IN THE NAME OF GOD A 57 yrs. old Man with - PowerPoint Presentation

1. IN THE NAME OF GODA 57 yrs. old Man with Weight loss & Hx of Pituitary Adenoma1Presentation By Dr. Ali Golshaian4th Bahman 1400

2. Patients ID:57 yrs. old Man Born & live in Salmas (West Azerbaijan)Retired – The bank chairman2

3. Chief Complaint:Weight loss (~ 5 kg in recent 4 months)3

4. Present Illness:A 57 yrs. old man Weight loss (~ 5 kg in recent 4 months)With Hx of TSH-oma:From Late 1392 until 1393.03, after the patient was retiring, within 6 months, he reduced 30 kg. (98 >> 68) In last days before surgery, his weight loss received to 0.5 kg per day.4

5. Present Illness:At that time, as well as, Now:Headache (-) Visual problem (-) Diarrhea (-) Palpitation (-) Diaphoresis alteration (-) Nervous & Anxiety disorders (-)Decreased of libido or Sexual problems (-) Vertigo (-)Organ enlargement (-) Obesity (-) 5

6. Present Illness:Laboratory data at that time demonstrated high FT4 & FT3 simultaneous with high TSH. Several times, laboratory exams was done.Methimazole was started for patient.MRI was taken and showed: (Pituitary Macroadenoma)6

7. Present Illness:In a medical document, we can see:7

8. ResultNormal RangeDateT415 μg/dL5.1 – 14.11393/3/20T-Uptake0.50.8 – 1.31393/3/20FTI30 μg/dL4.8 – 12.7 1393/3/20T32.7 ng/L0.7 - 21393/3/20TSH12.4 mIU/L0.3 – 4.21393/3/20FSH22.8 IU/L1.5 – 12.41393/3/20LH17 IU/L1.7 – 8.61393/3/20Testosterone8.8 ng/ml2.8 – 8.0 1393/3/20Prolactin11.8 ng/ml4 – 15.21393/3/20Cortisol AM17.6 μg/dL6.2 – 20 1393/3/20GH Basal0.8 ng/ml0.1 – 2.51393/3/20IGF-191 ng/ml54.3 – 194 1393/3/208

9. He underwent TSS (Adenectomy) at 1393.03.20PATHOLOGY 93/3/22SPECIMEN: Pituitary gland trans-nasal and trans-sphenoidal resection.CLINICAL: Pituitary adenomaMACROSCOPIC: The specimen is received in formalin ,consists of multiple irregular pinkish brown soft tissue fragments, measuring 2.5 x 2 x 1 cm in aggregate. Totally submitted in 1 block.MICROSCOPIC: Section show a neoplastic lesion, composed of polygonal cells with round to ovoid nuclei and amphophilic to clear cytoplasm. Forming anastomosing nests and trabecula. The stroma is vascular.DIAGNOSIS:Pituitary adenoma9

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11. Present Illness: He underwent TSS (Adenectomy) at 1393.03.20Weight increased to 90 kg.Then he has gone under treatment with:Methimazole 5 / BD Sandostatin LAR 30 mg (first every 6 weeks until late 96, then every 2 months until late 97, then every 3 months until 98.03, at this time, the patient discontinued drug)11

12. Present Illness:Methimazole 5 / BD was continued until 4 month ago.After stopping Methimazole, weight loss reoccurred about 5 kg within 4 months.Now, the patient has referred to Endocrinologist. 12

13. Past medical and Drug history: PMH: DM (-) HTN (+), from 1 yr. ago CKD (-) Liver Dis. (-)DH: Tab Valzomix 80/5 / dayTab Metoral 25 / BD13

14. Habitual History: Neg Social History : NegFamily History : Neg14

15. Review of Systems:Headache (-) Nausea & Vomiting (-) Visual problems (-)Skin: No pigmentationEars, nose, mouth: NlCardiovascular: NlRespiratory: NlGastrointestinal: Nl, Musculoskeletal: NlNeurological: NlPsychiatric: depression(-), anxiety(-)15

16. Physical Examination:GENERAL APPEARANCE: 57 yrs. old man , awake and alertVital Sign:BP: 120/80 mmHgHR: 80 / minNo frontal bossing, No moon face, No obvious ophthalmopathy, No supraclavicular fad pad 16

