Neurosurgery notes/Tumours/Sellar tumours/Pituitary adenoma/Pituitary neuroendocrine tumour/TSH secreting tumour

TSH secreting tumour

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Pituitary adenoma/Pituitary neuroendocrine tumour

General

  • Aka:
    • Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas)
    • Syndrome of ‘inappropriate secretion of TSH'
      • Can be caused by
        • TSHomas
        • Resistance to thyroid hormone action (RTH)
          • Mutation in T3/4 receptor causing increase in free T3/4 levels and normal or raised TSH
  • A rare cause of hyperthyroidism
    • Other more common causes
      • Autoimmune thyroid disorders
      • Toxic goitre

Numbers

  • Prevalence: 1/million
  • Account for about 0.5–3% of all pituitary adenomas
  • No gender preponderance
  • 50-60 years old

Genetic

  • MEN type 1

Pathology

  • TSHomas are monoclonal
  • No mutations common oncogenes and TSG found
  • Usually benign tumors
    • Transformation into a carcinoma with multiple metastases has only been described case reports
  • Chromophobe
  • Often large and invasive lesions and very fibrous;
    • Larger and more invasive TSHomas are more frequently observed in patients who have undergone thyroid ablation
  • Secretion
    • 70–80% of TSHomas secrete only TSH
      • Particularly the microadenomas
      • Also has unbalanced hypersecretion of the glycoprotein hormone α-subunit (α-GSU)
    • 20–25% of TSHomas are mixed adenomas
      • Concomitant hypersecretion of other anterior pituitary hormones
        • Growth hormone
        • Prolactin (PRL)
  • Express a variable number of somatostatin receptors
    • Use of somatostatin analogs in TSHoma treatment.

Clinical manifestation

  • Signs and symptoms of hyperthyroidism
    • Due to raised free T3/T4
    • Many are therefore
      • Misdiagnosed as Graves’ disease
      • May have been inappropriately treated by
        • Thyroidectomy
        • Radioiodine therapy
    • Features of hyperthyroidism are sometimes milder than expected given the circulating level of T3/4
      • Deleterious effects of thyroid hormone excess on the heart (i.e. atrial fibrillation and/or cardiac failure) are less frequently observed.
      • Progression of cases to frank toxic nodular goitre is very infrequent
      • Presence of differentiated thyroid cancer is reported in very few cases
      • Signs of orbitopathy or pretibial myxoedema are absent,
        • Though exophthalmos due to orbital invasion by the pituitary tumour or TSHoma arising in patients who subsequently developed autoimmune thyroiditis has been described
    • In the case of mixed TSH/ growth hormone tumours
      • The signs and symptoms of acromegaly may mask those of hyperthyroidism
  • Signs and symptoms of hypopituitarism

Diagnosis

  • Suspect TSHoma
    • High concentrations of circulating total or free thyroid hormones in the presence of non-suppressed TSH levels characterize TSHomas
      • Patients that have undergone thyroid ablation ‘by mistake’ may present as patients with unreasonable high TSH that thyroxine replacement cannot restore maintaining normal FT4.
  • Differentiating resistance to thyroid hormone (RTH)
      • ㅤ
      TSHoma
      Resistance to thyroid hormone
      Presentation
      Hyperthyroidism visual field defect
      Hypothyroidism, hyperthyroidism or euthyroidism
      Thyroid
      Goitre
      Goitre
      Thyroid hormones
      Elevated T4 and T3 with non-suppressed TSH
      Elevated T4 and T3 with non-suppressed TSH
      α-subunit
      Elevated
      Normal
      α-subunit/TSH ratio
      Elevated
      Normal
      TRH stimulation test
      TSH increase <2-fold basal level
      TSH increase >2-fold basal level
      T3 suppression test*
      Complete inhibition of TSH does not occur
      Inhibition of TSH
      Thyroid hormone reduction during long-acting somatostatin analog†
      T4 or T3 reduction/normalisation
      No change in T4 or T3 levels
      MRI
      Pituitary adenoma
      No pituitary adenoma
      Genetic test
      No mutation
      90% have mutation in THRB, rarely in THRA
      • * 80–100 μg/day divided in three administrations for 10 days, sampling at 0, 5 and 10 days.
      • † Two or more injections of somatostatin analogues (e.g., octreotide-LAR 20–30 mg every month or lanreotide autogel 120 mg every 6–8 weeks).
      • T3, tri-iodothyronine; T4, thyroxine; THRA, thyroid hormone receptor alfa gene; THRB, thyroid hormone receptor beta gene; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulation hormone; TSHoma, TSH-secreting pituitary adenoma.
       
