silent corticotroph adenomas: a clinico-pathologic entity ... · silent corticotroph adenomas: a...
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Silent Silent CorticotrophCorticotroph Adenomas: Adenomas:
A A clinicoclinico-pathologic entity distinct-pathologic entity distinct
from non-functioning tumorsfrom non-functioning tumors
Odelia Cooper, M.D.Odelia Cooper, M.D.
FellowFellow
Department of EndocrinologyDepartment of Endocrinology
Cedars-Sinai Medical CenterCedars-Sinai Medical Center
OutlineOutline
Aims of StudyAims of Study
BackgroundBackground
Preliminary DataPreliminary Data
MethodsMethods
ConclusionsConclusions
HypothesisHypothesis
Silent Silent corticotrophcorticotroph adenomas ( adenomas (SCAsSCAs), a), a
clinical subset of non-functioningclinical subset of non-functioning
adenomas (adenomas (NFAsNFAs), are more aggressive), are more aggressive
than than NFAsNFAs and Cushing and Cushing’’s Diseases Disease
Aims of StudyAims of Study
Determine whether Determine whether SCAsSCAs recur more frequently recur more frequentlyand have higher rate of post-operativeand have higher rate of post-operativehypopituitarismhypopituitarism than Cushing than Cushing’’s Disease ands Disease andNFAsNFAs
To validate potential pre-operative biochemicalTo validate potential pre-operative biochemicalteststests
To determine the efficacy of medical therapies inTo determine the efficacy of medical therapies inSCAsSCAs after resection of the adenoma in order to after resection of the adenoma in order toprevent recurrencesprevent recurrences
To closely follow To closely follow SCAsSCAs for potential for potentialtransformation into Cushingtransformation into Cushing’’s Diseases Disease
BackgroundBackground
Pituitary tumors compose 10% ofPituitary tumors compose 10% ofintracranial tumorsintracranial tumors
Are generally benignAre generally benign
Can be hormone-producing or functionallyCan be hormone-producing or functionallyinactiveinactive
Classified by size: micro Classified by size: micro vsvs macro macro
Subdivided by cell type from which theySubdivided by cell type from which theyarisearise
BackgroundBackground
NFAsNFAs (20% of pituitary tumors) (20% of pituitary tumors)
Null-cell tumorsNull-cell tumors
No pathologic marker of hormone excessNo pathologic marker of hormone excess
Are also Are also gonadotrophgonadotroph adenomas (FSH/LH +) adenomas (FSH/LH +)
CorticotrophCorticotroph adenomas adenomas11 (10% of pituitary (10% of pituitarytumors)tumors)
ACTH +ACTH +
Have elevated Have elevated cortisolcortisol and ACTH and ACTHlevelslevels CushingCushing’’ss Disease Disease
30% are silent (30% are silent (SCAsSCAs) and do not have) and do not havehypercortisolismhypercortisolism
1.Horvath E, et al. 1980. Silent corticotroh adenomas of the human pituitary gland.Am J Pathol. 98:617-38.
BackgroundBackground
SCAsSCAs are clinically silent are clinically silent
Determined to be Determined to be NFAsNFAs pre-operatively pre-operatively
Present due to mass effectsPresent due to mass effects
Often Often macroadenomasmacroadenomas
After resection, are classified as After resection, are classified as SCAsSCAs by bytheir positive staining for ACTHtheir positive staining for ACTH
Followed post-op for recurrences on Followed post-op for recurrences on MRIsMRIsand development of hypopituitarismand development of hypopituitarism22
2.Scheithauer BW, et al. 2000. Clinically silent corticotroph tumors of the pituitary gland. Neurosurg. 47:723-30.
BackgroundBackground
SCAsSCAs are thought to be more aggressive are thought to be more aggressive
than either CD or than either CD or NFAsNFAs
Study of 23 Study of 23 SCAsSCAs: : suprasellarsuprasellar extension, extension,
invasion in 52%, a number with repeatinvasion in 52%, a number with repeat
surgerysurgery22
Study of 28 Study of 28 SCAsSCAs vsvs 60 60 NFAsNFAs——similarsimilar
regrowthregrowth rates rates44
4. Bradley KJ, et al. 2003. Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave moreaggressively than ACTH immunonegative tumors but do not recur more frequently. Clin Endocrinol 58: 59-64.
