TSH SECRETING TUMORS:TSH SECRETING TUMORS:AN UPDATE AND THE AN UPDATE AND THE ISRAELI EXPERIENCEISRAELI EXPERIENCE

Rosane Abramof NessRosane Abramof Ness

Sapir Medical CenterSapir Medical Center

TSH-Secreting Pituitary TSH-Secreting Pituitary AdenomasAdenomas

Rare cause of hyperthyroidism Rare cause of hyperthyroidism Originate from pituitary Originate from pituitary thyrotrophs just 2 ectopic case thyrotrophs just 2 ectopic case (nasopharynx) reported.(nasopharynx) reported.

First case documented in 1960 First case documented in 1960 (TSH measured by bioassay)(TSH measured by bioassay)

Hamilton et al reported the Hamilton et al reported the first case of TSH-oma proved by first case of TSH-oma proved by measuring RIA in 1970.measuring RIA in 1970.

EpidemiologyEpidemiology

Prevalence: 1/1,000,000Prevalence: 1/1,000,000 0.5-1% of all pituitary tumors.0.5-1% of all pituitary tumors. 336 cases published (7/2004).336 cases published (7/2004). Since 1990 the number of reported Since 1990 the number of reported cases has tripled.cases has tripled.

TSH-omas are equally frequent in men TSH-omas are equally frequent in men and women.and women.

Familial cases have been reported Familial cases have been reported only as part of the multiple only as part of the multiple neoplasia type 1 syndrome (MEN1)neoplasia type 1 syndrome (MEN1)

PathologyPathology The majority of TSH-secreting adenomas The majority of TSH-secreting adenomas (75%) secrete TSH alone, often accompanied (75%) secrete TSH alone, often accompanied by unbalanced hypersecretion of its alpha-by unbalanced hypersecretion of its alpha-subunit (a-GSU)subunit (a-GSU)

Mixed adenomas: with concomitant Mixed adenomas: with concomitant hypersecretion of other pituitary hormones hypersecretion of other pituitary hormones are found in 25% of cases. The most are found in 25% of cases. The most frequent are cosecretion of GH and PRL frequent are cosecretion of GH and PRL with its respective syndromes.with its respective syndromes.

The somatotroph and lactotroph cells The somatotroph and lactotroph cells share with thyrotropes common share with thyrotropes common transcription factors such as Prop-1 and transcription factors such as Prop-1 and Pit-1.Pit-1.

Rare cases of mixed TSH/gonadotropin Rare cases of mixed TSH/gonadotropin adenomasadenomas

TSH-omaTSH-oma Mostly macroadenomas that show invasiveness Mostly macroadenomas that show invasiveness into the surrounding structure.into the surrounding structure.

Extrasellar extension in the supra- and/or Extrasellar extension in the supra- and/or parasellar area is present in the majority of parasellar area is present in the majority of cases.cases.

The occurrence of invasive macroadenomas is The occurrence of invasive macroadenomas is particularly high among patients with previous particularly high among patients with previous thyroid ablation by surgery or radioiodine.thyroid ablation by surgery or radioiodine.

Microadenomas < 1 cm reported in less than 15% Microadenomas < 1 cm reported in less than 15% although they are increasingly recognized.although they are increasingly recognized.

1974-1986: 1/11 (9%)1974-1986: 1/11 (9%) 1987-2001: 8/32 (25%)1987-2001: 8/32 (25%)Valdes Socin H et al. European Journal of Endocrinology 2003; Valdes Socin H et al. European Journal of Endocrinology 2003;

148: 433-442.148: 433-442.

EtiologyEtiology Molecular mechanisms leading to TSH-oma are Molecular mechanisms leading to TSH-oma are presently unknown.presently unknown.

Derive from the clonal expansion of a Derive from the clonal expansion of a single initially transformed cell.single initially transformed cell.

