Nonfunctional Pituitary Adenomas Manish K. Aghi, M.D., Ph.D. - - PDF document

▶
nonfunctional pituitary adenomas
SMART_READER_LITE
LIVE PREVIEW

Nonfunctional Pituitary Adenomas Manish K. Aghi, M.D., Ph.D. - - PDF document

Jul 15, 2023 121 likes •370 views

Nonfunctional Pituitary Adenomas Manish K. Aghi, M.D., Ph.D. Professor California Center for Pituitary Disorders Director, Center for Minimally Invasive Skull Base Surgery Department of Neurological Surgery University of California, San

slide-1
SLIDE 1

Page 1 Manish K. Aghi, M.D., Ph.D. Professor California Center for Pituitary Disorders Director, Center for Minimally Invasive Skull Base Surgery Department of Neurological Surgery University of California, San Francisco (UCSF)

Nonfunctional Pituitary Adenomas

Friday, January 24, 2020 2:45 – 3:30 pm

1

Disclosures

None

2

slide-2
SLIDE 2

Page 2

Overview

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

3

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

4

slide-3
SLIDE 3

Page 3

  • Definition – Pituitary adenoma that does not

produce any excessive hormone into the blood

  • Pathologic Subtypes –

Nonfunctional Pituitary Adenomas – Pathologic Subtypes

5

Nonfunctional Pituitary Adenomas – Silent Corticotrophic Adenomas

  • Nonfunctional Adenomas that Stain for ACTH

Source: Neurosurgery 73:8, 2013

6

slide-4
SLIDE 4

Page 4

  • Higher recurrence rate with Type I SCAs

Nonfunctional Pituitary Adenomas – Silent Corticotrophic Adenomas

Source: Neurosurgery 73:8, 2013

7

  • Pituitary adenomas have long been classified as

microadenomas (less than 10 mm in diameter) versus macroadenomas (10 mm or larger in diameter).

  • Recognition that outcomes can be worse for the 6-17%
  • f adenomas that are particularly large has led some to

further define: 1.Large adenomas (30 mm or larger) 2.Giant adenomas (40 mm or larger)

Pituitary Adenomas – Classification by Size

8

slide-5
SLIDE 5

Page 5

  • In 2004, WHO revised classification of pituitary adenomas

included an “atypical” variant with 1. MIB-1>3% 2. excessive p53 immunoreactivity 3. increased mitoses.

Old classification no longer used - Atypical Adenomas

  • In our UCSF series, atypical

adenomas were more invasive but not larger. We also found atypical adenomas to recur more frequently, but conversion from non-atypical to atypical did not

  • ccur.
  • This classification stopped being

used with the WHO 2016 critiera.

Source: Journal of Neurosurgery 128: 1058, 2018

9

What do you with an asymptomatic nonfunctional adenoma?

  • 42 asymptomatic incidentalomas followed for 1 to 14 years. Mean

initial tumor size 18 mm. In 21 patients, the tumor increased by at least 10%, with the increase occurring 8 to 58 months after diagnosis.

  • Symptoms were noted in 10 patients during follow up – 4 of these

had pituitary apoplexy. Twelve patients went to surgery – 10 with symptoms and 2 with asymptomatic enlargement. Symptoms only developed in tumors whose initial size was > 15 mm

Source: J Neurosurgery 104: 884, 2006

10

slide-6
SLIDE 6

Page 6 Changes in incidentoloma size in 236 patients followed

  • ver 2.3 to 8 years in 9 published series 1990-2006

↑ SIZE ↓ SIZE NO CHANGE 19% MICROADENOMAS 10% 6% 84% 42% MACROADENOMAS 20% 11% 69% 39% RATHKE’S CYST 5% 16% 78%

Source: Endocrin Metab Clin N America 37: 151, 2008

What do you with an asymptomatic nonfunctional adenoma?

11

  • 1. Vision loss – mass

effect on the overlying

  • ptic chiasm
  • 2. Hypopituitarism –

mass effect on the surrounding pituitary gland

  • 3. Headache – from mass

effect on the dura

Main symptoms of pituitary tumors

Example - how a pituitary adenoma could cause symptoms

12

slide-7
SLIDE 7

Page 7

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

13 0.0% 10.0% 20.0% 30.0% 40.0% 50.0%

% of patients with visual symptoms

Endocrine- active adenomas Endocrine- inactive adenomas Rathke’s cleft cyst Cranio- pharyngioma Other

Visual symptoms by pituitary pathology

Frequency of visual symptoms by pathology at UCSF

14

slide-8
SLIDE 8

Page 8

Visual symptoms caused by pituitary tumors based on patient anatomy (theory)

