ENDOCRINOLOGY ROUNDSKRISTIN CLEMENS PGY 5

NOVEMBER 7 T H , 2012

Pituitary Incidentalomas

Objectives

Epidemiology of pituitary incidentalomasUnderlying causesOutline understanding of natural historyReview recent practice guidelines on

pituitary incidentalomasIllustrative cases for work up and

management

Case – E.A.

70 year old manHTN, hypercholesterolemiaDiovan, CrestorNo family historyNon smoker, rare ETOH, lives independently

with wife

Acute onset memory impairment – ERDiagnosis of transient global amnesiaCT to rule out stroke demonstrated 2 x 1.9 x

1.6 cm pituitary macroadenomaMRI encroachment of left cavernous sinus,

touching L optic nerve

Pituitary MRI

How to assess him at follow-up endocrinology appointment?

Pituitary incidentaloma

Previously unsuspected pituitary lesion discovered on an imaging study performed for an unrelated reason

Increasingly common

Prevalence

Estimated from pituitary adenomas found at autopsy and from imaging inpatients who underwent CT or MRI

Combined autopsy data suggests frequency of 10.6%, distributed equally amongst genders, age range

MRI and CT incidence of 4-38%

Etiology

Rathke cleft cystsCraniopharyngiomasMeningiomasPituitary hyperplasiaMetastases Pituitary adenoma – 10%

Macroadenoma >1cm Microadenoma <1 cm, most common Functioning and non-functioning

Pituitary Adenomas

Variety of subtypesData from small observational studiesBuurman, 2006

Series of 3048 autopsy cases examined to detect incidence of subclinical adenomas in postmortem pituitaries

1991-2004

Buurman et al

Found a total of 334 adenomas out of 3048 cases (10.4%) examined

157 males and 159 females Mean age of 73

Size range from 0.1 to 20 mmOnly 3 were macroadenomasSome with multiple adenomasMultiple staining techniques

39.5% stained positive for prolactin31.7% null cell adenoma/oncocytomas13.8% stained positive for ACTH7.2% for gonadotropins1.8% stained positive for GH0.6% for TSH 3% for multiple hormonesSmall percentage unclassified

Clinical history

Clinical significance?99 patients with HTN, 65 with diabetesNo symptoms of adenohypophyseal hormone

hypersecretion were reportedRare cases of clinical hypo and

hyperthyroidismNo clear correlation between clinical data

and adenoma type in this sample

Natural History?

Small observational cohort studies

Fernandez-Balsells, 2011

Systematic review of longitudinal observational cohort studies that enrolled patients with: Incidentalomas (asymptomatic lesions) Non-functioning pituitary adenomas (mass

effect/hypopituitarism)Followed without any treatment from the

time of detection

Outcomes of interest including development of visual field defects, neurological defects, alteration in pituitary function, pituitary apoplexy

MEDLINE, EMBASE, Cochrane from 1966 through 2009

Abstraction of data in duplicateEvent rate per 100 person years and

associated 95% confidence interval

Subgroup analysis specified a priori according to tumour size at presentation (micro vs. macroadenoma), tumour characteristics (solid vs. cystic lesion), patients age and sex

Results

14 publications from 1069 referencesSmall studiesMajority single centre studiesLimited qualityOften >30 % lost to follow up

Median follow up of 3.9 years (range 1-15 years)

Frequency of PI/NFPA’s higher in femalesWide age range 5 months to 89 years

Among symptomatic patients most common complaint was headache at baseline

Most common pituitary dysfunction at baseline was hypogonadism

Outcomes

Outcomes reported in aggregate as unable to differentiate between incidentalomas and non-functioning pituitary macroadenomas

Event rate per 100 PY’s Tumour growth 5.8 (5-6.5) Pituitary apoplexy 0.2 (0.0-0.2) Worsening of visual field defects 0.7 (0.5-0.8) Overall incidence of new endocrine dysfunction 2.4 (0-

6.4)Significant heterogeneity

A priori subgroup analysisGreater event rate of growth in size in

macroadenomas (12.5) compared with microadenomas (3.3) and cystic lesions (0.1)

Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline

2011Consensus guided by systematic review of

evidence and expert opinion

Evidence developed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to describe strength of recommendations and quality of evidence

+Very low quality++++ High quality

Initial evaluation of a patient with a pituitary incidentaloma?