Candidate genes: Ras, gsp,mutation in TRH Candidate genes: Ras, gsp,mutation in TRH receptor gene, dopamine D2 receptor gene- receptor gene, dopamine D2 receptor gene- NEGATIVENEGATIVE

Pit-1 mutations: Pit-1 mutations: NEGATIVENEGATIVE Loss of function of antioncogenes: p53 Loss of function of antioncogenes: p53 (found in 1 tumor), MENIN- (found in 1 tumor), MENIN- NEGATIVENEGATIVE

Somatic mutations of thyroid hormone Somatic mutations of thyroid hormone receptor beta may be responsible for the receptor beta may be responsible for the defect in negative regulation of TSH defect in negative regulation of TSH secretion in some TSH-omas (few cases and secretion in some TSH-omas (few cases and not confirmed by all studies)not confirmed by all studies)

Cell CulturesCell Cultures

Somatostatin (SRIH): almost all Somatostatin (SRIH): almost all TSH-omas express a variable TSH-omas express a variable number of SRIH receptor.number of SRIH receptor.

Highest SRIH-binding site Highest SRIH-binding site density found in mixed GH/TSH density found in mixed GH/TSH adenomas.adenomas.

Dopamine receptors: large Dopamine receptors: large heterogeneity of TSH response heterogeneity of TSH response to dopamine agonists.to dopamine agonists.

Clinical FindingsClinical Findings

Hyperthyroidism (TSH: N- Hyperthyroidism (TSH: N- , FT4 , FT4 , , FT3 FT3 ) )

Neurologic symptoms associated to Neurologic symptoms associated to pressure effects of the pituitary pressure effects of the pituitary adenoma (visual field defects, adenoma (visual field defects, headaches)headaches)

Symptoms due to associated Symptoms due to associated hypersecretion.hypersecretion.

Loss of anterior pituitary functionLoss of anterior pituitary function

Thyrotoxicosis with Thyrotoxicosis with Inappropriately high Inappropriately high

TSH levelsTSH levels Mouse ab interfering with TSH Mouse ab interfering with TSH assayassay

Central hyperthyroidismCentral hyperthyroidism: : Pituitary tumor: TSH secreting.Pituitary tumor: TSH secreting. Resistance to thyroid hormone Resistance to thyroid hormone (RTH)(RTH)

Resistance to Thyroid Resistance to Thyroid HormoneHormone

Autosomal dominant disorder Autosomal dominant disorder characterized by reduced characterized by reduced responsiveness of target tissues responsiveness of target tissues to thyroid hormone due to a to thyroid hormone due to a mutation in the thyroid hormone mutation in the thyroid hormone receptor beta.receptor beta.

First reported in 1967.First reported in 1967. Variable severity of hormonal Variable severity of hormonal resistance in different tissues. 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 -GSU levels  69 %  3 %  <0.0001

High -GSU/TSH m.r.  81 %  2 %  <0.0001

Blunted TSH response to TRH test  94 %  2 %  <0.0001

Abnormal TSH response to T3 suppression a 100 % 100 % b  NS

Werner & Ingbar/s The Thyroid (eighth Edition) p560

A Pituitary Tumor A Pituitary Tumor in a Patient with in a Patient with Thyroid Hormone Thyroid Hormone Resistance: A Resistance: A

Diagnostic DilemmaDiagnostic DilemmaSafer et al Thyroid 2001Safer et al Thyroid 2001

LocalizationLocalization

MRIMRI Pituitary scintigraphy with Pituitary scintigraphy with radiolabeled octreotide radiolabeled octreotide (octreoscan)(octreoscan)

PET : (11)C-Methionine PETPET : (11)C-Methionine PET Petrosal sinus sampling (PSS)Petrosal sinus sampling (PSS)

TreatmentTreatment

SurgerySurgery Radiation therapyRadiation therapy Somatostatin analogues Somatostatin analogues Dopamine agonistsDopamine agonists

Surgical TreatmentSurgical Treatment

First therapeutic approach First therapeutic approach Normalization of TFT’s and Normalization of TFT’s and disappearance of tumor in disappearance of tumor in 33-44% of patients.33-44% of patients.

