TSH-Producing Adenomas

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Chapter 10

TSH-Producing Adenomas

Pituitary thyrotropin-producing adenomas (TSH-omas) are rare tumors that cause hyperthyroidism by chronically stimulating an intrinsically normal thyroid gland.1-4 The first case of hyperthyroidism related to TSH-oma (central hyperthyroidism) was reported in 1960 when serum TSH levels were measured with a bioassay.5 In 1970, Hamilton and coworkers6 documented the first case of TSH-oma that was indisputably proved by radioimmunoassay techniques. Since then, about 350 patients have been reported in the literature. Although early reports describe these tumors as invasive macroadenomas that cause high morbidity and, in general, are difficult to be removed surgically, some cases now are cured more easily owing to earlier diagnosis. In fact, with the advent of ultrasensitive immunometric assays for TSH measurement, which are performed routinely in association with direct measurement of circulating free thyroid hormones (free thyroxine [FT4] and free triiodothyronine [FT3]), it is expected that patients with TSH-oma at the stage of microadenoma will be recognized with increasing frequency, thus permitting an improved clinical outcome.

Classically, TSH-omas, together with resistance to thyroid hormone,7-9 were defined as syndromes of “inappropriate secretion of TSH,” based on the common hormonal profile characterized by high levels of FT4 and FT3 in the presence of measurable TSH concentrations—a finding that contrasted with that observed in primary hyperthyroidism in which TSH is always undetectable. Nonetheless, the term central hyperthyroidism seems to be more pertinent for these disorders. However, clinically and biochemically, euthyroid patients with pituitary adenomas that secrete TSH molecules, possibly with reduced bioactivity, have been described but not clearly documented.10,11 Moreover, pituitary hyperplasia and, in rare instances, true adenoma1214 related to long-standing primary hypothyroidism are well-known clinical conditions.4 In most of these so-called feedback tumors, resolution of the pituitary lesion and normalization of TSH levels occur after levothyroxine (LT4) replacement therapy, thus bringing into question the actual functional autonomy of such tumors.

The clinical importance of these rare entities is based on the diagnostic and therapeutic challenges they present. Failure to recognize these different disorders may result in dramatic consequences, such as improper thyroid ablation in patients with central hyperthyroidism or unnecessary pituitary surgery in patients with resistance to thyroid hormone. In contrast, early diagnosis and correct treatment of pituitary tumors prevent the occurrence of complications (visual defects by compression of the optic chiasm, headache, hypopituitarism) and should improve the rate of cure.

Epidemiology

TSH-producing adenoma is a rare disorder, accounting for about 0.5% to 2% of all pituitary adenomas in both clinical and surgical or pathologic series.1,1517 The prevalence in the general population is 1 to 2 cases per million. Indeed, the number of reported cases of TSH-omas has tripled in the decade from 1989 to 1999 (Fig. 10-1). This increased number of recorded cases results from the introduction of ultrasensitive immunometric assays for TSH as a first-line test for the evaluation of thyroid function. On the basis of the finding of measurable serum TSH levels in the presence of elevated thyroid hormone concentrations, many patients who previously were thought to have Graves’ disease can be diagnosed correctly as having a TSH-secreting pituitary adenoma or, alternatively, resistance to thyroid hormone. Moreover, increased awareness by the endocrinologist and general practitioner regarding the existence of central hyperthyroidism has contributed greatly to the disclosure of a higher number of patients with such a rare disorder.

Pathology and Etiopathogenesis

The thyrotroph is the cell type of origin in TSH-omas. These tumors are nearly always benign; at present, transformation of a TSH-oma into a carcinoma with multiple metastases has been reported in only two patients.18,19 Most of them (72%) secrete TSH alone, although this often is accompanied by unbalanced hypersecretion of the α subunit. About one fourth of TSH-omas are mixed adenomas, characterized by concomitant hypersecretion of other anterior pituitary hormones, mainly growth hormone (GH), prolactin (PRL), or both, which are known to share with TSH the common transcription factor Pit-1. Indeed, hypersecretion of TSH and GH is the most frequent association (16%), followed by hypersecretion of TSH and PRL (10.4%) and occasionally TSH and gonadotropins (1.4%) (Fig. 10-2). No association with adrenocorticotropic hormone (ACTH) hypersecretion has been documented to date. