Challenging Pituitary Cases

Transcription

1 Challenging Pituitary Cases Sue Samson, MD, PhD, FRCPC, FACE Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center Baylor College of Medicine, Houston TX Tom Blevins, MD, FNLA, FACE, ECNU Texas Diabetes and Endocrinology Austin, TX

2 Disclosures Speaker s bureau Lilly, Sanofi, Novo, BI, Amgen Clinical research support Novo, Diasome, Sanofi, Lilly

3 Case of Recurrent Cushings Disease 42 y/o male In 2005 presented with facial swelling and lower extremity edema 24 hr ufc was 853 mcg/24 hrs, ACTH 187 pg/ml and cortisol 44 ug/dl Pituitary MRI -? Fullness on the L Repeat 24 hour UFC was 1610 ug/24 hours and ACTH 23 and cortisol 27.6 mcg/dl 8mg overnight dex suppression-cortisol was 25 mcg/dl and ACTH 25 What next? a. CRH test b. Further imaging studies c. IPSS d. All of the above

4 Case of Recurrent Cushings Disease Chest CT neg, Abdominal CT-adrenal glands hypertrophied Octreoscan-neg CRH test Baseline cortisol 39.8 increased by 76% Baseline ACTH 106 increased by 791% IPSS IPS :Peripheral ACTH ratio 4.6 CRH stim: IPS: Peripheral ratio was 13.0 Left to Right ratio was 3.8 at baseline and 2.8 after CRH Sellar CT showed? Bony erosion of the sella on the L

5 Case of Recurrent Cushings Disease 11/05 TPS, removal of L sided adenoma, cortisol 1.2 ug/dl post op Post op MRI clear 4/07 ufc 317 ug/day and asymptomatic 5/07--Repeat TPS followed by persistent hypercortisolism ++ACTH staining of tissue both surgeries 8/07 stereotactic radiosurgery followed by ketoconazole 8/08- off ketoconazole and cortisols normal 2012-ufc 123 ug/day --restarted ketoconazole LFT elevation Trial of cabergoline --nausea and headache What next?

6 Cushings Disease Transsphenoidal surgery is the primary therapy in most patients, with remission rates of 65 to 90% Relapse occurs in up to 30% of patients.

7 Treatment of Cushing s Syndrome: An Endocrine Society Clinical Practice Guideline Nieman et al, J Clin Endocrinol Metab, August 2015, 100(8): Susmeeta T. Sharma, MBBS, MD; AACE Adrenal Scientific Committee ENDOCRINE PRACTICE Vol 23 No. 6 June 2017

8 Pasireotide Somatostatin analog indicated for the treatment of adult patients with Cushing s disease for whom pituitary surgery is not an option or has not been curative Mifepristone Glucocorticoid receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery

9 Recurrent Cushings Back to our patient 2013-started Pasireotide 0.3mg bid UFC decreased to 12.7 ug/day 12/16 -On 0.5mg bid-no Cushing's sx. Ufc 35 ug/day. Glucose pre-pasireotide was mg/dl and on treatment, mg/dl - fasting 4/17 -fbs was 105 with an A1c of 6.0% Igf-1 was has ranged between 46 and 82 ng/ml on rx ( ng/ml)

10 Pasireotide Binds with high affinity to 4 of the 5 somatostatin receptor subtypes (sst)- particularly high affinity for sst5 Pituitary corticotroph adenomas primarily express sst5 sst2-preferential somatostatin analogs (octreotide and lanreotide)-not effective in treating ACTH dependent hypercortisolism sst expression (%) sst1 sst2 sst % Beta cells % Alpha cells

11 ULN- 145 nmol per 24 hours [52.5 μg per 24 hours]) Double-blind, phase 3 study, 162 adults with Cushing s disease and a UFC of at least 1.5 times ULN to receive subcutaneous pasireotide at a dose of 600 μg (82 patients)or 900 μg (80 patients) twice daily. NEJM 366;10 March 8, 2012

12 Pasireotide-Hyperglycemia and Diabetes 118 of 162 patients (73%) had a hyperglycemia-related adverse event; 9% developed diabetes and 6% of patients discontinued treatment because of a hyperglycemia-related adverse event Increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation and were sustained during the treatment period. At one-month follow-up visits following discontinuation, mean FPG and HbA1c levels decreased but remained above baseline values QT prolongation and biliary sludge/gallstones Colao, et al. NEJM 366;10 March 8, 2012

