Transcript Slide 1

TSH SECRETING TUMORS:
AN UPDATE AND THE
ISRAELI EXPERIENCE
Rosane Abramof Ness
Sapir Medical Center
TSH-Secreting Pituitary Adenomas
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Rare cause of hyperthyroidism
Originate from pituitary thyrotrophs just 2
ectopic case (nasopharynx) reported.
First case documented in 1960 (TSH
measured by bioassay)
Hamilton et al reported the first case of
TSH-oma proved by measuring RIA in 1970.
Epidemiology
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Prevalence: 1/1,000,000
0.5-1% of all pituitary tumors.
336 cases published (7/2004).
Since 1990 the number of reported cases has
tripled.
TSH-omas are equally frequent in men and
women.
Familial cases have been reported only as part of
the multiple neoplasia type 1 syndrome (MEN1)
Pathology
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The majority of TSH-secreting adenomas (75%)
secrete TSH alone, often accompanied by
unbalanced hypersecretion of its alpha-subunit (aGSU)
Mixed adenomas: with concomitant
hypersecretion of other pituitary hormones are
found in 25% of cases. The most frequent are
cosecretion of GH and PRL with its respective
syndromes.
The somatotroph and lactotroph cells share with
thyrotropes common transcription factors such as
Prop-1 and Pit-1.
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Rare cases of mixed TSH/gonadotropin
adenomas
TSH-oma
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Mostly macroadenomas that show invasiveness into the
surrounding structure.
Extrasellar extension in the supra- and/or parasellar area is
present in the majority of cases.
The occurrence of invasive macroadenomas is particularly
high among patients with previous thyroid ablation by
surgery or radioiodine.
Microadenomas < 1 cm reported in less than 15% although
they are increasingly recognized.
1974-1986: 1/11 (9%)
1987-2001: 8/32 (25%)
Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442.
Etiology
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Molecular mechanisms leading to TSH-oma are presently
unknown.
Derive from the clonal expansion of a single initially
transformed cell.
Candidate genes: Ras, gsp,mutation in TRH receptor gene,
dopamine D2 receptor gene- NEGATIVE
Pit-1 mutations: NEGATIVE
Loss of function of antioncogenes: p53 (found in 1 tumor),
MENIN- NEGATIVE
Somatic mutations of thyroid hormone receptor beta may
be responsible for the defect in negative regulation of TSH
secretion in some TSH-omas (few cases and not confirmed
by all studies)
Cell Cultures
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Somatostatin (SRIH): almost all TSH-omas
express a variable number of SRIH receptor.
Highest SRIH-binding site density found in
mixed GH/TSH adenomas.
Dopamine receptors: large heterogeneity of
TSH response to dopamine agonists.
Clinical Findings
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Hyperthyroidism (TSH: N- , FT4 , FT3  )
Neurologic symptoms associated to pressure
effects of the pituitary adenoma (visual field
defects, headaches)
Symptoms due to associated hypersecretion.
Loss of anterior pituitary function
Thyrotoxicosis with
Inappropriately high TSH levels
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Mouse ab interfering with TSH assay
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Central hyperthyroidism:
Pituitary tumor: TSH secreting.
 Resistance to thyroid hormone (RTH)
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Resistance to Thyroid Hormone
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Autosomal dominant disorder characterized by
reduced responsiveness of target tissues to
thyroid hormone due to a mutation in the
thyroid hormone receptor beta.
First reported in 1967.
Variable severity of hormonal resistance in
different tissues.
Differential diagnosis between TSH secreting adenomas (TSH-omas) and
resistance to thyroid hormones (RTH)
(16 TSHomas 64 RTH)
Parameter
TSH-omas
RTH
P
Female/Male ratio
1.3
1.4
NS
Familial cases
0%
84 %
<0.0001
TSH mU/L
3.0 ±0.5
2.3 ±0.3
NS
FT4 pmol/L
38.8 ±4.0
29.9 ±2.4
NS
FT3 pmol/L
14.0 ±1.2
11.3 ±0.9
NS
SHBG nmol/L
117 ±18
61 ±4
<0.0001
Lesions at CT or MRI
100 %
6%
<0.0001
High a-GSU levels
69 %
3%
<0.0001
High a-GSU/TSH m.r.
81 %
2%
<0.0001
Blunted TSH response to TRH test
94 %
2%
<0.0001
100 %
100 %
Abnormal TSH response to T3 suppression
a
b
NS
A Pituitary Tumor in a
Patient with Thyroid
Hormone Resistance: A
Diagnostic Dilemma
Safer et al Thyroid 2001
Localization
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MRI
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Pituitary scintigraphy with radiolabeled
octreotide (octreoscan)
PET : (11)C-Methionine PET
Petrosal sinus sampling (PSS)
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Treatment
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Surgery
Radiation therapy
Somatostatin analogues
Dopamine agonists
Surgical Treatment
First therapeutic approach
 Normalization of TFT’s and
disappearance of tumor in 33-44% of
patients.
