TSH SECRETING TUMORS AN UPDATE AND THE ISRAELI

TSH SECRETING TUMORS: AN UPDATE AND THE ISRAELI EXPERIENCE Rosane Abramof Ness Sapir Medical Center

TSH-Secreting Pituitary Adenomas Rare cause of hyperthyroidism n Originate from pituitary thyrotrophs just 2 ectopic case (nasopharynx) reported. n First case documented in 1960 (TSH measured by bioassay) n Hamilton et al reported the first case of TSH -oma proved by measuring RIA in 1970. n

Epidemiology n n n Prevalence: 1/1, 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 (MEN 1)

Pathology n n The majority of TSH-secreting adenomas (75%) secrete TSH alone, often accompanied by unbalanced hypersecretion of its alpha-subunit (a. GSU) 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 thyrot common transcription factors such as Prop-1 and Pit-1. n Rare cases of mixed TSH/gonadotropin adenomas

TSH-oma n n 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 n n n 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 D 2 receptor gene- NEGATIVE Pit-1 mutations: NEGATIVE Loss of function of antioncogenes: p 53 (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 Somatostatin (SRIH): almost all TSH-omas express a variable number of SRIH receptor. n Highest SRIH-binding site density found in mixed GH/TSH adenomas. n Dopamine receptors: large heterogeneity of TSH response to dopamine agonists. n

Clinical Findings Hyperthyroidism (TSH: N- , FT 4 , FT 3 ) n Neurologic symptoms associated to pressure effects of the pituitary adenoma (visual field defects, headaches) n Symptoms due to associated hypersecretion. n Loss of anterior pituitary function n

Thyrotoxicosis with Inappropriately high TSH levels n Mouse ab interfering with TSH assay n Central hyperthyroidism: q Pituitary tumor: TSH secreting. q Resistance to thyroid hormone (RTH)

Resistance to Thyroid Hormone Autosomal dominant disorder characterized by reduced responsiveness of target tissues to thyroid hormone due to a mutation in the thyroid hormone receptor beta. n First reported in 1967. n Variable severity of hormonal resistance in different tissues. n

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 m. U/L 3. 0 ± 0. 5 2. 3 ± 0. 3 NS FT 4 pmol/L 38. 8 ± 4. 0 29. 9 ± 2. 4 NS FT 3 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 % Abnormal TSH response to T 3 suppression a b NS

A Pituitary Tumor in a Patient with Thyroid Hormone Resistance: A Diagnostic Dilemma Safer et al Thyroid 2001

Localization n MRI Pituitary scintigraphy with radiolabeled octreotide (octreoscan) n PET : (11)C-Methionine PET n Petrosal sinus sampling (PSS) n

Treatment Surgery n Radiation therapy n Somatostatin analogues n Dopamine agonists n

Surgical Treatment n First therapeutic approach n Normalization of TFT’s and disappearance of tumor in 33 -44% of patients. n Normalization of TFT’s in 25% n Unsuccessful in 25%

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 n n n n Remission from hyperthyrodism Disappearance of neurological signs Normalization of FT 4 and FT 3 Normalization of TSH undetectable TSH one week after neurosurgery Normalization of alpha. GSU Positive T 3 suppression test with undetectable TSH and no response to n § § § 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 n 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- eccoz Persani. Medical Management of Peccoz and. Thyrotropin -Secreting Pituitary Adenomas. P Pituitary 2002 : 83 -88

Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT 4) 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 No long term effect in obtaining normalization of TFT’s or tumor shrinkage n Effective in cases of TSH-PRL co secretion n

TSH-secreting tumors: The Israeli Experience Ness-Abramof R, Ishay A, Greenman Y, Harel G and Shimon I.

Patient’s Characteristics n n n § 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 n TSH 5. 0 m. U/L ± 1. 5 (nl: 0. 3 -4) (range: 3 -8. 6 m. U/L) n FT 4 45. 7 pmol/L ± 17. 5 (nl: 10 -20) (range 24. 3 - > 77 pmol/L) (6/9 pts) n TT 4 228 ± 23. 3 nmol/L (nl: 53 -143) ( 2/9 pts) n T 3 T 5. 49 nmol/L ± 3. 8 (nl: 1 -2. 8) (range 3. 1 - 13 nmol/L) (6/9 pts)

Laboratory tests n Alpha subunits: n Alpha subunit/ TSH molar ratio: TRH test: Normal response Abnormal response normal 3/3 patients n 1/5 4/5 (20%) (80%) normal

Characteristics of Pituitary Tumors n Size of adenoma: 25. 7 ± 14 mm Intrasellar n Extrasellar extension Suprasellar Cavernous sinus n Sphenoid sinus (range: 9 -41 mm) 1/9 8/9 7/8 3/6 2/6

n Visual Fields: Normal 5 pts (55%) Abnormal 4 pts (45%) (bitemporal hemianopsia) 2/9 hypogonadism 1/9 on OC n Diabetes insipidus: 0/9 n Co secretion of hormone: 2/9 (22%) GH n Hypopituitarism:

Primary Medical Therapy n 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 n Pt 7: Lanreotide 30 mg q 3 weeks: Normalization of TFT, tumor shrinkage (1 year) 10 mm→ 4 mm (60%) n

Surgical Therapy n 8 patients ( 2/8 had 2 surgeries) n Normalization of TFT’s: 1 pt (transient) n Abnormal TFT’s : 5 pts ( The patient with a microadenoma didn’t have surgery) n 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) n Residual tumor: 8 pts

Post Operative Therapy n Radiation therapy: 3 patients (2 due to residual tumor and 1 tumor regrowth) Medical therapy (7 pts) Lanreotide: 3 pts (Somatuline 30 mg, Autogel 60 mg) Octreotide: LAR: 3 pts (dose 30 mg) s. c: 2 pts (dose 100 mic/day) Dopamine agonists: 2 pts (1 s/e, 1 ineffective) n (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 n Tumor shrinkage: 2/8 patients (10 mm→ 4 mm) (12 mm → 9 mm) n Tumor growth : 0/8 patients n Central hypothyroidism: 2/8 patients n Side effects: cholelithiasis (1) abdominal pain: (4) n

Conclusions n n 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.

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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%) v Medical therapy with somatostatin analogues was the first line therapy in 26 patients (19 had surgery) v TSH levels were reduced by more than 50% in 23/26 patients (normalization of TFT 22/26 – 85%) v Tumor shrinkage of more than 20% was observed in 5/13 cases (36%). v Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433 -442.