BackgroundBackground
SCAsSCAs may have 29-57% recurrence rates may have 29-57% recurrence rates2,32,3
Report of an SCA with rapid Report of an SCA with rapid regrowthregrowth of tumor of tumorafter resectionafter resection55
Study on Study on SCAsSCAs found that found that SCAsSCAs may not recur may not recurmore frequently than more frequently than NFAsNFAs but when they did but when they didrecur, they act more aggressivelyrecur, they act more aggressively44
Series of 5 cases of silent Series of 5 cases of silent corticotrophcorticotrophcarcinomas which metastasized widelycarcinomas which metastasized widely66
A report of SCA converting post-op intoA report of SCA converting post-op intoCushingCushing’’s Diseases Disease77
5. Reincke M, et al. 1987. A pituitary adenoma secreting high molecular weight adrenocorticotropin without evidence of
Cushing’s Disease. JCEM. 65:1296-99.6. Roncaroli F, et al. 2003. Silent corticotroph carcinoma of the adenohypophysis: a report of five cases. Am J Surg Path.27:477-86.
7. Sano T, et al. 2002. Pituitary adnoma with “honeycomb Golgi” appearance showing a phenotypic change at recurrencefrom clinically nonfunctioning to typical Cushing’s Disease. 13: 125-30.
BackgroundBackground
Pre-operative diagnosis of Pre-operative diagnosis of SCAsSCAs is not yet is not yet
validatedvalidated
Use of high molecular weight ACTH to diagnoseUse of high molecular weight ACTH to diagnose
SCASCA
One patient with SCA secreted inactive high molecularOne patient with SCA secreted inactive high molecular
weight ACTH with authentic ACTH, possiblyweight ACTH with authentic ACTH, possibly
competing with each other at the receptor andcompeting with each other at the receptor and
preventing Cushingpreventing Cushing’’s manifestationss manifestations88
Another report of SCA patients who have elevatedAnother report of SCA patients who have elevated
ACTH with normal ACTH with normal cortisolcortisol compared to CD with high compared to CD with high
ACTH and cortisolACTH and cortisol33
8. Matsuno et al. 2004. Secretion of high-molecular-weight adrenocorticotrophic hormone from a pituitary adenoma in apatient without Cushing stigmata. J Neurosurg. 101:874-7.
BackgroundBackground
If can make pre-op diagnosis, canIf can make pre-op diagnosis, can
consider medical therapy either asconsider medical therapy either as
alternative to surgery or as adjunctivealternative to surgery or as adjunctive
therapytherapy
Given that Given that SCAsSCAs may have a more may have a more
aggressive course post-op, other therapiesaggressive course post-op, other therapies
could be of benefit in preventingcould be of benefit in preventing
recurrencesrecurrences
BackgroundBackground
Studies in CD show questionable efficacyStudies in CD show questionable efficacyof agents that modulate pituitary ACTHof agents that modulate pituitary ACTHrelease such as release such as cabergolinecabergoline, octreotide, octreotide99
ProliferatorProliferator activating receptor-gamma activating receptor-gamma(PPAR-(PPAR-__) ) ligandsligands ( (egeg rosiglitazonerosiglitazone) may) mayreduce reduce cortisolcortisol levels in CD levels in CD1010
In In NFAsNFAs, , octreotideoctreotide and and cabergolinecabergoline have havelimited efficacy in tumor size reductionlimited efficacy in tumor size reduction1111
No studies yet of use of these agents inNo studies yet of use of these agents intreating treating SCAsSCAs
9. Nieman LK, et al. 2002. Medical therapy of Cushing’s Disease. Pituitary. 5: 77-82.
10.Ambrosi B, et al. 2004. Effects of chronic administration of PPAR-_ receptor ligand rosiglitazone in Cushing’s Disease.Eur J Endo. 151:1-7.
11. Shomali ME, et al. 2002. Medical therapy of gonadotropin-producing and nonfunctioning pituitary adenomas. Pituitary.5: 89-98.
