1. Pituitary Incidentalomas
Endocrinology Rounds
Kristin Clemens PGY 5
November 7th, 2012

2. Objectives Epidemiology of pituitary incidentalomas Underlying causes
Outline understanding of natural history
Review recent practice guidelines on pituitary incidentalomas
Illustrative cases for work up and management

3. Case – E.A. 70 year old man HTN, hypercholesterolemia Diovan, Crestor
No family history
Non smoker, rare ETOH, lives independently with wife

4. Acute onset memory impairment – ER
Diagnosis of transient global amnesia
CT to rule out stroke demonstrated 2 x 1.9 x 1.6 cm pituitary macroadenoma
MRI encroachment of left cavernous sinus, touching L optic nerve

5. Pituitary MRI

7. How to assess him at follow-up endocrinology appointment?

9. Pituitary incidentaloma
Previously unsuspected pituitary lesion discovered on an imaging study performed for an unrelated reason
Increasingly common

10. 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%

11. Etiology Rathke cleft cysts Craniopharyngiomas Meningiomas
Pituitary hyperplasia
Metastases
Pituitary adenoma – 10%
Macroadenoma >1cm
Microadenoma <1 cm, most common
Functioning and non-functioning

12. Pituitary Adenomas Variety of subtypes
Data from small observational studies
Buurman, 2006
Series of 3048 autopsy cases examined to detect incidence of subclinical adenomas in postmortem pituitaries

13. 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

14. Size range from 0.1 to 20 mm
Only 3 were macroadenomas
Some with multiple adenomas
Multiple staining techniques

15. 39.5% stained positive for prolactin
31.7% null cell adenoma/oncocytomas
13.8% stained positive for ACTH
7.2% for gonadotropins
1.8% stained positive for GH
0.6% for TSH
3% for multiple hormones
Small percentage unclassified

16. Clinical history Clinical significance?
99 patients with HTN, 65 with diabetes
No symptoms of adenohypophyseal hormone hypersecretion were reported
Rare cases of clinical hypo and hyperthyroidism
No clear correlation between clinical data and adenoma type in this sample

17. Natural History?

18. Small observational cohort studies

19. 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

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

21. MEDLINE, EMBASE, Cochrane from 1966 through 2009
Abstraction of data in duplicate
Event rate per 100 person years and associated 95% confidence interval

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

23. Results 14 publications from 1069 references Small studies
Majority single centre studies
Limited quality
Often >30 % lost to follow up

24. Median follow up of 3.9 years (range 1-15 years)
Frequency of PI/NFPA’s higher in females
Wide age range 5 months to 89 years

25. Among symptomatic patients most common complaint was headache at baseline
Most common pituitary dysfunction at baseline was hypogonadism

26. 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 ( )
Worsening of visual field defects 0.7 ( )
Overall incidence of new endocrine dysfunction 2.4 (0-6.4)
Significant heterogeneity

27. A priori subgroup analysis
Greater event rate of growth in size in macroadenomas (12.5) compared with microadenomas (3.3) and cystic lesions (0.1)

29. Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline
2011
Consensus guided by systematic review of evidence and expert opinion

30. 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

31. Initial evaluation of a patient with a pituitary incidentaloma?

32. Recommendation (+++)
All patients with a pituitary incidentaloma should undergo complete history and physical and evaluation for hormone hypersecretion

33. What hormones to be assessed?
Prolactin
Adenoma, stalk compression
Recommended as hyperprolactinemia treatable medically

34. Growth hormone
Generally recommended as silent growth hormone secretion has been reported
Medical comorbidity

35. ACTH
Variable recommendations
Cushing's with significant morbidity and risk of progression to overt Cushing’s
One small study noted progression to overt Cushing disease in 4/22 or 18% of cases

36. Focused assessment of gonadotropins
High gonadotropins rarely cause clinical symptoms so screening would not necessarily influence therapy
Focused assessment of TSH
Rare for TSH secreting adenomas

37. If hormonal overproduction treat medically or surgically as per guidelines

38. Recommendation (+++)
We recommend that patients with a pituitary incidentaloma with or without symptoms also undergo clinical and laboratory evaluations for hypopituitarism

39. 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%

40. Favoured testing in macroadenomas but variable amongst contributors

41. 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

42. Growth may lead to sight loss
5-15% may have unrecognized visual fields at presentation

43. 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

44. Follow-up testing of the pituitary incidentaloma?

45. 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

46. 2.1.2 (++++)
Visual field testing in those with an incidentaloma that enlarges to abut the chiasm or optic nerves

47. 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

48. Indications for surgical therapy of the pituitary incidentaloma?

49. 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 apoplexy
Hypersecreting tumours other than prolactinomas

50. Recommendation 3.2 (++) Surgery if:
Clinically significant growth of the incidentaloma
Loss of endocrine function
A lesion close to the chiasm with a plan to become pregnant
Unremitting headache

