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TSH SECRETING TUMORS: AN UPDATE AND THE ISRAELI EXPERIENCE

TSH SECRETING TUMORS: AN UPDATE AND THE ISRAELI EXPERIENCE. Rosane Abramof Ness Sapir Medical Center. TSH-Secreting Pituitary Adenomas. Rare cause of hyperthyroidism Originate from pituitary thyrotrophs just 2 ectopic case (nasopharynx) reported.

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TSH SECRETING TUMORS: AN UPDATE AND THE ISRAELI EXPERIENCE

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

  2. TSH-Secreting Pituitary Adenomas • 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.

  3. Epidemiology • 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)

  4. Pathology • 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 thyrotropes common transcription factors such as Prop-1 and Pit-1. • Rare cases of mixed TSH/gonadotropin adenomas

  5. TSH-oma • 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.

  6. Etiology • 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)

  7. Cell Cultures • 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.

  8. Clinical Findings • 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

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

  10. 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. • First reported in 1967. • Variable severity of hormonal resistance in different tissues.

  11. 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 Abnormal TSH response to T3 suppression a 100 % 100 % b  NS Werner & Ingbar/s The Thyroid (eighth Edition) p560

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

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

  14. Treatment • Surgery • Radiation therapy • Somatostatin analogues • Dopamine agonists

  15. 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%

  16. Pituitary Radiotherapy

  17. Remission from hyperthyrodism Disappearance of neurological signs Normalization of FT4 and FT3 Normalization of TSH undetectable TSH one week after neurosurgery Normalization of alpha-GSU Positive T3 suppression test with undetectable TSH and no response to TRH 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 Criteria of Cure

  18. Medical Therapy • 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

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

  20. Dopamine Agonists • No long term effect in obtaining normalization of TFT’s or tumor shrinkage • Effective in cases of TSH-PRL co secretion

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

  22. Patient’s Characteristics • 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 )

  23. Laboratory tests • TSH 5.0 mU/L ± 1.5 (nl: 0.3-4) (range: 3-8.6 mU/L) • FT4 45.7 pmol/L ± 17.5 (nl: 10-20) (range 24.3 - > 77 pmol/L) (6/9 pts) • TT4 228 ± 23.3 nmol/L(nl: 53-143) ( 2/9 pts) • T3T 5.49 nmol/L ± 3.8 (nl: 1-2.8) (range 3.1- 13 nmol/L) (6/9 pts)

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

  25. Characteristics of Pituitary Tumors • Size of adenoma: 25.7 ± 14 mm (range: 9-41 mm) • Intrasellar 1/9 • Extrasellar extension 8/9 Suprasellar 7/8 Cavernous sinus 3/6 Sphenoid sinus2/6

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

  27. Primary Medical Therapy • 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%)

  28. 8 patients ( 2/8 had 2 surgeries) ( The patient with a microadenoma didn’t have surgery) Approach: Transphenoidal: 7/8 Transfrontal: 1/8 Hypopituitarism: 3/7 Hypogonadism : 2/7 Adrenal insufficiency : 1/7 Diabetes insipidus: 0/7 Normalization of TFT’s: 1 pt (transient) Abnormal TFT’s : 5 pts (2 patients were treated perioperatively) Residual tumor: 8 pts Surgical Therapy

  29. Post Operative Therapy • 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) (1 patients lost to f/u)

  30. 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)

  31. Conclusions • 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.

  32. THANK YOU

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

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