       
      A diagram of a medical procedure AI-generated content may be incorrect.
      Flow-chart for the differential diagnosis between TSHoma and RTH. After exclusion of methodological interferences, central hyperthyroidism is confirmed. A panel of clinical, biochemical and genetic tests may be necessary to reach a differential diagnosis. Red findings are more consistent with RTH and blue findings with TSHoma. Solid lines indicate findings giving a stronger diagnostic indication.
  • Support of TSHoma
    • The possible presence of neurological signs and symptoms (visual defects, headache) or clinical features (acromegaly, galactorrhea, amenorrhea) of concomitant hypersecretion of other pituitary hormones points to the presence of a TSHoma.
    • Presence of pituitary lesion in MRI
    • High α-GSU concentrations and/or high α-GSU/TSH molar ratios are typically present in patients with TSH-secreting tumors.
  • Support of RTH
    • A partial inhibition of TSH secretion after T3 suppression test is seen only in RTH patients
    • The TSH response to TRH stimulation is usually preserved in RTH patients
    • Since RTH occurs as a dominantly-inherited disorder in ∼ 70% of cases, the finding of a similar thyroid biochemical phenotype in other first-degree relatives is highly suggestive of RTH.
      • Mutations in the thyroid hormone receptor beta gene are identified in ∼ 75–80% of RTH, especially familial cases.
    • Serum TSH levels within the normal range are more frequently found in RTH,
    • Chronic administration of long-acting somatostatin analogs (20–30 mg i.m. every 28 days for 2–4 months, sampling at 0 and every 28 days just before the new injection) in patients with central hyperthyroidism caused a marked decrease of free T4 and free T3 levels in all but one patient with TSHoma, while patients with RTH did not respond at all
  • Diagnostic criteria for TSHoma
    • Measurable TSH levels in the presence of high FT4 and FT3 concentrations is the hallmark of TSHomas
    • Presence of a pituitary lesion on MRI

Investigation

Biochemical

  • Screening test
    • T4 level (total or free), thyroid-stimulating hormone (TSH) (AKA thyrotropin).
      • Normal values:
        • Free T4 index is 0.8–1.5,
        • TSH 0.4–5.5 mcU/ml,
        • Total T4 4–12 mcg/100ml
        • (NB: be sure to check both T4 AND TSH)
      • Abnormal High
        • Free T3
        • Free T4
        • TSH
  • Further testing:
    • Thyrotropin-releasing hormone (TRH) stimulation test (indicated if T4 is low or borderline):
      • Procedure
        • Check baseline TSH,
        • Give 500 mcg TRH IV,
        • Check TSH at 30 & 60 mins
      • Response
        • Normal response:
          • Peak TSH twice baseline value at 30 mins.
        • Impaired response with a low T4
          • Pituitary deficiency.
        • Exaggerated response
          • Primary hypothyroidism
    • T3 suppression test
      • Method
        • 80–100 μg/day divided in 3 administrations for 10 days
        • Sampling at 0, 5 and 10 days
      • Results
        • Normal: TSH inhibition
        • TSHoma: TSH not inhibited
    • Measurement of α-GSU
      • Serum glycoprotein hormone alpha-subunit (α-GSU)
        • TSHoma: high circulating levels (70%)
          • Esp pt with macroadenoma
      • A high α-GSU/TSH molar ratio {[α-GSU (μg/l)/TSH (mU/l)] x 10} is present in about 80% of TSHomas.
        • Not good test: molar ratios ranging from 0.3 in normal men to 29.1 in postmenopausal women have been described
          • Therefore, it is no longer tenable to use a single molar ratio cutoff of >1.0 as indicative of TSHoma
  • Basis for thyroid screening (T4 and TSH)
      • Rationale
      T₄
      TSH
      Primary hypothyroidismᵃ (problem with thyroid gland itself)
      - Chronic primary hypothyroidism may produce secondary pituitary hyperplasia (pituitary pseudotumor); indistinguishable from adenoma on CT or MRI. Must be considered in any patient with a pituitary mass.
      - Pathophysiology: loss of negative feedback from thyroid hormones causes increased TRH release from the hypothalamus producing secondary hyperplasia of thyrotrophic cells in the adenohypophysis (thyrotroph hyperplasia). The patient may present due to pituitary enlargement (visual symptoms, elevated PRL from stalk effect, enlarged sella turcica on X-rays...).
      - Chronic stimulation from elevated TRH may rarely produce thyrotroph adenomas
      - Labs: T₄ low or normal, TSH elevated (>90–100 in patients presenting with thyrotroph hyperplasia), prolonged and elevated TSH response to TRH stimulation test
      ↓
      ↑
      Secondary hypothyroidismᵃ (insufficient TSH stimulation of thyroid)
      - Pituitary hypothyroidism accounts for only ≈ 2–4% of all hypothyroid cases
      - Secondary hypothyroidism was found in 8–81% of patients with nonfunctioning pituitary tumors (pituitary compression reduces TSH)
      - Labs: T₄ low, TSH low or normal, reduced response to TRH stimulation test
      ↓
      ↓ or nl
      Primary hyperthyroidism (problem with thyroid gland itself)
      - Etiologies: localized hyperactive thyroid nodule, circulating antibody that stimulates the thyroid, or diffuse thyroid hyperplasia (Graves’ disease, AKA ophthalmic hyperthyroidism)
      - Labs: T₄ elevated, TSH subnormal (usually undetectable)
      ↑
      ↓
      Secondary hyperthyroidism (central hyperthyroidism)
      - Etiologies:
      1. TSH-secreting pituitary adenoma (rare)
      2. Pituitary resistance to thyroid hormones (disrupts negative feedback loop)
      - Labs: T₄ elevated, TSH elevated or inappropriately normal
      ↑
      ↑ or nl
    • ᵃ Caution: replacing thyroid hormone with inadequate cortisol reserves (as may occur in panhypopituitarism) can precipitate adrenal crisis