 Normalization of TFT’s in 25%
 Unsuccessful in 25%
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Pituitary Radiotherapy
Treatment No
Improved
%
33
No change
%
Surgery
alone
129
Cured
%
33
Irradiation
alone
6
33
50
17
35
42
23
Surgery
57
and
irradiation
34
Criteria of Cure
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Remission from
hyperthyrodism
Disappearance of
neurological signs
Normalization of FT4 and
FT3
Normalization of TSH
undetectable TSH one
week after neurosurgery
Normalization of alphaGSU
Positive T3 suppression
test with undetectable
TSH and no response to
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May be transient
No predictive value
Poor predictive value
Biochemical remission
may be transient. Poor
predictive value
Good prognostic value
Lack of sensitivity (good
sign)
Optimal sensitivity and
specificity. C/I in elderly
of patients with IHD
Medical Therapy
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Somatostatin analogues:
TSH reduction (> 50%)
90%
Alpha-GSU reduction
93%
Thyroid hormone normalization 96%
Goiter size reduction
20%
Tumor mass shrinkage (>20%) 45%
Resistance
4%
Discontinuation of therapy (s/e) 7%
Beck-Peccoz and Persani. Medical Management of Thyrotropin-Secreting
Pituitary Adenomas. Pituitary 2002 : 83-88
Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4)
during short-term (1 to 2 weeks) octreotide therapy in patients with TSHsecreting adenomas
Chanson, P. et. al. Ann Intern Med 1993;119:236-240
Dopamine Agonists
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No long term effect in obtaining
normalization of TFT’s or tumor shrinkage
Effective in cases of TSH-PRL co secretion
TSH-secreting tumors:
The Israeli Experience
Ness-Abramof R, Ishay A, Greenman
Y, Harel G and Shimon I.
Patient’s Characteristics
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No :
9
Sex:
4 M/ 5 F
Age
44 ± 18 years (range: 18-80 y)
Goiter:
5/7 pts
Symptoms of TX: 5/9 (tremor, PAF)
Duration of symptoms before diagnosis:
2.5 y ± 1.7 ( range 0.5- 4 years)
Duration of follow up: 9.4 ± 5.5 years (range 1.5-16 )
Laboratory tests
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TSH
5.0 mU/L ± 1.5 (nl: 0.3-4)
(range: 3-8.6 mU/L)
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FT4
45.7 pmol/L ± 17.5 (nl: 10-20)
(range 24.3 - > 77 pmol/L)
(6/9 pts)
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TT4
228 ± 23.3 nmol/L (nl: 53-143) ( 2/9 pts)
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T3T
5.49 nmol/L ± 3.8 (nl: 1-2.8)
(range 3.1- 13 nmol/L)
(6/9 pts)
Laboratory tests
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Alpha subunits:
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Alpha subunit/ TSH molar ratio:
TRH test:
Normal response
Abnormal response
normal 3/3 patients
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1/5
4/5
(20%)
(80%)
normal
Characteristics of Pituitary Tumors
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Size of adenoma: 25.7 ± 14 mm
Intrasellar
Extrasellar extension
Suprasellar
Cavernous sinus
Sphenoid sinus
(range: 9-41 mm)
1/9
8/9
7/8
3/6
2/6
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Visual Fields: Normal
5 pts (55%)
Abnormal 4 pts (45%)
(bitemporal hemianopsia)
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Hypopituitarism:
2/9 hypogonadism
1/9 on OC
Diabetes insipidus:
0/9
Co secretion of hormone: 2/9 (22%) GH
Primary Medical Therapy
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Pt 1: Lanreotide 30 mg –1 year
Normalization of TFT’s but no tumor shrinkage
(tumor size 16 mm)
Pt 2: Bromocriptine - 1 year
No effect
 Pt 7: Lanreotide 30 mg q3 weeks:
Normalization of TFT, tumor shrinkage (1 year)
10 mm→ 4 mm (60%)
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Surgical Therapy
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8 patients
( 2/8 had 2 surgeries)
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Normalization of TFT’s:
1 pt (transient)
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Abnormal TFT’s :
5 pts
( The patient with a microadenoma didn’t
have surgery)
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Approach:
Transphenoidal:
Transfrontal:
•
7/8
1/8
Hypopituitarism: 3/7
Hypogonadism : 2/7
Adrenal insufficiency : 1/7
Diabetes insipidus: 0/7
(2 patients were treated
perioperatively)
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Residual tumor:
8 pts
Post Operative Therapy
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Radiation therapy: 3 patients
(2 due to residual tumor and 1 tumor regrowth)
Medical therapy (7 pts)
Lanreotide:
3 pts (Somatuline 30mg,
Autogel 60 mg)
Octreotide:
LAR: 3 pts (dose 30 mg)
s.c: 2 pts (dose 100mic/day)
Dopamine agonists: 2 pts (1 s/e, 1 ineffective)
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(1 patients lost to f/u)
Chronic Somatostatin Analogue
Therapy
(post surgical and primary therapy)
Duration of therapy: 4.6 ± 4.3 years
(range: 1.5-14 years)
 Normalization of TFT’s: 8/8 patients
 Tumor shrinkage:
2/8 patients
(10mm→4 mm) (12mm → 9 mm)
 Tumor growth :
0/8 patients
 Central hypothyroidism: 2/8 patients
 Side effects: cholelithiasis (1) abdominal pain:(4)
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Conclusions
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Surgical therapy was not curative.
Somatostatin analogues were highly effective in
normalizing thyroid function tests (100%)
No tumor growth during somatostatin analogue
therapy was observed.
The role of somatostatin analogues as primary
therapy for TSH secreting tumors, particularly
microadenomas needs to be further evaluated.
THANK YOU
The changing spectrum of TSH-secreting pituitary
adenomas: diagnosis and management in 43 patients
Proportion of microadenoma X macroadenoma
1974-1986: 1/11 (9%)
1987-2001: 8/32 (25%)
 Medical therapy with somatostatin analogues was the
first line therapy in 26 patients (19 had surgery)
 TSH levels were reduced by more than 50% in 23/26
patients (normalization of TFT 22/26 – 85%)
 Tumor shrinkage of more than 20% was observed in
5/13 cases (36%).
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Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442.