  • 1. Chiasm over

tuberculum (prefixed)

  • 3. Chiasm over

dorsum (postfixed)

  • 2. Chiasm over

diaphragm

Bitemporal hemianopsia Contralateral hemianopsia Monocular deficit Tumor visual symptoms % of patients 10% 80% 10%

15

Visual symptoms caused by pituitary tumors (reality)

  • From January 2003 to

July 2012, 967 nonfunctional adenomas resected at UCSF

  • 492 (51%) presented

with visual symptoms

  • Median duration of

vision loss prior to surgery was 6.5 months

Deficit Share of patients Bitemporal hemianopsia 49% Monocular 31% Quandrantopia in

  • ne eye combined

with quadrantopia

  • r hemianopia in

the other eye 20%

Visual deficits observed in UCSF adenoma patient cohort (n=967)

16

slide-9
SLIDE 9

Page 9

Example of monocular deficit from nonfunctional adenoma

  • 48 year old male on coumadin for pacemaker
  • status post transsphenoidal resection of nonfunctional

adenoma at outside hospital

  • referred to us for radiosurgery for residual tumor in left

cavernous sinus.

  • reoperation due to persistent left eye monocular deficit.

17

Rectifying monocular deficits can require slightly more lateral exposure

18

slide-10
SLIDE 10

Page 10

Vision Improvement after Surgery for nonfunctional adenomas

Analysis of postoperative visual improvement after surgery for nonfunctional adenoma patients with preop visual deficits at UCSF 2007-2012:

  • 77% had some postoperative improvement in vision
  • 37% had postoperative return to baseline vision
  • Multivariate analysis revealed increased age and increased

duration of visual symptoms before surgery to decrease chance of return to baseline vision after surgery.

Source: Journal of Neurosurgery 116: 283, 2011

19

6 or fewer months

  • ver 6 months

0% 20% 40% 60%

Delay in Diagnosing Nonfunctional Adenomas Lowers Chance of Surgery Correcting Vision

Percent of patients with postop return to baseline vision

Age at diagnosis Duration

  • f visual

symptoms

  • Elderly patients tend to have a greater delay from onset of visual symptoms to

adenoma diagnosis (over 6 months compared to 2 months in younger patients).

  • Elderly patients often due to not seeking care or being diagnosed with other

conditions (cataracts, retinopathy, glaucoma).

  • Unfortunately elderly patients with prolonged duration of visual symptoms are

unlikely to return to baseline vision after surgery

Source: JNS 116: 283, 2011

Age 20s- 30s Age 40s- 50s Age 60s- 70s

20

slide-11
SLIDE 11

Page 11

20s-30s Caucasian n=6 20s-30s non- Caucasian n=12

40s-50s Caucasian n=10

40s-50s non- Caucasian n=22 60s-70s Caucasian n=12 60s-70s non- Caucasian n=13

Age/Race Group Duration of visual symptoms (months)

0.1 1 10 100

Race and age both increase duration of visual symptoms, reducing postop improvement

Source: Journal of Neurosurgery 116: 283, 2011

21

  • The extreme form of vision loss in

adenoma patients is apoplexy.

  • Apoplexy lowers chances of

postoperative visual improvement (81% in non-apoplexy cases, 53% in apoplexy cases at UCSF 2003-2012).

Apoplexy has less postop visual improvement and associated socioeconomic risk factors

  • Apoplexy patients were more

likely to lack insurance and primary care and in retrospect had symptoms that could have led to the diagnosis of adenoma before apoplexy if they had access to care.

Source: Journal of Neurosurgery 119: 1432, 2013

22

slide-12
SLIDE 12

Page 12

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

23

Hypopituitarism assessment and confirmation

  • f central (pituitary) source

Need to confirm deficiency in downstream hormone and the pituitary hormone to confirm that the deficiency is central (pituitary) rather than at the level of the downstream gland (thyroid, adrenal, etc.) Hypothalamic hormones Downstream

  • rgan

hormones Anterior pituitary hormones

24

slide-13
SLIDE 13

Page 13

Some theorize that differential robustness of cells in the normal pituitary gland leads to a growing adenoma causing endocrine deficits in the following sequence: (1) growth hormone, (2) LH/FSH, (3) thyroid, and (4) cortisol.