Normalization of TFT’s in Normalization of TFT’s in 25% 25%

Unsuccessful in 25%Unsuccessful in 25%

Pituitary RadiotherapyPituitary Radiotherapy

TreatmenTreatmentt

NoNo CuredCured

%%ImprovedImproved

%%

No No changechange

%%

Surgery Surgery alonealone

129129 3333 3333 3434

IrradiatiIrradiation aloneon alone

66 3333 5050 1717

Surgery Surgery and and irradiatirradiationion

5757 3535 4242 2323

Criteria of CureCriteria of Cure Remission from Remission from hyperthyrodismhyperthyrodism

Disappearance of Disappearance of neurological signsneurological signs

Normalization of FT4 Normalization of FT4 and FT3and FT3

Normalization of TSHNormalization of TSH undetectable TSH one undetectable TSH one week after neurosurgeryweek after neurosurgery

Normalization of alpha-Normalization of alpha-GSUGSU

Positive T3 suppression Positive T3 suppression test with undetectable test with undetectable TSH and no response to TSH and no response to TRHTRH

May be transientMay be transient No predictive valueNo predictive value Poor predictive valuePoor predictive value

Biochemical remission Biochemical remission may be transient. Poor may be transient. Poor predictive valuepredictive value

Good prognostic valueGood prognostic value

Lack of sensitivity Lack of sensitivity (good sign)(good sign)

Optimal sensitivity and Optimal sensitivity and specificity. C/I in specificity. C/I in elderly of patients with elderly of patients with IHDIHD

Medical TherapyMedical Therapy Somatostatin analoguesSomatostatin analogues::TSH reduction (> 50%) 90%TSH reduction (> 50%) 90%Alpha-GSU reduction 93%Alpha-GSU reduction 93%Thyroid hormone normalization 96% Thyroid hormone normalization 96% Goiter size reduction Goiter size reduction 20%20%

Tumor mass shrinkage (>20%) 45%Tumor mass shrinkage (>20%) 45%Resistance Resistance 4% 4%

Discontinuation of therapy (s/e) 7% Discontinuation of therapy (s/e) 7% Beck-Peccoz and Persani. Medical Management of Thyrotropin-Beck-Peccoz and Persani. Medical Management of Thyrotropin-

Secreting Pituitary Adenomas. Pituitary 2002 : 83-88Secreting Pituitary Adenomas. Pituitary 2002 : 83-88

Chanson, P. et. al. Ann Intern Med 1993;119:236-240

Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) during short-term (1 to 2 weeks) octreotide therapy in patients with TSH-

secreting adenomas

Dopamine AgonistsDopamine Agonists

No long term effect in No long term effect in obtaining normalization of obtaining normalization of TFT’s or tumor shrinkageTFT’s or tumor shrinkage

Effective in cases of TSH-PRL Effective in cases of TSH-PRL co secretionco secretion

TSH-secreting TSH-secreting tumors:tumors:

The Israeli The Israeli ExperienceExperience

Ness-Abramof R, Ishay A, Ness-Abramof R, Ishay A, Greenman Y, Harel G and Greenman Y, Harel G and

Shimon I.Shimon I.

Patient’s Patient’s CharacteristicsCharacteristics

No : 9No : 9 SexSex: 4 M/ 5 F: 4 M/ 5 F AgeAge 44 ± 18 years (range: 18-80 y) 44 ± 18 years (range: 18-80 y) Goiter: 5/7 ptsGoiter: 5/7 pts Symptoms of TXSymptoms of TX: 5/9 (tremor, PAF): 5/9 (tremor, PAF) Duration of symptoms before diagnosisDuration of symptoms before diagnosis:: 2.5 y ± 1.7 ( range 2.5 y ± 1.7 ( range 0.5- 4 years)0.5- 4 years)

