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