13 Hyperglycemia Associated With Pasireotide: Results From a Mechanistic Study in Healthy Volunteers (45) Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):

14 Glucose Insulin 45 healthy males randomized to pasireotide -600 (n 19) or -900 (n 19) -sq bid for 7days -OGTT, 3 consecutive days at baseline and treatment end Glucagon GIP GLP-1 Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):

15 Case of Recurrent Cushings Disease Back to our patient What would you do if his fbs was 134mg/dl and A1c was 7.5% after starting pasireotide? A. Stop the med as having diabetes is worse than having Cushing s B. Change to mifepristone C. Suggest dietitian and exercise and start a medication

16 Case of Recurrent Cushings Disease Which med would you start for the hyperglycemia? a. Metformin and then an SGLT-2 if needed b. A TZD since pasireotide causes insulin resistance c. Metformin and then a DPP 4 inhibitor or GLP 1-RA d. Insulin since oral meds have proven to be ineffective in this setting

17 Management of hyperglycemia associated with pasireotide: Healthy volunteer study 1 dose Pasireotide Metformin Baseline 7 days Pasireotide Nateglinide Vildigliptin Liraglutide Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers Breitschaft et al Diabetes Res Clinical Practice 103:

18 Managing hyperglycemia in patients with Cushing s disease treated with pasireotide: medical expert recommendations Colao et al, Pituitary (2014) 17:

19 Recurrent Cushings: Case 2 56 y/o female- Cushing's disease dxed in two TPS surgeries and Petrosal sinus sampling in did not lateralize- MRI-? L sided 3 mm adenoma Repeat TPS in 5/14- adenoma removed. Pre surgery UFC high at 92.0 ug/day and ACTH was 40 ng/l Post op her 24 hour ufc was 54 ug/day 10/14 lab showed a 24 hour ufc of 66.7 mcg/24 hours and an ACTH of 26 ng/l, 11 pm salivary cortisol elevated Declined XRT and was placed on Pasireotide 0.6 mcg bid in late May (h/a with cabergoline) 24 hour ufc of 16.2 in 11/16 and her am cortisol was hour ufc was 18.7 in 3/17 Pre-pasireotide fbs was 98 mg/dl and A1c was 5.8%. Fbs rose to 128 mg/dl (SMBG mg/dl) and A1c to 7.2% after 6 months of pasireotide Didn t tolerate metformin and minimal response to a DPP 4 med. Placed on a GLP-1 RA in 2016 and her 3/17 fbs was 104mg/dl and her A1c was 6.4%.

20 Recurrent Cushings: Case 2 Would mifepristone have been a better choice for her?

21 Mifepristone Progesterone receptor antagonist that has glucocorticoid receptor antagonist (GR-II) activity at higher concentrations More than three times the binding affinity for the glucocorticoid receptor than dexamethasone It does not bind to the mineralocorticoid receptor ACTH and cortisol levels remain unchanged or increase during mifepristone therapy. Hormonal measurements cannot be used for dose titration or to diagnose adrenal insufficiency

22 Mifepristone-Warnings and Precautions Adrenal insufficiency: Monitor for signs and symptoms Discontinuation of mifepristone and high-dose Dex is needed in the event of clinical adrenal insufficiency Hypokalemia: Correct prior and monitor for during treatment Vaginal bleeding and endometrial changes QT interval prolongation: Avoid use with QT intervalprolonging drugs

23 Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing s Syndrome (SEISMIC) 24-wk multicenter, open-label trial after failed multimodality therapy 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT). (43 pituitary source) Mifepristone was administered at doses of mg daily Main Outcome Measures: Change in area under the curve for glucose on 2-h oral glucose test for C-DM Change in diastolic blood pressure from baseline to wk 24 for C-HT Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

24 SEISMIC During treatment, 72% of the 43 patients had at least a 2-fold increase in ACTH, cortisol, or both. Observed early (by d 14), plateaued wk 10 24, and declined to baseline levels 6 wks after discontinuation Late-night salivary cortisol increased 7.92-fold at wk 16, and urinary free cortisol increased 7.70-fold at wk patients had a serum potassium level less than 3.5 meq/liter, but only 3 experienced severe hypokalemia <2.5 meq/liter Mifepristone does not decrease cortisol production, measurement of this hormone should not be performed during treatment Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