Duration of follow up: 9.4 Duration of follow up: 9.4 ± 5.5 years ± 5.5 years (range 1.5-16 )(range 1.5-16 )

Laboratory testsLaboratory tests TSH 5.0 mU/L ± 1.5 (nl: 0.3-4)TSH 5.0 mU/L ± 1.5 (nl: 0.3-4) (range: 3-8.6 mU/L)(range: 3-8.6 mU/L)

FT4 45.7 pmol/L ± 17.5 (nl: 10-20)FT4 45.7 pmol/L ± 17.5 (nl: 10-20) (range 24.3 - > 77 pmol/L) (range 24.3 - > 77 pmol/L) (6/9 pts) (6/9 pts)

TT4 228 ± 23.3 nmol/LTT4 228 ± 23.3 nmol/L (nl: 53-143)(nl: 53-143) ( 2/9 pts) ( 2/9 pts)

T3T 5.49 nmol/L ± 3.8 (nl: 1-2.8)T3T 5.49 nmol/L ± 3.8 (nl: 1-2.8) (range 3.1- 13 nmol/L) (range 3.1- 13 nmol/L) (6/9 pts) (6/9 pts)

Laboratory testsLaboratory tests

Alpha subunitsAlpha subunits: normal 3/3 : normal 3/3 patientspatients

Alpha subunit/ TSH molar ratioAlpha subunit/ TSH molar ratio: : normalnormal

TRH testTRH test: :

Normal response 1/5 Normal response 1/5 (20%)(20%)

Abnormal response 4/5 (80%)Abnormal response 4/5 (80%)

Characteristics of Characteristics of Pituitary TumorsPituitary Tumors

Size of adenomaSize of adenoma: 25.7 ± 14 mm: 25.7 ± 14 mm

(range: 9-41 mm(range: 9-41 mm))

IntrasellarIntrasellar 1/91/9

Extrasellar extensionExtrasellar extension 8/9 8/9

Suprasellar 7/8 Suprasellar 7/8

Cavernous sinus 3/6 Cavernous sinus 3/6

Sphenoid sinusSphenoid sinus 2/62/6

Visual FieldsVisual Fields: Normal 5 pts (55%): Normal 5 pts (55%)

Abnormal 4 pts Abnormal 4 pts (45%) (45%)

(bitemporal (bitemporal hemianopsia)hemianopsia)

HypopituitarismHypopituitarism: 2/9 hypogonadism: 2/9 hypogonadism

1/9 1/9 on OC on OC

Diabetes insipidusDiabetes insipidus: : 0/9 0/9 Co secretion of hormoneCo secretion of hormone: 2/9 (22%) GH: 2/9 (22%) GH

Primary Medical TherapyPrimary Medical Therapy

Pt 1: Lanreotide 30 mg –1 year Pt 1: Lanreotide 30 mg –1 year Normalization of TFT’s but no tumor shrinkageNormalization of TFT’s but no tumor shrinkage

(tumor size 16 mm)(tumor size 16 mm)

Pt 2: Bromocriptine - 1 yearPt 2: Bromocriptine - 1 year

No effectNo effect Pt 7: Lanreotide 30 mg q3 weeks: Pt 7: Lanreotide 30 mg q3 weeks:

Normalization of TFT, tumor Normalization of TFT, tumor shrinkage (1 year)shrinkage (1 year)

10 mm→ 4 mm (60%)10 mm→ 4 mm (60%)

Surgical TherapySurgical Therapy 8 patients8 patients ( 2/8 had 2 surgeries)( 2/8 had 2 surgeries)( The patient with a microadenoma ( The patient with a microadenoma

didn’t have surgery)didn’t have surgery)

Approach:Approach: Transphenoidal: 7/8Transphenoidal: 7/8Transfrontal: 1/8Transfrontal: 1/8