Recommendation 1.1.1 (+++)

All patients with a pituitary incidentaloma should undergo complete history and physical and evaluation for hormone hypersecretion

What hormones to be assessed?

ProlactinAdenoma, stalk compressionRecommended as hyperprolactinemia

treatable medically

Growth hormoneGenerally recommended as silent growth

hormone secretion has been reportedMedical comorbidity

ACTHVariable recommendations Cushing's with significant morbidity and risk

of progression to overt Cushing’sOne small study noted progression to overt

Cushing disease in 4/22 or 18% of cases

Focused assessment of gonadotropins High gonadotropins rarely cause clinical symptoms so

screening would not necessarily influence therapyFocused assessment of TSH

Rare for TSH secreting adenomas

If hormonal overproduction treat medically or surgically as per guidelines

Recommendation 1.1.2 (+++)

We recommend that patients with a pituitary incidentaloma with or without symptoms also undergo clinical and laboratory evaluations for hypopituitarism

Systematic review Hypopituitarism in 7/66 (10%) and 19/46

(40%) patients in smaller observational studies

Hypogonadism in 30%Hypothyroidism 28%Adrenal insufficiency in 18%Growth hormone insufficiency in 8%

Favoured testing in macroadenomas but variable amongst contributors

Recommendation 1.1.3 (++++)

We recommend that all patients presenting with a pituitary incidentaloma abutting or compressing the optic nerves or chiasm on MRI undergo formal visual field testing

Growth may lead to sight loss5-15% may have unrecognized visual fields at

presentation

Recommendation 1.1.4 (++++)

We recommend that all patients have a MRI scan to better delineate the nature and extent of the incidentaloma

Specific pituitary protocol with fine cuts through the sella

Follow-up testing of the pituitary incidentaloma?

Recommendation 2.1 (++)

Patients with incidentalomas who do not meet criteria for surgical removal, should receive non surgical follow-up with:

2.1.1 MRI scan 6 months after initial scan for macroadenoma or 1 year if microadenoma (++) Repeat MRI every year for macroadenoma MRI every 1-2 years for microadenoma for 3 years and

then less frequently Systematic review on natural history

2.1.2 (++++)Visual field testing in those with an

incidentaloma that enlarges to abut the chiasm or optic nerves

2.1.3 (++)Clinical and biochemical evaluation for

hypopituitarism 6 months after the initial testing and 1 year thereafter in macroadenoma

Follow up to continue for several years

Indications for surgical therapy of the pituitary incidentaloma?

Recommendation 3.1 (++++)

Refer for surgery if:Evidence of VF defect or other visual field

abnormalities Relatively higher value put on prevention of VF

abnormalities than on avoiding the morbidity (hypopituitarism) and cost of the surgery

Lesion abutting or compressing the optic nerves or chiasm on MRI

Pituitary apoplexyHypersecreting tumours other than

prolactinomas

Recommendation 3.2 (++)

Surgery if:Clinically significant growth of the

incidentalomaLoss of endocrine functionA lesion close to the chiasm with a plan to

become pregnantUnremitting headache

Transphenoidal approach favoured

Algorithm

Although guidelines, variable practice among clinicians

Given prevalence of pituitary adenomas, cost concern

Randall et al, 2010

Single institution review of patients with pituitary tumour, adenoma, Cushing disease, acromegaly, prolactinoma

2002-2009Pituitary tumours that were discovered

incidentally were about 15% of sample

King et al, 1997

Cost effective analysis using Markov modeling to compare strategies for management of asymptomatic patient with incidental pituitary microadenoma

Expectant- no management unless symptoms PRL screening with treatmentPanel of hormone secreting tests – PRL, IGF 1,

cortisol after dexamethasone administration with treatment

Follow up MRI screening – 6 and 12 months with hormone testing if size change

Incorporated natural history, pharmacological and surgical treatment outcomes

Direct medical costs - costs of hormone testing, MRI’s, hospitalization for surgery and physician services into analysis

Mortality, morbidity from endocrine and neurological dysfunction, anxiety about knowing about the tumour

Quality of life (QALY)- measure of quality of life that assigns to each year, a weight of quality of life

Results most sensitive to patient anxiety and shifts to endocrine panel

Concluded that single PRL may be most cost effective screen for microadenoma

Thus….

