65 year old female with headaches and nausea. Olesya Krivospitskaya, MD and Jamie Lee Steinmetz, MD (pathology) Endorama 08/08/2013
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1 65 year old female with headaches and nausea Olesya Krivospitskaya, MD and Jamie Lee Steinmetz, MD (pathology) Endorama 08/08/2013
2 HPI: 65 y.o. female presented with a c/o headaches and nausea for 4 months, which she attributed to a side effect of her sleeping pill. Her PCP ordered head MRI, which showed a 23x17 mm mixed solid/cystic mass in the sellar and suprasellar region with a significant supracellar extension, compression to optic chiasm, invasion of the L cavernous sinus and possible invasion of the medial wall of the R cavernous sinus. The pt was referred to neurosurgery
3 MRI:
4 PMH: PMH: DM2 (diagnosed 10 years ago, controlled on metformin and victoza), HTN, hypothyroidism (diagnosed 10 years ago), GERD, remote hx of breast cancer, s/p bilateral mastectomy, hyperlipidemia, depression, insomnia and anxiety Past surgical history: total hysterectomy with bilateral oophorectomy at the age 39, bilateral mastectomy, cholecystectomy, adenectomy. FH: Hypothyroidism in her daughter and sister, DM2 in her sister, mother, father, paternal grandparents, CAD in her father. SH: Retired, no smoking, alcohol or illegal drugs.
5 Medications: Atenolol-chlorthalidone mg/day Atorvastatin 20 mg/day Buspirone 10mg BID Cholecalciferol 2000 IU/day Cyanocobalamin 1000 mg/day Dexlansoprazol 60 mg/day Flaxseed 1000 mg BID Folic acid 400 mcg/day Iron 65mg BID Levothyroxine 50 mcg/day Victoza 1.8 mg/day Metformin 1000 mg BID Niacin 500 mg TID Olmesartan 20 mg/day Paroxetine 20 mg/day Temazepame 30mg PRN for sleep
6 Review of systems: Constitutional: No fevers. No weight changes. + Fatigue. HEENT: No vision changes. Cardiovascular: No chest pain. No palpitations. Respiratory: No dyspnea. No orthopnea. Gastrointestinal: + Nausea. No diarrhea. No constipation. Musculoskeletal: No myalgias. Skin: No rash. No skin changes. No hair loss. Neurologic: No tremor. No weakness. + Headaches. Psychiatric: + Depression. + Anxiety. Endo: No polyuria. No polydypsia.
7 Physical exam: Constitutional: Patient appears well-developed, well-nourished, in no acute distress. HEENT:PERLA. No thyromegaly or nodules palpated. Cardiovascular: Regular rhythm and rate. No murmurs appreciated. Intact distal pulses. Respiratory/Chest: Normal respiratory effort. No wheezes or crackles. Gastrointestinal/Abdomen: Normoactive bowel sounds. Soft, nontender, nondistended. Musculoskeletal/extremities: No peripheral edema. Neurological: AAOx3. Normal deep tendon reflexes. No cranial nerve deficit. Skin: Skin is warm and dry. No acanthosis nigricans noted. BP 135/80, Pulse 84, Temp 36.8 C, Resp 19, Ht cm (5' 6"), Wt kg (156 lb), BMI kg/m2, SpO2 96%.
8 Labs: Ca 9.7 ( mg/dl) Mg 1.7 ( mg/dl) Phos 3.3 ( mg/dl) HA1C 6.4% (per patient report) LFTs: Total Protein 7.0 (6-8.3 g/dl) Albumin 4.6 (3.5-6 g/dl) Total Bilirubin 0.5 (0.1-1 mg/dl) Alk Phos 79 ( U/L) AST 25 (8-37 U/L) ALT 28 (8-35 U/L) TSH 1.10 ( mcu/ml) Free T ( ng/dl) Total T3 56 ( ng/dl) Total T4 6 ( mcg/dl) ACTH 74 pg/dl at 3PM Cortisol 17.3 mcg/dl at 3PM Prolactin ( ng/ml) Growth hormone <0.1 (0-4.2 ng/ml) at 3PM
9 The patient underwent a transnasal/transsphenoidal resection of the tumor
10 Postoperative labs Ref. Range 5/20/ :10 5/30/ :49 5/30/ :53 5/31/ :34 5/31/ :47 5/31/ :00 5/31/ :30 6/1/ :27 ACTH Latest Range: <52 pg/ml 74.0 (H) (H) 58.8 (H) (H) 63.0 (H) 56.6 (H) 60.7 (H) Cortisol No range found Prolactin ( ng/ml)
11 Pathology
12 Normal Pituitary
13 Normal anterior pituitary has a lobular architecture with a mixture of cell types
14 Normal staining for ACTH
15
16
17 IHC for TSH, prolactin, FSH,LH and GH was negative IHC for ACTH was strongly positive
18 Corticotroph adenomas ~15% of all pituitary adenomas 3.5% of all adenomas are clinically silent but demonstrate ACTH staining with IHC Clinically silent adenomas can be composed of basophilic or chromophobic cells and are histologically identical to clinically active adenomas The hormone product produced by the adenoma may be chemically aberrant or secreted intermittently and therefore not result in hypercortisolemia Silent corticotroph adenomas behave aggressively and have a high recurrence rate
19 The patient is undergoing an evaluation at Evanston Hospital The decision is to be made regarding radiation vs stereotactic radiosurgery
20 What is biologically inactive ACTH? What is silent corticotroph adenoma? Do they carry a worse prognosis and higher recurrence rate?