17. Physical Examination:Thyroid: Symmetrically enlargement more than 40 gr, FirmPemberton sign (Neg)Thorax: NlLungs : ClearHeart : Normal Abdomen : No striae , no organomegaly Skin: No acne, No pigmentationExtremities : Upper : Normal, No abnormal enlargement Lower : Normal, No abnormal enlargement17

18. PROBLEM LIST A 57-year-old man; with recent weight loss, ~ 5 kg in 4 months, after discontinuing MethimazoleHx of TSHoma 7 yrs. ago with presentation by weight loss ~ 30 kgTSS (Adenectomy) at 1393.03Sandostatin LAR was prescribed in 6 weeks to 3 months intervals until 1398.03Also Methimazole 5 / BD was consumed until 4 months ago.18

19. ResultNormal RangeDateT411.7 μg/dL5.1 – 14.11400/10/20T-Uptake0.690.8 – 1.31400/10/20FTI17.0 μg/dL4.8 – 12.7 1400/10/20T31.58 ng/L0.7 - 21400/10/20TSH7.59 mIU/L0.3 – 4.21400/10/20Anti TgLess then 1.0Up to 501400/10/20Anti TPO2.2 IU/ml< 5.611400/10/20Cr 1.1 mg/dl0.7 – 1.3 1400/10/20ALT26 U/L5 – 40 1400/10/20AST29 U/L5 – 41 1400/10/20FSH5.9 IU/L0.95 – 11.951400/10/20LH2.7 IU/L0.57 – 12.071400/10/20Testosterone, Total4.01 ng/ml1.29 – 7.671400/10/20Prolactin7.2 ng/ml2.1 – 17.71400/10/20Cortisol AM10.83 μg/dL6.2 – 20 1400/10/20GH Basal0.09 ng/ml0.1 – 2.51400/10/20IGF-1147.1 ng/ml54.3 – 194 1400/10/20CEA2.52 ng/ml0 - 51400/10/2019

20. Sonography1400/10/20THYROID AND SOFT TISSUES OF NECK ULTRASOUNDRight lobe of the thyroid gland measures 46 x 19 x 22 mm and diameters of the left lobe are 47 x 18 x 25 mm. Thyroidal echotexture is homogeneous . A 10 mm hypoechoic nodule is seen in the lower pole of left lobe.Thickness of thyroid isthmus is 5 mm. 2-3 reactive lymph nodes are seen in each side.20

21. 21MRI1400/10/21Clinical information provided by the patient: H/O excised pituitary lesion about 7 yrs agoPost-op changes in sphenoid sinus seen.There is abnormal signal in right side of sella turcica without suprasellar extension with mild parasellar extension crossing superior medial line measuring about 14*9.6*6.3 mm mostly remnant of resected pituitary adenoma.The pituitary stalk is deviated to the left side. Left side of pituitary gland is intact. Supra sellar cistern is intact. Both cavemous sinuses & visible ant. visual pathway are unremarkable. Both thalami and hypothalamus are otherwise unremarkable.Imp.: Post-op changes in sphenoid sinus.Abnormal signal in right side of sella turcica without suprasellar extension with mildparasellar extension crossing superior medial line measuring about 14*9.6*6.3 mm mostly remnant of resected pituitary adenoma. Deviation of pituitary stalk to the left side

22. 22MRI

23. 23BMD

24. Persistent TSHoma24

25. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up25

26. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up26

27. Brief review of TSHoma - EpidemiologyThese tumors account for about 0.5% to 1% of all pituitary adenomas, whose prevalence in the general population is about 0.02%. Thus, the prevalence of TSH-secreting tumors is about one case per million. The presence of a TSH-secreting tumor has been observed in patients of all ages, from 8 to 87 years. However. most patients are diagnosed between the third and the sixth decade of life. 27(2021) Werner & Ingbar`s The Thyroid, 11th Edition

28. Brief review of TSHoma - Epidemiology The great majority of TSH-secreting tumors (about 75%) are macroadenomas having a diameter >10 mm at the time of diagnosis.Extrasellar extension is present in more than two-thirds of cases. 28(2021) Werner & Ingbar`s The Thyroid, 11th Edition