• HypopituitarismHypopituitarism: 3/7: 3/7 Hypogonadism : 2/7 Hypogonadism : 2/7 Adrenal insufficiency : Adrenal insufficiency : 1/7 1/7 Diabetes insipidusDiabetes insipidus: : 0/70/7

Normalization of Normalization of TFT’s: TFT’s:

1 pt 1 pt (transient)(transient)

Abnormal TFT’s :Abnormal TFT’s :

5 pts5 pts(2 patients were treated (2 patients were treated perioperatively)perioperatively)

Residual tumor: Residual tumor:

8 pts8 pts

Post Operative TherapyPost Operative Therapy Radiation therapyRadiation therapy: 3 patients: 3 patients (2 due to residual tumor and 1 tumor (2 due to residual tumor and 1 tumor regrowth)regrowth)

Medical therapy (7 pts)Medical therapy (7 pts)LanreotideLanreotide: 3 pts (Somatuline 30mg, : 3 pts (Somatuline 30mg, Autogel Autogel 60 mg)60 mg)

OctreotideOctreotide: LAR: 3 pts (dose 30 mg): LAR: 3 pts (dose 30 mg) s.c: 2 pts (dose s.c: 2 pts (dose 100mic/day)100mic/day)

Dopamine agonists: Dopamine agonists: 2 pts (1 s/e, 1 ineffective)2 pts (1 s/e, 1 ineffective)

(1 patients lost to f/u)(1 patients lost to f/u)

Chronic Somatostatin Chronic Somatostatin Analogue Therapy Analogue Therapy

(post surgical and primary (post surgical and primary therapy)therapy) Duration of therapyDuration of therapy: 4.6 : 4.6 ± 4.3 years± 4.3 years

(range: (range: 1.5-14 years)1.5-14 years)

Normalization of TFT’sNormalization of TFT’s: 8/8 patients: 8/8 patients Tumor shrinkageTumor shrinkage: 2/8 patients: 2/8 patients

(10mm→4 mm) (12mm → 9 mm)(10mm→4 mm) (12mm → 9 mm) Tumor growthTumor growth : 0/8 patients : 0/8 patients Central hypothyroidismCentral hypothyroidism: 2/8 patients: 2/8 patients Side effectsSide effects: cholelithiasis (1) abdominal : cholelithiasis (1) abdominal pain:(4) pain:(4)

ConclusionsConclusions

Surgical therapy was not curative.Surgical therapy was not curative. Somatostatin analogues were highly Somatostatin analogues were highly effective in normalizing thyroid effective in normalizing thyroid function tests (100%)function tests (100%)

No tumor growth during somatostatin No tumor growth during somatostatin analogue therapy was observed.analogue therapy was observed.

The role of somatostatin analogues The role of somatostatin analogues as primary therapy for TSH secreting as primary therapy for TSH secreting tumors, particularly microadenomas tumors, particularly microadenomas needs to be further evaluated.needs to be further evaluated.

THANK YOUTHANK YOU

The changing spectrum of TSH-The changing spectrum of TSH-secreting pituitary adenomas: secreting pituitary adenomas: diagnosis and management in 43 diagnosis and management in 43

patientspatients

Proportion of microadenoma X macroadenoma Proportion of microadenoma X macroadenoma 1974-1986: 1/11 (9%)1974-1986: 1/11 (9%)1987-2001: 8/32 (25%)1987-2001: 8/32 (25%) Medical therapy with somatostatin analogues Medical therapy with somatostatin analogues was the first line therapy in 26 patients was the first line therapy in 26 patients (19 had surgery)(19 had surgery)

TSH levels were reduced by more than 50% in TSH levels were reduced by more than 50% in 23/26 patients (normalization of TFT 22/26 – 23/26 patients (normalization of TFT 22/26 – 85%)85%)

Tumor shrinkage of more than 20% was Tumor shrinkage of more than 20% was observed in 5/13 cases (36%).observed in 5/13 cases (36%).

Valdes Socin H et al. European Journal of Endocrinology Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442.2003; 148: 433-442.