A 46 year old woman
  25. 25. Case 2 A 46 year old woman Probably had a Silent Corticotroph Adenoma 44% of all ACTH-producing adenomas Immunostain for ACTH or T-pit Can recur with hormonal hyperfunction
  26. 26. Silent corticotrophic adenomas (SCAs) which stain for ACTH but do not cause Cushing’s disease have been reported to be aggressive. Study # of Pts Major Findings Horvath et al, American Jouranl of Pathology (1980) 17 1st paper to define SCAs and subtypes and increased aggressiveness Scheithauer et al, Neurosurgery (2000) 23  Recurrence and aggressiveness K. M. Webb/E. R. Laws et al, Neurosurgery (2003) 27  Recurrence and aggressiveness Bradley et al, Clinical Endocrinology (2003) 28 Similar recurrence compared to HNA but more aggressive once recur Baldeweg et al, British Journal of Neurosurgery (2005) 22 4 patients developed hypercortisolaemia, Yamada et al, Neurosrugery (2007) 26 Increased cavernous sinus invasion Raverot et al, European Journal of Endocrinology (2010) 14 Increased expression of POMC, TPIT in SCAs compared to Cushings Cho et al, Clinical Endocrinology (2010) 28  Recurrence and aggressiveness in younger SCA pts
  27. 27. Methods We performed a comprehensive retrospective analysis of clinical features of SCAs and hormone-negative adenomas (HNAs) resected at our institution 1990-2011, along with transcriptional profiling of SCAs and HNAs archived in our brain tumor bank. Real time RT-PCR was used for transcriptional profiling.
  28. 28. Results – Preoperative Data • Younger (mean age 48 versus 56; P<0.001) • More female (52% versus 36% female; P<0.001). SCA patients (n=88) • were larger than SCAs (2.7 vs. 1.9 cm; P<0.001) • more frequently presented with • visual complaints (96% versus 42%; P<0.001) • apoplexy (10% versus 6%; P<0.01). HNAs (n=97)
  29. 29. Results – Preoperative Data • HNAs and SCAs • had similar (P>0.05) rates of: • hypopituitarism (59%/60%) • headache (32%/24%). • Mean AM preoperative serum cortisol although normal (6-23mg/dL) was higher in SCAs than HNAs (18 versus 10 mg/dL; P<0.05).
  30. 30. Surgical outcomes • Gross total resection rates were 53% (SCAs) and 66% (HNAs) (P>0.05). 0 20 40 60 80 100 SCA HNA Gross Total Resection Gross Total Resection
  31. 31. Pathology • Both groups had comparable MIB-1 labeling (2%; P=0.8) • ACTH staining was classified using the standard SCA subtype designation used when Horvath et al. first described SCAs in 1980: • 1, Those staining +ACTH in >5% of cells were categorized as Type I SCAs (n=45 ) • 2. Those staining +ACTH in <5% of cells were categorized as Type II SCAs (n = 43 )
  32. 32. SCA Type I SCA Type II • Peroxidase staining with anti-ACTH antibody  Hematoxylin and eosin staining
  33. 33. Recurrence • Kaplan-Meier analysis revealed 3 year recurrence rates of • 3% (HNA), • 15% (Type II SCA=weakly ACTH+, n=43) • 46% (Type I SCA=strongly ACTH+, n=45) (P<0.001). • Three Type I SCA patients developed Cushing’s disease an average of 7 years (range 4-9) after SCA diagnosis. •P=0.6 Type I vs Type II •P<0.0001 Type I vs HNA •P<0.0001 Type II vs HNA
  34. 34. Normal Corticotroph Cell
  35. 35. Molecular Analysis • RT-PCR revealed: • ACTH precursor POMC • 600-1200-fold elevated in Cushings and SCAs versus HNAs;  PC1/3, which cleaves POMC into ACTH was  5-fold elevated in Cushings compared to SCAs and HNAs;  ACTH-cleaving PC2, AVP receptor V1bR, and Corticotroph-specific transcription factor Tpit  were 3-36-fold elevated in Type I SCAs compared to Type II SCAs, CDCAs, or HNAs.
  36. 36. Normal Corticotrophic Cell Cushings SCA Type 1 SCA Type II
  37. 37. Summary of Findings: • In one of the largest SCA series to date, we found SCAs to be smaller, but with increased recurrence compared to HNAs. • SCA patients exhibited higher (but normal) cortisol levels compared to HNA patients. • We found elevated POMC in SCAs and Cushings, with inability to cleave POMC distinguishing SCAs from Cushings. Dividing SCAs into those staining strongly versus weakly for ACTH revealed numerous ACTH- related transcriptional upregulations, increased recurrence, and three cases that developed Cushing’s disease in the former. • These findings suggest aggressive surgery, radiosurgery for residual tumor, and close follow-up are warranted for SCAs.
  38. 38. Case 3 A 50 year old woman • Chief complaint of 110 pound weight gain over one year, hair loss and fatigue • Also had newly diagnosed DM, HTN, hyperlipidemia, and DVT • Examination showed classic cushingoid features • 24h UFC 187 mcg • ACTH 90 pg/mL • DST cortisol 15.8 • LNSC 0.32 Despite these findings underwent repeat testing over 2.5 years with similar results.
  39. 39. Case 3. A 50 year old woman
  40. 40. Case 3 A 50 year old woman • Surgical pathology confirmed an ACTH immunopositive tumor • Postoperative MRI showed no residual tumor • Postoperative Laboratory Data: • ACTH 100 pg/mL • Cortisol 27.2 mcg/dL • 24h UFC 93 mcg
  41. 41. Fleseriu M. Neurosurg Clinics. 2012, in press. Aminoglutethimide Osilodrostat (Isturisa)
  42. 42. Ketoconazole • 38 patients, 5 stopped 1st week. • 200-1200 mg (daily) for 23 months (mean). • 45% responders. • All controlled patients responded within 3 months. Castinetti F. Eur J Endocrinol 2008;158(1):91-99.
  43. 43. Pasireoride • Pasireotide is a 2nd- generation somatostatin analog • Binds to sst receptors → inhibits ACTH secretion → ↓ cortisol • High binding affinity for sst1, 2, 3, 5 • Pituitary adenomas causing CD frequently over-express sst5 Figure 1: Pharmacologic action of pasireotide. Source: Novartis Endocrinologic and Metabolic Drugs Advisory Committee Meeting, Nov. 7, 2012
  44. 44. Pasireotide Colao A, et al. NEJM. 2012 Treatment Regimens: pasireotide 600 µg BID (n = 82), 900 µg BID (n = 80) Results: – Proportion with normalization of UFC levels at Month 6 w/out prior dose increase: 600 μg: 15% (95% CI 7, 22), 900 μg: 26% (95% CI 17, 36) – Proportion with mean UFC ≤ ULN or ≥ 50% decrease from baseline at Month 6: 600 μg: 34%, 900 μg: 41% Table 1: Mean change in UFC levels from baseline to Month 12
  45. 45. Osilodrostat (Isturisa) 11-beta hydroxylase inhibitor • 2mg bid to 30 mg bid • 137 patients treated for 24 weeks: half of patients normalized cortisol secretion • 86% maintained normal cortisol levels in an 8 week study; 81% had normal levels after 36 weeks • Side effects include: adrenal insufficiency, long QTc, elevated androgens, hypokalemia and apparent mineralocorticoid excess with edema
  46. 46. Case 3 A 50 year old woman Ketoconazole therapy largely unsuccessful due to escape following each increase in dose up to 1600mg/d. No clinical improvement noted during therapy over 8 months despite UFC ranging 30-55 mcg. Isturisa 2 mg bid lowered 24h UFC to 30 mcg but no clinical improvement Isturisa 3 mg bid lowered 24h UFC to 20 mcg and maintained control over 6 mos during which patient had dramatic improvement in clinical symptoms and signs
  47. 47. 24h UFC What is normal? • I believe that we all have our own “normal range.” • Excretion rates can vary with stress, illness, fluid intake, etc. • Find the “normal” level for your treated patients.