51. Transphenoidal approach favoured

52. Algorithm
No prospective testing of algorithm

53. Although guidelines, variable practice among clinicians
Given prevalence of pituitary adenomas, cost concern

54. Randall et al, 2010
Single institution review of patients with pituitary tumour, adenoma, Cushing disease, acromegaly, prolactinoma
Pituitary tumours that were discovered incidentally were about 15% of sample

56. 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 treatment
Panel 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

57. 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

59. Results most sensitive to patient anxiety and shifts to endocrine panel
Concluded that single PRL may be most cost effective screen for microadenoma

60. Thus….
Some groups suggest only prolactin for hyperfunction and other hormonal work up depending on clinical suspicion
No routine visual field testing
No routine screening for hormone hypofunction

62. Back to E.A
History
No headaches, visual impairment, facial weakness or parasthesias
No overt symptoms of hormone hyperfunction
No symptoms of hypofunction

63. Physical exam
No orthostatic change in vitals
Normal visual fields to confrontation, normal extraocular movements
Clinical euthyroid, no features of acromegaly, Cushing’s, well-androgenized
Clinical suspicion for hormone dysfunction low

64. Investigations Cortisol 498 nmol/L
LH 4.8 IU/L, FSH 12.9 IU/L, total testosterone 14 nmol/L
Prolactin 5 ug/L
TSH 1.57 mIU/L, free T4 15 pmol/L, free T3 4.4 pmol/L
IGF 1 normal

65. Visual fields unreliable with multiple false positives and negatives
Repeat examination normal

66. Follow-up Repeat MRI at 6 months stable Repeat MRI at 1 year stable
Plan to repeat visual fields and assess for hormone hypofunction

67. Case 2 – Z.K. 78 year old man CVA, HTN “Blood pressure pill”
No family history
Non smoker, no alcohol, lives independently with wife

68. Presented to ER with history of headache
CT 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

69. Pituitary MRI

71. Endocrine follow-up Son translator Headaches improved
Denied vision impairment, facial weakness or parasthesia
No symptoms of pituitary hyperfunction
?Cold intolerance – multiple layers of clothing around the house

72. Physical exam
No orthostatic change in vitals, no lightheadedness
Visual fields difficult to assess
No features of Cushing’s or acromegaly, well androgenized
Wearing double layers and hat in summer

73. Investigations AM cortisol 144 nmol/L
LH 1 IU/L, FSH 3.1 IU/L, total testosterone <0.1 nmol/L
TSH 1.14 mIU/L, free T4 9 pmol/L, free T3 3.5 pmol/L
Prolactin 21 ug/L
IGF 1 <15 ug/L

74. What next?

75. Started hydrocortisone 20 mg q am and 10 mg q pm
Levothyroxine 75 micrograms po daily
BMD and consideration of testosterone replacement
Growth hormone replacement?

76. Case Visual field examination unreliable as language barrier
Suggested ongoing MRI’s for follow up

77. Repeat MRI at 6 months stable
Plan for 1 year repeat exam
Low threshold for surgical management

78. Case #3 – R. J.
50 year old lady
Colonic polyps, hypercholesterolemia, thyroid nodule
Previous hysterectomy
Family history of DMII
Previous smoker

79. 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

80. MRI

82. History
Increased shoe size and hand size over last several year
20 lb weight gain
Flushing
Snoring
Voice deepening
No galactorrhea
No symptoms suggestive of hormone insufficiency

83. Physical Exam No orthostatic change in blood pressure
Normal visual fields to confrontation
Several clinical manifestations of acromegaly

84. Investigations ACTH, cortisol normal
LH 2.2 IU/L, FSH 4.7 IU/L, estradiol 164 pmol/L
TSH 0.93 mIU/L, fT4 14 pmol/L, fT3 5.9 pmol/L
Prolactin 40 ug/L
GH 35 ug/L, IGF ug/L

85. Management 75 g OGTT confirmed acromegaly Visual field testing normal
Referral for surgical management

86. Take home messages
With increased imaging, more pituitary incidentalomas
Relatively common endocrinology referral
Pituitary adenomas among other etiologies

87. Clinical guidelines helpful but need to consider individual patient
Detailed history and physical
Screen for hormone hyperfunction – prolactin, IGF 1, others if clinically suspicious
Screen for hormone hypofunction – macroadenomas
Refer for visual field assessment if close to the optic chiasm
Consider medical or surgical management
Long term monitoring for clinical changes

88. References
Buurman H, Saeger W. Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. European Journal of Endocrinology 2006; 154:
King JT et al. Management of incidental pituitary microadenomas: a cost effectiveness analysis. JCEM 1997; 82:
Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline 2011
Randall BR et al. Cost of evaluation of patients with pituitary incidentaloma. Pituitary 2010; 13:

89. Thanks!