29. Brief review of TSHoma - Pathology & Pathogenesis About 75% of these tumors secrete TSH alone, which is often accompanied by an unbalanced hypersecretion of the α-subunit of glycoprotein hormones. Hypersecretion of growth hormone (GH) and/or prolactin (PRL) are the most frequent associations. (TSH)/gonadotropin adenoma is rare, while no association with (ACTH) hypersecretion has been documented to date.Immuno-positivity for one or more pituitary hormones does not necessarily result in in vivo hypersecretion.29(2021) Werner & Ingbar`s The Thyroid, 11th Edition

30. Brief review of TSHoma - Pathology & Pathogenesis Secretion of the α-subunit by these tumors is in excess not only of the TSH β-subunit but also of the intact TSH molecule. This results in an α-subunit/TSH molar ratio, which usually is higher than 1.Similar values may be recorded in normal subjects, particularly postmenopausal women, indicating the need for appropriate control groups matched for TSH and gonadotropin levels. 30(2021) Werner & Ingbar`s The Thyroid, 11th Edition

31. Pituitary Hyperplasia in Long-Standing HypothyroidismMost TSPAs are primary pituitary lesions unassociated with thyroid failure and suggesting that TRH stimulation does not play a central role in tumorigenesis.Impaired Thyroid Hormone Negative Feedback One possible could be alterations in expression or activity of deiodinase enzymes, leading to decreased T3 concentration in the tumoral tissue. Type 3 deiodinase (D3) has been found to have a 6.5-fold increased expression in pituitary tumors. The TSH-secreting tumor expressed a 13.1-fold excess of D3 mRNA and reduced D2 mRNA (0.1-fold of normal pituitaries)Alterations in TR function; germline mutations in TRβ are not sufficient to induce tumor formation. 31(2017) Shlomo Melmed, The Pituitary, 4th Edition Brief review of TSHoma - Pathology & Pathogenesis

32. Pituitary Altered Hypothalamic Signaling No mutations on the TRH receptor, Gαq, Gα11, or Gαs were detected in the tumors No mutations on the dopamine type 2 receptor SSTR mutations have not been described in TSPAs. Hence, the somatostatin inhibitory pathway seems to be intactAlterations in Pituitary Transcription Factors The β-TSH gene is under transcriptional control of Pit-1. No mutations on Pit-1 were detected, but overexpression of the gene was found in most cases investigated 32(2017) Shlomo Melmed, The Pituitary, 4th Edition Brief review of TSHoma - Pathology & Pathogenesis

33. Oncogenes, Tumor Suppressor Genes, and Growth Factors No activating mutations of putative proto-oncogenes, such as RAS, G-protein, TRH. And Pit-1, or loss of genes with tumor suppressor activity, such as p53 and menin gene, have been reported ¹Basic fibroblast growth factor (bFGF) has been found to be overexpressed in TSH-secreting adenomas, suggesting that it may play a role in cell proliferation and development of fibrosis in these tumors. ²Familial/Genetic Syndromes TSPA associated with the MEN1 syndrome has been reported in very few cases. 331 = (2021) Werner & Ingbar`s The Thyroid, 11th Edition2 = (2017) Shlomo Melmed, The Pitutary, 4th Edition Brief review of TSHoma - Pathology & Pathogenesis

34. Patients with TSH-secreting tumor present with signs andsymptoms of thyrotoxicosis that are frequently associated withthose related to the pressure effects of the pituitary adenomas, causing loss of vision, visual field defects, and/or loss of other anterior pituitary functions.Most patients with a TSH-secreting macroadenoma seek medical attention because of signs or symptoms of an expanding intracranial tumor. 34(2021) Werner & Ingbar`s The Thyroid, 11th Edition Brief review of TSHoma - Sign & Symptoms

35. 35(2021) Werner & Ingbar`s The Thyroid, 11th Edition Patients with a tumor n/total (%)Patients with a tumor D!total (%)Age range (years) 7-88Female/male: ratio 1.2Previous thyroidectomy 105/380 (27.6)Severe thyrotoxicosis 63/222 (28.4)Goiter201/286 (70.3)Thyroid nodule(s) 53/102 (51.9)Macroadenomas285/390 (73.1)Visual field defect 72/180 (40.0)Headache30/130 (23.1)Menstrual disorders40/120 (33.3)Galactorrhea15/48 (31.3)Acromegaly70/352 (19.9)Brief review of TSHoma - Sign & Symptoms