Background SummaryBackground Summary
SCAsSCAs have overall been shown to have have overall been shown to have
more recurrences than more recurrences than NFAsNFAs or CD though or CD though
no prospective trials have yet beenno prospective trials have yet been
designeddesigned
No evidence of pre-op diagnosis in No evidence of pre-op diagnosis in SCAsSCAs
No trials of medical therapy for No trials of medical therapy for SCAsSCAs
either pre-op or post-opeither pre-op or post-op
Preliminary StudiesPreliminary Studies
Preliminary StudiesPreliminary Studies
Looked at pathology database of CedarsLooked at pathology database of Cedars
Pulled out all consecutive Pulled out all consecutive NFAsNFAs from 1994-2004 from 1994-2004
Identified 106 consecutive patientsIdentified 106 consecutive patients
22 of 106 identified as 22 of 106 identified as SCAsSCAs (21%) (21%)
Retrospective cohort study comparing clinical andRetrospective cohort study comparing clinical and
pathological characteristics of pathological characteristics of SCAsSCAs vsvs NFAsNFAs
WilcoxonWilcoxon test for continuous variables test for continuous variables
Fisher exact test for two group comparisonFisher exact test for two group comparison
Pre-op ManifestationsPre-op Manifestations
43%43%38%38%HypopituitarismHypopituitarism
11%11%14%14%HypotensionHypotension
13%13%30%30%ErectileErectile
dysfunctiondysfunction
12%12%18%18%DecreasedDecreased
libidolibido
61%61%64%64%Visual fieldVisual field
deficitsdeficits
37%37%50%50%HeadacheHeadache
NFAsNFAsSCAsSCAsSymptomSymptom
Nonsignificant values
RadiologicRadiologic Characteristics Characteristics
33%33%32%32%Encasing of carotidsEncasing of carotids
56%56%41%41%Cavernous sinusCavernous sinus
extensionextension
58%58%59%59%SuprasellarSuprasellar extension extension
5%5%9%9%Erosion of Erosion of sellasella
76%76%68%68%Chiasm compressionChiasm compression
NFAsNFAsSCAsSCAsMRI findingMRI finding
Nonsignificant values
Postoperative ResultsPostoperative Results
Residual tumor on MRI:Residual tumor on MRI:
38% of 38% of SCAsSCAs vsvs 46% 46% NFAsNFAs
Recurrences:Recurrences:
29% 29% SCAsSCAs vsvs 19% 19% NFAsNFAs (NS) (NS)
Repeat Surgery:Repeat Surgery:
27% of 27% of SCAsSCAs vsvs 30% 30% NFAsNFAs
New onset post-op New onset post-op hypopituitarismhypopituitarism::
52% 52% SCAsSCAs vsvs 27% 27% NFAsNFAs (p<0.04) (p<0.04)
Conclusions of StudyConclusions of Study
Incidence of 21% of Incidence of 21% of SCAsSCAs as subgroup of as subgroup ofNFAsNFAs in Cedars database in Cedars database
See some See some nonsignificantnonsignificant clinical and clinical andradiologicradiologic characteristics characteristics
Significant difference in post-opSignificant difference in post-ophypopituitarismhypopituitarism
Suggests need for closer post-opSuggests need for closer post-opsurveillance and pituitary hormone testingsurveillance and pituitary hormone testing
Further studies to investigate Further studies to investigate SCAsSCAs
Comparison of Comparison of SCAsSCAs to CD to CD
Determine if Determine if SCAsSCAs behave post-op as behave post-op as
typical Cushingtypical Cushing’’s adenomas or as s adenomas or as NFAsNFAs
Will pool from pathology database 22Will pool from pathology database 22
CushingCushing’’s adenomas to match 22 s adenomas to match 22 SCAsSCAs
Assess development of post-op Assess development of post-op hypopithypopit
and recurrences on and recurrences on MRIsMRIs in Cushing in Cushing’’ss
Compare data to Compare data to SCAsSCAs
Pre-op diagnosis of Pre-op diagnosis of SCAsSCAs
Prospective study of Prospective study of SCAsSCAs vsvs Cushing Cushing’’ss
Recruit patients referred to Pituitary CenterRecruit patients referred to Pituitary Center100 100 NFAsNFAs
20 CD20 CD
Will be classified pre-operatively as either Will be classified pre-operatively as either NFAsNFAs or CD or CD
Will have biochemical profile to determine if NFA or CDWill have biochemical profile to determine if NFA or CD
Will perform functional tests on both groupsWill perform functional tests on both groupsCRH and lysine-vasopressin testCRH and lysine-vasopressin test——one study showed SCAone study showed SCApatients had exaggerated ACTH/patients had exaggerated ACTH/cortisolcortisol response response1212
Low dose Low dose dexamethasonedexamethasone study study——to confirm CDto confirm CD
12.Ambrosi B, et al. 1992. The silent corticotropinoma: is clinical diagnosis possible? J Endocrinol Invest. 15:443-52.