Some groups suggest only prolactin for hyperfunction and other hormonal work up depending on clinical suspicion

No routine visual field testingNo routine screening for hormone

hypofunction

Back to E.A

HistoryNo headaches, visual impairment, facial

weakness or parasthesiasNo overt symptoms of hormone hyperfunctionNo symptoms of hypofunction

Physical examNo orthostatic change in vitalsNormal visual fields to confrontation, normal

extraocular movementsClinical euthyroid, no features of acromegaly,

Cushing’s, well-androgenizedClinical suspicion for hormone dysfunction

low

Investigations

Cortisol 498 nmol/LLH 4.8 IU/L, FSH 12.9 IU/L, total

testosterone 14 nmol/LProlactin 5 ug/LTSH 1.57 mIU/L, free T4 15 pmol/L, free T3

4.4 pmol/LIGF 1 normal

Visual fields unreliable with multiple false positives and negatives

Repeat examination normal

Follow-up

Repeat MRI at 6 months stableRepeat MRI at 1 year stablePlan to repeat visual fields and assess for

hormone hypofunction

Case 2 – Z.K.

78 year old man CVA, HTN“Blood pressure pill”No family historyNon smoker, no alcohol, lives independently

with wife

Presented to ER with history of headacheCT showed 3.1 x 2.8 x 3.8 cm macroadenoma MRI demonstrated suprasellar extension and

extension into the sphenoid sinus and R cavernous sinus

Mild compression of the optic chiasm

Pituitary MRI

Endocrine follow-up

Son translatorHeadaches improvedDenied vision impairment, facial weakness or

parasthesiaNo symptoms of pituitary hyperfunction?Cold intolerance – multiple layers of clothing

around the house

Physical examNo orthostatic change in vitals, no

lightheadednessVisual fields difficult to assessNo features of Cushing’s or acromegaly, well

androgenizedWearing double layers and hat in summer

Investigations

AM cortisol 144 nmol/LLH 1 IU/L, FSH 3.1 IU/L, total testosterone

<0.1 nmol/LTSH 1.14 mIU/L, free T4 9 pmol/L, free T3

3.5 pmol/LProlactin 21 ug/LIGF 1 <15 ug/L

What next?

Started hydrocortisone 20 mg q am and 10 mg q pm

Levothyroxine 75 micrograms po dailyBMD and consideration of testosterone

replacementGrowth hormone replacement?

Case

Visual field examination unreliable as language barrier

Suggested ongoing MRI’s for follow up

Repeat MRI at 6 months stablePlan for 1 year repeat examLow threshold for surgical management

Case #3 – R. J.

50 year old ladyColonic polyps, hypercholesterolemia, thyroid

nodulePrevious hysterectomyFamily history of DMIIPrevious smoker

ENT for feelings of oropharyngeal swelling and shortness of breath

Referred for “incidental” 14 x 21 x 21 mm macroadenoma on sinus CT

MRI mild stalk deviation, suprasellar extension

Encroachment of right optic nerve without compression

MRI

HistoryIncreased shoe size and hand size over last

several year20 lb weight gainFlushingSnoringVoice deepeningNo galactorrheaNo symptoms suggestive of hormone

insufficiency

Physical Exam

No orthostatic change in blood pressureNormal visual fields to confrontationSeveral clinical manifestations of acromegaly

Investigations

ACTH, cortisol normalLH 2.2 IU/L, FSH 4.7 IU/L, estradiol 164

pmol/LTSH 0.93 mIU/L, fT4 14 pmol/L, fT3 5.9

pmol/LProlactin 40 ug/LGH 35 ug/L, IGF 1 711 ug/L

Management

75 g OGTT confirmed acromegalyVisual field testing normalReferral for surgical management

Take home messages

With increased imaging, more pituitary incidentalomas

Relatively common endocrinology referralPituitary adenomas among other etiologies

Clinical guidelines helpful but need to consider individual patient

Detailed history and physicalScreen for hormone hyperfunction – prolactin,

IGF 1, others if clinically suspiciousScreen for hormone hypofunction –

macroadenomasRefer for visual field assessment if close to the

optic chiasmConsider medical or surgical managementLong term monitoring for clinical changes

References

Buurman H, Saeger W. Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. European Journal of Endocrinology 2006; 154: 753-758.

King JT et al. Management of incidental pituitary microadenomas: a cost effectiveness analysis. JCEM 1997; 82: 3625-3632.

Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline 2011

Randall BR et al. Cost of evaluation of patients with pituitary incidentaloma. Pituitary 2010; 13: 383-384.

Thanks!