36. In contrast to Graves' disease, the occurrence of antithyroid autoantibodies is similar to that found in the general population, being about 8%. Bilateral exophthalmos occurred in a few patients who subsequently developed autoimmune thyroiditis, while unilateral exophthalmos due to orbital invasion by a pituitary tumor was reported in three patients. While tumoral thyrotropes are totally or partially resistant to the inhibitory action of high thyroid hormone levels, they have a preserved or even increased sensitivity to low serum thyroid hormone levels. 36(2021) Werner & Ingbar`s The Thyroid, 11th Edition Brief review of TSHoma - Sign & Symptoms

37. Classically, the T3 suppression test has been used to assess the presence of a TSH-secreting tumor. From the analysis of different cases, complete inhibition of TSH secretion after T3 administration (80 to 100 μg/day for 8 to 10 days) has never been recorded in patients with a TSH-secreting tumor.This test is contraindicated in elderly patients or those with coronary heart disease. 37(2021) Werner & Ingbar`s The Thyroid, 11th Edition Brief review of TSHoma - Diagnostic testing

38. In 83% of patients, TSH and a-subunit levels did not increase after TRH injection.Classically The majority of patients with a TSH-secreting tumor are sensitive to somatostatin or its analogs. Administration of native somatostatin or its analogs (octreotide and lanreotide) induces a reduction of TSH levels in the majority of cases, and these tests may be predictive of the efficacy of long-term treatment as well as useful in the differential diagnosis between TSH-secreting tumors and PRTH.38(2021) Werner & Ingbar`s The Thyroid, 11th Edition Brief review of TSHoma - Diagnostic testing

39. Classically The majority of patients with a TSH-secreting tumor are sensitive to somatostatin or its analogs. ¹ 391 = (2021) Werner & Ingbar`s The Thyroid, 11th EditionFigure = (2017) Shlomo Melmed, The Pitutary, 4th Edition Brief review of TSHoma - Diagnostic testing

40. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up40

41. Passible causes of inappropriate secretion of TSH41(2021) Ohba K. An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone. Int J Mol Sci. 2021 Jun 21;22(12):6611

42. TSHoma & RTHSigns and symptoms of thyrotoxicosis along with biochemical findings similar to those found in TSH-secreting tumors may occur in a minority of patients with resistance to thyroid hormones (RTHs). This form of RTH is called pituitary RTH (PRTH), as the RTH is more severe in the pituitary than in the peripheral tissues.42(2021) Werner & Ingbar`s The Thyroid, 11th Edition

43. TSHoma & RTH43(2021) Werner & Ingbar`s The Thyroid, 11th Edition Table 23.3. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-SERETING TUMORS AND RESISTANCE TO THYROID HORMONES (RTHS)

44. Chemotherapy, BMT & subsequent POI44(2013) Beck-Peccoz P, et all. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013 Jun;2(2):76-82

45. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up45

46. Simultaneous coexistence of TSHoma and papillary thyroid carcinomaSimultaneous coexistence of TSHoma and papillary thyroidcarcinoma (PTC) is still exceptional, and so far, only sixteen cases have been reported. The role of TSH in carcinogenesis and development of PTC have been suggested in several studies and a meta-analysis of 28 studies have objectified a significant association between TSH levels and the risk of PTC. Unusual association of PTC with TSHomas enriches the hypothesis of a potential link between thyrotropic hypersecretion and thyroid carcinogenesis. 46(2021) Safi Somaya, et al. Coexistence of Thyrotropin Prolactin-Secreting Adenoma and Papillary Thyroid Carcinoma. Case Rep Endocrinol. 2021 Nov 30;2021:6564765

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48. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up48

49. Treatment - Surgery Surgical removal of the adenoma is the first-line therapy for TSHomas, with transsphenoidal or sub frontal adenectomy being able to completely remove the tumor and to restore normal pituitary/thyroid function. Complete removal of the tumor is achieved in the majority of patients with microadenoma, whereas no more than 60% of patients with macroadenoma may be cured. Quality of evidence: high (+++) Strength of recommendations: strong 49(2013) Beck-Peccoz P, Lania A, Beckers A, Chatterjee K, Wemeau JL. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013 Jun;2(2):76-82