Editor's Notes

  • Go to
  • Need to add the new KM
  • -Vasopressin (VP) regulates pituitary corticotroph function by acting upon plasma membrane G-protein receptors of the V1b subtype (V1bR),
    -CRHR: Important mediator in stress response. corticotropes in anterior pituitary express the CRH receptors and will secrete adrenocorticotropic hormone (ACTH) when stimulated.[3]
    Tpit Activates POMC Transription in Cooperation with Pitx Homeproteins
  • Pasireotide (Signifor)–approved for
    Cushing’s Disease
    in Europe January 2012


    Mifepristone ( Korlym)- FDA approved
    for Cushing’s in pts with diabetes
    February 2012
  • In the largest study to date,33 38 CD patients treated long-term (range: 6-72 months, mean 23 months) with ketoconazole were reviewed; the majority as primary therapy (21 patients), the other 17 patients had previously undergone TSS. Ketoconazole dose was 200-1200 mg daily with 45% of patients considered responders based on the intention to treat analysis. Five patients stopped taking the drug within 1 week due to intolerance. Interestingly, 5 of 15 patients who did not have a pituitary adenoma initially had a visible tumor after 20-30 months of treatment. There was no adrenal insufficiency with the titration used in the study. Responders were identified early in the treatment course (all controlled patients responded within 3 months of the treatment start). Unfortunately, none of the initial biochemical parameters were good predictors of response.
  • Due to their somatostatin receptor binding pattern, octreotide and lanreotide are essentially ineffective for the treatment of Cushing’s disease
    Pasireotide has higher binding affinity for sst receptors frequently over-expressed in pituitary corticotroph tumor cells (ie, sst5) vs. first-generation somatostatin anaolgs (ie, octreotide, lanreotide)

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