25 Significant decreases in plasma and fasting plasma glucose (P 0.03), as measured by OGTT from baseline to wk 24. The OGTT response curves at each visit were statistically different compared with baseline Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

26 Weight Waist Circumference Total Body Fat Truncal Fat Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

27 Mifepristone-safety AEs were reported in 88% of patients during mifepristone treatment, Nausea (48%) fatigue (48%) headache (44%) hypokalemia (34%) arthralgia (30%) vomiting (26%) Peripheral edema (26%) HTN (24%) dizziness (22%) Decreased appetite (20%) endometrial thickening (20%) Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

28 Mifepristone Pituitary MRIs were obtained in 41patients; 17 had visible tumors 10 of which were macroadenomas 24 did not have visible tumors MRIs were stable at wk 10 and 24 in all cases except one. This patient s adenoma increased in size at wk 10, leading to treatment discontinuation. Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):

29 SEISMIC LTE 43 CD patients were enrolled in SEISMIC with 27 continuing into the LTE study Long-term extension (LTE) - a multicenter U.S. studymedian f/u of 11.3 months Fleseriu et al. J Clin Endocrinol Metab, October 2014, 99(10):

30 Recurrent Cushings: Case 3 35 y/o female- Cushings disease diagnosed in Transsphenoidal resection in 2009, 2013 and most recently again in First 2 surgeries in Austin, her most recent surgery UTSW - Dallas. UFC and salivary cortisol in 2017 show persistent Cushing's Radiation is being considered. She takes desmopressin for DI and T4 for hypothyroidism. She has IGT, 6/17 HgA1C - 6.1% and fbs 96-acanthosis nigricans on examon metformin Hx of infertility. Seeing a Reproductive Endocrinologist and diagnosed as having secondary hypogonadism. She is interested in fertility and is currently on an OCP

31 What is the next step? a) Start cabergoline b) Start mifepristone c) Start pasireotide d) Stereotactic radiosurgery e) IPSS and consider another TPS f) Send her to see Dr Samson

32 What is the next step? a) Start cabergoline b) Start mifepristone c) Start pasireotide d) Stereotactic radiosurgery e) IPSS and consider another TPS f) Send her to see Dr Samson

33 Susmeeta T. Sharma, MBBS, MD; AACE Adrenal Scientific Committee ENDOCRINE PRACTICE Vol 23 No. 6 June 2017

34 Susmeeta T. Sharma, MBBS, MD; AACE Adrenal Scientific Committee ENDOCRINE PRACTICE Vol 23 No. 6 June 2017

35 Susmeeta T. Sharma, MBBS, MD; AACE Adrenal Scientific Committee ENDOCRINE PRACTICE Vol 23 No. 6 June 2017

36 Cabergoline as monotherapy for CD Non-Responders Pivonello et al JCEM 94: Escape 33% Long term Responders 40% 0.5 mg twice weekly increased 1 mg/week every month until UFC normalized or a max dose of 7 mg/wk was reached (median was 3.5 mg/week after 3 months) 75% had a short term response with 35% full response (normalized UFC) 40% partial (25% decrease in UFC) 75% of early partial responders became full responders by 12 months 33% of responders escaped after months 40% achieved long term response

37 Challenging Pituitary cases Susan L Samson MD PhD FRCPC FACE Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center Baylor College of Medicine, Houston TX

38 Cushing s: When all else fails 64 yo female Presented Jan 2017 to outside clinic to establish care Had had mild weight gain (went on Weight watchers and lost 10 lbs) Increased BP and started on lisinopril No specific complaints Routine bloodwork Na 145/K 3.1/Glucose 154 mg/dl

39 Cushing s: When all else fails Repeat blood work 4 weeks later Na 145 K+ <2 Glucose 242 mg/dl Cortisol 110 mcg/dl, ACTH 162 pg/ml Started on spironolactone 50 mg, KCL 40 meq twice a day, metformin Referred to Endocrinologist who documented No history of rapid weight gain Muscle weakness and easy bruising Mild facial rounding, mildly increased dorsal cervical and supraclavicular fat pads No abdominal striae Bruise on leg from a fall Bilateral pedal edema, 2+ Normal mood and affect