50. Surgical In a recent series of 68 patients undergoing transsphenoidal surgery; 75% normalized thyroid function after surgery, 58% normalized both pituitary imaging and TSH hypersecretion, 3% experienced tumor recurrence. 50(2016) Ross DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421Treatment - Surgery

51. If surgery is contraindicated or declined, as well as in the case of surgical failure, pituitary radiotherapy has to be considered. The recommended dose is no less than 45 Gy fractionated at 2 Gy/day or 10 to 25 Gy in a single dose if a stereotactic gamma unit is available. Experience with proton beam and heavy particle radiotherapy in TSH-secreting tumors is lacking.The radiosensitivity of these tumors has not been clearly evaluated. ¹ Quality of evidence: low (+); strength of recommendations: weak. ²511 = (2021) Werner & Ingbar`s The Thyroid, 11th Edition 2 = (2013) Beck-Peccoz P, et all. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013 Jun;2(2):76-82 Treatment - Radiotherapy

52. Radiotherapy controlled thyroid hypersecretion in 37% of patients treated with this modality, but hypopituitarism occurred in 32% of those treated. ¹The use of radiotherapy should be carefully weighed in light of the current availability of efficacious medical treatment such as somatostatin analogues. This treatment modality should probably be reserved for patients with residual tumors unresponsive to medical treatment. ²521 = (2016) Ross DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-14212 = (2017) Shlomo Melmed, The Pitutary, 4th Edition Treatment - Radiotherapy

53. Medical treatment of TSHomas is mainly based on the administration of somatostatin analogs.Circulating thyroid hormone levels normalized in more than 90% of patients and goiter size is significantly reduced in about 30% of cases. ¹During octreotide therapy, tumor shrinkage occurs in about a half of the patients and vision improvement in 75%. Resistance to octreotide has been documented in only 4% of cases. ²Quality of evidence: high (+++); strength of recommendations: strong ¹531 = (2013) Beck-Peccoz P, et all. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013 Jun;2(2):76-82 2 = = (2021) Werner & Ingbar`s The Thyroid, 11th Edition Treatment - Medical treatment

54. The presence of SSTR2 in all tumors tested may explain their good clinical response to treatment with the currently available somatostatin analogues, which preferentially bind to this SSTR subtype, but it has been suggested that SSTR5 expression is required for optimal response to treatment.54(2017) Shlomo Melmed, The Pitutary, 4th Edition Treatment - Medical treatment

55. Treatment with Sandostatin LAR should be started at a dose of 20 mg at 4-weekly intervals for 3 months before considering dose adjustment. The dose is then adjusted on the basis of the TSH and thyroid hormone response.55Treatment - Medical treatment

56. Importantly, all therapies directed to the thyroid gland result in increased TSH secretion by the pituitary gland, and in the long-term carry the potential risk of causing tumor expansion. As such, direct antithyroid treatment should be avoided, reserving the use of antithyroid drugs only for short-term preparation for pituitary surgery. 56(2017) Shlomo Melmed, The Pitutary, 4th Edition Treatment - Medical treatment

57. AGENDACase PresentationBrief review of TSHoma - Epidemiology - Pathology & Pathogenesis - Sign & Symptom - Diagnostic testing Passible causes of inappropriate secretion of TSH - RTH & TSHomaSimultaneous coexistence of TSHoma and papillary thyroid carcinomaTreatment - Surgery - Medical treatment - Radiotherapy Follow up57

58. The most sensitive and specific test to document the complete removal of the adenoma remains the T3 suppression test. In fact, only patients in whom T3 administration completely inhibits basal and TRH-stimulated TSH secretion appear to be truly curedThe patient should be evaluated clinically and biochemically two or three times the first year postoperatively, and then every year. Pituitary imaging should be performed every 2 or 3 years, but should be done promptly whenever an increase in serum TSH and thyroid hormone levels or clinical symptoms occur. 58(2021) Werner & Ingbar`s The Thyroid, 11th Edition Follow up

59. Thanks for your attention59