Pre-op diagnosis of Pre-op diagnosis of SCAsSCAs
Elevated late night salivaryElevated late night salivarycortisolcortisol
Elevated urinary free Elevated urinary free cortisolcortisol
Unsuppressed AM ACTH levelsUnsuppressed AM ACTH levels
Low dose Low dose dexamethasonedexamethasonesuppression testsuppression test
Measure high molecular weightMeasure high molecular weightACTHACTH
Measure PRL, IGF-Measure PRL, IGF-1,LH,FSH,TSH1,LH,FSH,TSH
Perform CRH and lysine-Perform CRH and lysine-vasopressin testvasopressin test
Normal Normal cortisolcortisol levels levels
Measure bioactive ACTHMeasure bioactive ACTH
Measure high molecular weightMeasure high molecular weightACTHACTH
Measure PRL, IGF-1, LH, FSH,Measure PRL, IGF-1, LH, FSH,TSHTSH
Perform CRH and lysine-Perform CRH and lysine-vasopressin testvasopressin test
Cushing’s Disease Patients NFA patients
Pre-op diagnosisPre-op diagnosis
Patients will then proceed to surgicalPatients will then proceed to surgicalresectionresection
Will review pathology and determine if anyWill review pathology and determine if anyof the of the NFAsNFAs were ACTH+ on staining thus were ACTH+ on staining thusclassifying them as classifying them as SCAsSCAs
Will retroactively evaluate pre-op data toWill retroactively evaluate pre-op data todetermine if determine if SCAsSCAs have a profile unique have a profile uniquefrom from NFAsNFAs or CD or CD
Evaluation of Medical Therapies inEvaluation of Medical Therapies in
SCAsSCAs
Propose that post-operative medical therapy willPropose that post-operative medical therapy willreduce recurrence ratesreduce recurrence rates
Will randomize the Will randomize the SCAsSCAs we recruited from prior we recruited from priorstudy to 4 groups post-op:study to 4 groups post-op:
IrradiationIrradiation
RosiglitazoneRosiglitazone
OctreotideOctreotide
ControlsControls
Follow with serial Follow with serial MRIsMRIs, ACTH levels, and full, ACTH levels, and fullbiochemical profilesbiochemical profiles
Evaluate Evaluate SCAsSCAs for conversion to CD for conversion to CD
Determine if Determine if SCAsSCAs have potential to have potential toconvert to a convert to a hypersecretoryhypersecretory state known state knownas CDas CD
Use SCA patients recruited aboveUse SCA patients recruited above
Follow with biannual Follow with biannual MRIsMRIs
Measure salivary and urinary free Measure salivary and urinary free cortisolcortisollevelslevels
Follow for 5 yearsFollow for 5 years
ConclusionsConclusions
Goal is to characterize nature of Goal is to characterize nature of SCAsSCAs
Determine if Determine if SCAsSCAs possess a biochemical and possess a biochemical andradiologicradiologic profile unique from profile unique from NFAsNFAs and CD and CD
Find a means of pre-op diagnosis of Find a means of pre-op diagnosis of SCAsSCAs
Evaluate medical adjunctive therapies of Evaluate medical adjunctive therapies of SCAsSCAs in inattempt to reduce recurrencesattempt to reduce recurrences
Follow Follow SCAsSCAs for potential conversion to non- for potential conversion to non-silent form, CDsilent form, CD
Will thus determine a new class of pituitaryWill thus determine a new class of pituitaryadenomasadenomas
Thank YouThank You