40 Cushing s: When all else fails Repeat blood work 4 weeks later Na 145/K <2/Glucose 242 mg/dl Cortisol 110 mcg/dl, ACTH 162 pg/ml Started on spironolactone 50 mg, KCL 40 meq twice a day, metformin Referred to Endocrinologist who documented No history of rapid weight gain Muscle weakness and easy bruising Mild facial rounding, mildly increased dorsal cervical and supraclavicular fat pads No abdominal striae Bruise on leg from a fall Bilateral pedal edema, 2+ Normal mood and affect UFC 13000

41 Pituitary MRI Suspected right-sided subtle pituitary microadenoma maximal transverse dimension 4 mm seen only on dynamic

42 Cushing s: When all else fails Referred to the Pituitary Center

43 IPSS

44 IPSS Minutes post-crh ACTH Peripheral pg/ml Right pg/ml Left pg/ml

45 IPSS Minutes post-crh ACTH Peripheral pg/ml Right pg/ml Left pg/ml

46 What next? The search for ectopic sources

47 Chest CT 1 x 1.3 cm nodule is seen in the left lung base 7 mm calcified granuloma is seen in the right lower lobe

48 1.6 cm hypodense lesion in pancreatic tail

49 Abdominal CT

50 Tracer distribution is physiological. Bilateral pleural effusions. Octreotide Scan

51 PET Scan Chest: Within the right upper lobe there is a hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31 Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

52 Work-up interrupted. 4/7 to 4/26/2017 Perforated bowel from diverticulitis Sigmoid colectomy with colostomy 5/2/2017 Readmitted from SNF for shortness of breath Required intubation and ICU care Trach

53 PET Scan Chest: Within the right upper lobe there is a hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31 Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

54 Still looking. FNA by bronchoscopy Small fragments of bronchial epithelium Negative for malignancy Addendum: rare fungal hyphae elements 1 out of 4 media Aspergillus fumigatus

55 1.6 cm hypodense lesion in pancreatic tail

56 Radiation fractionated external beam or stereotactic radiosurgery cure in 50-60% of good candidates but requires years for full effect Cabergoline Targeting ACTH secretion at the level of the adenoma Not FDA approved for this indication A subset of patients with mild-moderate CD Steroidogenesis inhibitors (adrenostatic) Ketoconazole Multiple steps in cortisol synthesis EMA/FDA 2013 black box warning re: liver failure Cushing s is off-label Etomidate Multiple steps in cortisol synthesis ICU monitoring Metyrapone 11-β-hydroxylase inhibitor approved as a diagnostic agent Have to contact the distributer for special allocation Cushing s is off-label Mitotane (adrenolytic) Multiple steps in cortisol synthesis Adrenalectomy risk of Nelson s

57 Cushing s: When all else fails. Ketoconazole 200 mg BID Voriconazole Metyrapone 250 mg q6h Intubation Ketoconazole 200 mg BID Metyrapone 250 mg q6h Ketoconazole Etomidate 3 mg/h Ketoconazole 400 mg BID Metyrapone 500 mg q6h Metyrapone 750 mg q6h Metyrapone 1000 mg q6h

58 CT Abdomen Feb 22, 2017 April 10, 2017

59 Pathology "right adrenal" consists of a 35 gm adrenalectomy measuring 6.6 x 4.5 x 1.5 cm. "left adrenal" consists of a 47 gm adrenalectomy measuring 7 x 4 x 2 cm. adrenal gland to be mottled, red-brown, green-yellow discoloration with no distinct mass seen. Scattered extramedullary hematopoiesis is seen in the adrenal parenchyma. Focal nuclear atypia are seen in the hyperplastic adrenocortical tissue. No definitive mass or malignancy is seen.

60 Cushing s: when all else fails 6/26/2017 Discharged to rehabilitation at SNF Currently on maintenance dose hydrocortisone and fludrocortisone. 08/01/2017 Trach removed Walking/talking

61 Where do we go from here? Could normalization of cortisol help to manifest an elusive ectopic tumor? 7-27% are remain occult after all imaging modalities explored Cortisol effects on SSTR expression? Removal of cortisol feedback on tumor? % octreotide inhibition of CRHstimulated ACTH secretion Tyrrell et al JCEM 40: Lamberts et al Acta Endocrinologica 120: De Bruins et al Mifepristone effects on Tumor somatostatin receptor expression.. JCEM 97:

62 Where do we go from here? 68 Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) approval by the U.S. Food and Drug in 2016 NETSPOT (SSTR Gallium 68 DOTATATE PET/CT imaging) now included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology version 2017 update for the evaluation of neuroendocrine tumors Meta-analysis of 14 studies SSTR PET/CT after Octreotide scanning led to a change in management in 39% of patients Barrio et al J. Nucl. Med. 58(5):