Radiology

  • MRI
    • Macro-adenomas (about 80% of patients)
    • Microadenomas
      • Cases with the clinical and biochemical characteristics of TSHoma but negative MR imaging, presumably reflecting microadenomas that cannot be visualized, have been described

Management

Criteria for cure

  • No concrete definition
  • Clinical remission of hyperthyroidism
  • Disappearance of neurological symptoms
  • Resolution of neuroradiological alterations and normalization of thyroid hormones
  • TSH, or α-GSU/TSH molar ratio
    • Undetectable TSH levels 1 week after surgery are likely to indicate complete adenomectomy, provided that presurgical treatment with antithyroid drugs or daily somatostatin analog injections were stopped at least 10 days before surgery
    • 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 cured

Surgery

  • First-line therapy for TSHomas
  • Preop
    • Antithyroid drugs (methimazole or propylthiouracil) or somatostatin analogs, such as octreotide and lanreotide, along with propranolol, should be administered in order to restore euthyroidism before surgery
  • Options
    • Transsphenoidal
    • Subfrontal adenomectomy
  • Outcome
    • Microadenoma: majority of patients get complete removal
    • Macroadenoma: 60% of patients may be cured
      • Reasons of surgical failure are
        • Marked fibrosis within the adenoma
        • Frequent extra- and parasellar extension
    • The recurrence of the adenoma does not appear to be frequent, at least in the first years after successful surgery
    • Should be evaluated clinically and biochemically 2 or 3 times the first year postoperatively, and then every year.

Medical treatment

Somatostatin analogs

  • Highly effective in reducing TSH secretion from neoplastic thyrotropes
  • Option
    • Octreotide LAR ®
    • Ianreotide SR ®
    • Ianreotide Autogel ®
  • Outcome
    • Normalizes T3/4 levels in 90% of pt and reduce goiter in 30%
    • Significant tumour mass shrinkage 40%
    • Vision improvement in 70%
  • Side effects
    • Cholelithiasis
    • Hyperglycemia
    • Hypothyroidism → may need replacement

Dopamine agonists

  • Dopamine type 2 receptors are present in most TSHomas
  • Options
    • Bromocriptine
    • Cabergoline
  • Outcome
    • Results are mixed
    • Only partial TSH suppression is seen in the majority of cases

Radiotherapy

  • Indication
    • When surgery and medical treatment are contraindicated or declined
  • Options
    • Pituitary fractionated stereotaxic radiotherapy
    • Radiosurgery
  • No data on success rate with primary radiotherapy
  • Some data on Adjuvant RT after TSS

Follow up

  • Evaluate clinically and biochemically 2 or 3 times the first year postoperatively, and then every year.
    • Measurement of
      • TSH
      • Free T4
      • Other pituitary hormones
  • Pituitary imaging
    • If no TSH or T4 hormone changes do every two or three years,
    • If increase in TSH and T4 level, or clinical symptoms occur → do one immediately
  • Persistent macroadenoma
    • A close follow-up of visual fields