Predicting incidence of deficits by axis based

  • n anatomy/susceptibility

Nature Reviews Cancer 4: 285, 2004

25

Hypopituitarism by Axis – Real Incidences

  • Rates of preoperative central hormonal deficits at UCSF 2007-2012 for

1015 cases, 305 nonfunctional adenomas. Every patient had some endocrine evaluation but some patients had incomplete evaluations:

0% 10% 20% 30% 40% 50%

Male reproductive Female reproductive Growth hormone Cortisol Thyroid axis

All cases Nonfunctional adenomas

  • Comparison to Nomikos et al. (Acta Neurochir 146:27, 2004): 721

nonfunctional adenomas with full preop lab panels – 35% adrenocortical, 77% gonadal, 19% thyroid. 26

slide-14
SLIDE 14

Page 14

Variables associated with Preoperative Pituitary Deficits

  • Patients with preoperative endocrine deficit(s)

were

– older (mean age=60 vs. 54 years; P=0.004) – More male (64% male vs. 36% female; P=0.0005), – Had larger NFAs (mean diameter=2.4 cm vs. 2.1 cm; P=0.02)

  • Effect of size on specific axes: size correlated

with male/female hypogonadism but not with low thyroid, GH/IGF-1, or cortisol.

27

Improvement/Normalization of Endocrine Deficits after Nonfunctional Adenoma Surgery

  • Difference between nonfunctional adenomas vs. other sellar tumors:

delayed improvement unique to nonfunctional adenomas

Percentage

  • f patients

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%

Ce ntral Hyp

  • th

yro id (TSH, T 4 , T3) Male Hypogo nadism (FSH, LH, testosterone) Low G rowth Ho rmone (GH, IGF1) Female Hypog

  • nadism (FSH,

LH, estra diol) Ce ntral Hyp

  • adrenalism (ACT H,

Co rti sol) 30% 38% 19% 14% 28% 30% 26% 9% 0% 3% 49% 36% 22% 5% 8%

Improvement at 6 weeks Normalization at 6 weeks Normalization at 6 months

Hormone Axis

Source: Journal of Neurosurgery 124: 588, 2016

28

slide-15
SLIDE 15

Page 15

New Endocrine Deficits after Surgery by axis

0% 10% 20% 30% 40% 50%

Ce ntral Hy po thyroid (TSH, T 4 , T3) Male Hy po gona d ism (FSH, L H, te stosterone) Low Growth Hormone (GH, IGF1) Female Hy po gona d ism (FSH, L H, amenorrhea) Ce ntral Hypo- adrena lism (ACTH, Cortisol)

3% 3% 4% 1% 6%

Percentage

  • f patients

Hormone Axis

  • No variables predicted development of new deficits
  • Comparison to largest previous study (Webb et al.; JCEM

84: 3696, 1999): 56 NFAs – 25% new hypoadrenalism, 16% new reproductive, 14% new GH, 10% new TSH

Source: Journal of Neurosurgery 124: 588, 2016

29 – TSH: No correction if < 0.03 mlU/mL (normal=0.45-4.12) – Testosterone: No correction if < 2.0 ng/dL (normal =250-1100) – Cortisol: No correction if < 1 µg/dL (normal=4-22) – IGF-1: No correction if < 25 µg/dL (normal =34-246)

0.01 0.1 1 10 1 10 100 1000 1 10 100 10 100 1000 TSH (mIU/mL) Testosterone (ng/dL) Cortisol (µg/dL) IGF-1 (µg/dL)

Threshold for Surgical Correction of Pituitary Deficits

30

slide-16
SLIDE 16

Page 16

Multivariate Analysis – Factors Predicting Endocrine Improvement after NFA surgery

  • Male reproductive and thyroid axes were the two axes

most commonly impaired and most likely to get better.

  • For these 2 axes, younger age and less severe deficit

predicted normalization (P<0.05)

  • No variables predicted normalization in other axes:

– Female Reproductive Axis – Cortisol – IGF-1

31

Preoperative and postoperative gland volume

  • Measurements of normal pituitary gland volume reveal that

most patients experience postoperative expansion of gland

Source: Journal of Neurosurgery 124: 588, 2016

32

slide-17
SLIDE 17

Page 17

  • Patients who do not exhibit postoperative endocrine

improvement exhibit lower preoperative gland volume than those who go onto exhibit endocrine improvement (P<0.01).

Preoperative and postoperative gland volume

No endocrine improvement postop Endocrine improvement postop

Gland volume (cm3)

0.2 0.4 0.6 0.8 1

Preop Postop

No preop deficit

Preop deficit

Source: Journal of Neurosurgery 124: 588, 2016

33

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

34

slide-18
SLIDE 18

Page 18

Headaches

  • Preoperative presentation with headache at UCSF

2007-2012:

0% 5% 10% 15% 20% 25% 30% 35%

HA as a Sx HA Chief Complaint HA only

Percent of Patients

Headache Presentation

35

Rates of headaches as a complaint versus sole complaint per pathology

0% 10% 20% 30% 40% 50% 60%

Apoplexy Rathke’s cleft cysts Craniopharyngioma Endocrine (+) Adenoma Endocrine (-) Adenomas Misc.