63 68 Gallium-SSTR-PET/CT had 100% sensitivity among covert cases Isidori et al Conventional and Nuclear Medicine Imaging in Ectopic Cushing's Syndrome: A Systematic Review.J Clin Endocrinol Metab. 2015;100(9):

64 Refractory Acromegaly

65 Refractory Acromegaly 53 yo teacher from Colorado Increased ring size (up by 5 sizes)---prior to dx, now stable Increased shoe size 8 >>> 11--prior to dx, now stable Carpal Tunnel Syndrome- stable Skin Tags Hair Loss Snoring and diagnosis of sleep apnea Enlarged tongue and difficulty with speech Loss of menstrual cycles 6 years previous. Knee pain Uncontrolled diabetes on 180 units insulin per day (HbA1C 9%)

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67 53 yo teacher from Colorado Increased ring size (up by 2 sizes)---prior to dx, now stable Increased shoe size 8 >>> 11--prior to dx, now stable Carpal Tunnel Syndrome- stable Skin Tags Hair Loss Snoring and diagnosis of sleep apnea Enlarged tongue and difficulty with speech Loss of menstrual cycles 6 years previous. Knee pain Uncontrolled diabetes on 180 units insulin per day (HbA1C 9%)

68 Very Vascular tumor Pre-op

69 MRI FINDINGS: There is a lobulated, noncystic, diffusion restricted sellar based mass with negligible peripheral enhancement that measures 3.2 cm AP x 2.9 cm transverse x 3.5 cm craniocaudal. The mass extends superiorly to splay and thin the optic chiasm. The mass invades the left cavernous sinus. The mass remodels the floor of the sella turcica, with encroachment into the left greater than right sphenoid sinuses. The mass extends posteriorly to contact the left mammillary body and partially efface the interpeduncular and superior prepontine cisterns. The mass encircles, but does not compress, the left carotid siphon and P1 segment left posterior cerebral artery, which has a fetal origin. The mass partially encircles, but does not compress, the supraclinoid right internal carotid and distal basilar arteries. The native pituitary gland is displaced to the right, lying over the superior margin of the cavernous segment right internal carotid artery. The infundibulum is thinned and draped over the right superolateral margin of the tumor.

70 Dr. Yoshor (NSx) conveyed that there was a lot of involvement of the tumor around vascular structures including a posterior communicating artery which required caution rather than an aggressive resection. The pathology also was unique and with co-staining for GH and PRL and there was neuronal metaplasia.

71 MICROSCOPIC DIAGNOSIS: PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #1): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #3): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA SMALL FRAGMENT OF ADENOHYPOPHYSIS Comment: The tumor cells are positive for growth hormone and prolactin, including the metaplastic neuronal component. Some of the neuronal component is also positive for epithelial markers (Cam 5.2 and pan-cytokeratin). Tumor is negative for GFAP and EMA. Stains for TSH, LH, FSH, p53, and ACTH are negative in tumor. Both neuropil and neurons are strongly positive for neurofilament. MIB-1 labeling index is less than 1%.

72 Post-op 1 month

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75 Cabergoline and Acromegaly: Sandret L et al. JCEM 2011;96: a Meta-analysis IGF-I levels during treatment with somatostatin analogs alone and after cabergoline addition 5 studies 52% achieved normal IGF-I levels The change in IGF-I was related to baseline IGF-I level not to the dose of cabergoline, the duration of treatment, or the baseline prolactin concentration.

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84 1 month 3 years

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86 3 years

87 Pasireotide increases hyperglycemic evens or worsens glycemic control for patients without diabetes/igt/diabetes on oral medications BUT.for insulin dependent patients, decreased insulin requirements over time (down from 180 units to 40 units per day with episodes of hypoglycemia and improved HbA1C). Ref. Range 3/4/ :12 6/3/ :40 9/16/ :44 11/3/ :00 6/7/ :32 HbA1C Latest Ref Range: % 9.0 (H) 8.1 (H) 7.5 (H) 7.9 (H) 7.6 (H)

88 Acknowledgements Daniel Yoshor MD Mas Takashima MD Steve Carpenter MD Sherly Sebastian NP Baylor St. Luke s Medical Center