21 POMC processing Talbot JA, Kane JW, White A. Analytical and clinical aspects of adrenocorticotrophin determination. Ann Clin Biochem Sep;40(Pt 5):
22 Radioimmunoassay and chemiluminscent immunoassay two-site immunometric assay relies on two antibodies binding two different epitopes of the ACTH peptide. In general, antibodies have been raised to N and C-terminal regions of ACTH in order to ensure that ACTH 1-39 is detected rather than fragments derived from ACTH, such as amsh and CLIP. Antibodies are radioactively or chemiluminiscently labeled. Specificity is antibody dependent. Have cross-reactivity with ACTH precursors (between 0.4% and 10% for pro-acth and < 0.1% for POMC for the in-house IRMA, other commercially available assay do not provide this information).
23 Limitations of assays: Some assay will report low levels of ACTH when the concentration of ACTH precursors is very high (such as in the ectopic ACTH syndrome, Nelson s syndrome and patients with large invasive pituitary macroadenomas). Other assays will report high levels of ACTH due to cross reactivity with ACTH precursors. Susceptible to,,hook,, effect.
24 Silent corticotroph adenoma (SCA) pituitary tumors with positive immunohistochemical staining for corticotropin (ACTH) but without clinical evidence of excess cortisol The majority of SCAs are macroadenomas upon presentation and secrete mostly biologically inactive, high-molecular-weight ACTH
25 Silent corticotroph adenoma (SCA) subtype 1 -- (basophilic, strongly periodic acid Schiff positive, with strong and diffuse ACTH and b- endorphin immunoreactivity, similar to functional ACTH adenomas) subtype 2 -- (chromophobic, weakly periodic acid Schiff positive with scattered ACTH and b-endorphin immunoreactivity, and secretory granules in a characteristic teardrop shape on ultrastructural examination) Scheithauer BW, Jaap AJ, Horvath E, Kovacs K, Lloyd RV, Meyer FB, Laws ER Jr, Young WF Jr. Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery Sep;47(3):723-9; discussion
26 SCA subtype 1 and 2 Subtype 1 Subtype 2
27 Scheithauer BW, Jaap AJ, Horvath E, Kovacs K, Lloyd RV, Meyer FB, Laws ER Jr, Young WF Jr. Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery Sep;47(3):723-9; discussion
28 Scheithauer BW, Jaap AJ, Horvath E, Kovacs K, Lloyd RV, Meyer FB, Laws ER Jr, Young WF Jr. Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery Sep;47(3):723-9; discussion
29
30 Ioachimescu AG, Eiland L, Chhabra VS, Mastrogianakis GM, Schniederjan MJ, Brat D, Pileggi AV, Oyesiku NM. Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery Aug;71(2): ; discussion 304.
31 Ioachimescu AG, Eiland L, Chhabra VS, Mastrogianakis GM, Schniederjan MJ, Brat D, Pileggi AV, Oyesiku NM. Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery Aug;71(2): ; discussion 304.
32 Ioachimescu AG, Eiland L, Chhabra VS, Mastrogianakis GM, Schniederjan MJ, Brat D, Pileggi AV, Oyesiku NM. Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery Aug;71(2): ; discussion 304.
33 SCA express both corticotroph and gonadotroph transcription factors Cooper O, Ben-Shlomo A, Bonert V, Bannykh S, Mirocha J, Melmed S. Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. Horm Cancer Apr;1(2):80-92.
34 Is clinical diagnosis possible? Some studies suggest exaggerated response to CRH and/or lysinevasopressin and the lack of suppression of ACTH/cortisol secretion to opioid agonists Ambrosi B, Colombo P, Bochicchio D, Bassetti M, Masini B, Faglia G. The silent corticotropinoma: is clinical diagnosis possible? J Endocrinol Invest Jun;15(6):
35 Take home points SCAs are macroadenomas that secrete mostly biologically inactive, high-molecular-weight ACTH Currently used assays for ACTH measurement have limitations (inability to detect ACTH precursors by some assays, cross reactivity with ACTH precursors by other assays,,,hook,, effect) SCA carry slightly higher recurrence rate and shorter overall survival SCA express both corticotroph and gonadotroph transcription factors Some studies suggest that clinical diagnosis could be possible
36 References Talbot JA, Kane JW, White A. Analytical and clinical aspects of adrenocorticotrophin determination. Ann Clin Biochem Sep;40(Pt 5): Scheithauer BW, Jaap AJ, Horvath E, Kovacs K, Lloyd RV, Meyer FB, Laws ER Jr, Young WF Jr. Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery Sep;47(3):723-9; discussion Ioachimescu AG, Eiland L, Chhabra VS, Mastrogianakis GM, Schniederjan MJ, Brat D, Pileggi AV, Oyesiku NM. Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery Aug;71(2): ; discussion 304. Cooper O, Ben-Shlomo A, Bonert V, Bannykh S, Mirocha J, Melmed S. Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. Horm Cancer Apr;1(2): Ambrosi B, Colombo P, Bochicchio D, Bassetti M, Masini B, Faglia G. The silent corticotropinoma: is clinical diagnosis possible? J Endocrinol Invest Jun;15(6):
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