Preoperative Headache Rates

36

slide-19
SLIDE 19

Page 19

Multivariate Analysis - factors associated with headache in pituitary tumor patients

  • Factors associated with headache as a complaint

– Diagnosis (P=0.01)

  • Most commonly with Rathke’s Cleft Cysts
  • Endocrine-inactive adenomas least common

– Younger Age (P=0.001) – Female Gender (P=0.002) – Recurrent Lesions (P=0.04)

  • Factors not associated with headache as a complaint

– Lesion size – Suprasellar extension – Hypopituitarism

Source: Clin Neurol Neurosurg 132: 16, 2015

37

Headache in pituitary adenoma patients

  • Headache in adenoma patients does not become

more common with increasing size (unlike vision loss and hypopituitarism)

Percent

  • f

patients Symptom

0.0% 20.0% 40.0% 60.0% 80.0% 100.0%

VISION LOSS HYPOPIT HEADACHE

less than 1 cm ≥ 1 cm but < 2 cm ≥ 2 cm but < 3 cm ≥ 3 cm

Source: Clin Neurol Neurosurg 132: 16, 2015

38

slide-20
SLIDE 20

Page 20

  • For all pathologies combined at UCSF 2007-2012, headache

improvement recorded at 6 weeks and 6 months postop

Rates of headache improvement after pituitary surgery for all patients with headache

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0%

headache headache as chief complaint

6 months postop 6 weeks postop

% of patients with headache improvement

  • High independent incidences of headaches and pituitary tumors

in the general population means that failure of headache to improve postop could mean failure to resolve mass effect or headache unrelated to tumor.

39

Multivariate Analysis for Headache Improvement

  • Factors associated with improvement

– Gross total resection (GTR) P=0.04 – Younger Age P=0.03

  • Factors not associated with improvement

– Duration & location of HA – Gender – Pathology – Lesion size

Source: Clin Neurol Neurosurg 132: 16, 2015

40

slide-21
SLIDE 21

Page 21

Mechanism of Headache from Pituitary Tumors – is it sellar pressure?

Two patients with suprasellar Rathke’s cleft cysts and headache Headache better postop Headache not better postop

41

  • A bolt (ICP monitor) placed into the dura can be used to measure

intrasellar pressure, which is elevated in patients with headache

Measuring sellar pressure and correlating with headache

Source: JCEM 85: 1789, 2000

We are working to:

  • confirm that intrasellar pressure is particularly elevated in

patients whose headaches improve with surgery

  • identify imaging biomarkers of sellar pressure so that we

can better predict from MRI whether the headache is being caused by the sellar lesion or is unrelated.

42

slide-22
SLIDE 22

Page 22

  • 1. Introduction to Nonfunctional Pituitary Adenomas
  • 2. Visual Outcomes after Nonfunctional Adenoma Surgery
  • 3. Endocrine Outcomes after Nonfunctional Adenoma

Surgery

  • 4. Headache Outcomes after Nonfunctional Adenoma

Surgery

  • 5. Recurrence after Nonfunctional Adenoma Surgery

43

Nonfunctional adenoma recurrence – role

  • f extent of resection
  • STR worsens

recurrence rate compared to NTR or GTR

  • Postop radiosurgery or

radiation therapy improves PFS but still well behind outcomes seen with NTR alone

  • Postop radiosurgery or

radiation therapy improves PFS potentially more than that seen with GTR alone

Source: Brain Tum Res Treat 4:1, 2016

44

slide-23
SLIDE 23

Page 23

Conclusions

  • Nonfunctional Adenomas include null cell adenomas as well

as silent adenomas staining for hormones.

  • Symptomatic Outcomes

– Vision (absolute indication for surgery by Society guidelines)

  • Return to baseline vision unlikely in patients over age 60 AND if visual symptoms

present longer than 6 months.

– Endocrine (relative indication for surgery by Society guidelines)

  • Thyroid and male reproductive function most commonly affected axes by nonfunctional

adenomas and most likely to improve

  • Thyroid/male reproductive improvement unlikely in older patients, with more severe

deficits, and smaller preoperative gland volume.

– Headache (not mentioned in endocrine society guidelines for NFAs)

  • Less likely to improve in older patients, STR
  • Recurrence

– More likely with silent corticotrophic adenomas and STR so consider radiation for these 45

Contact information

Manish Aghi manish.aghi@ucsf.edu 415-353-2948 for referrals or to discuss cases

46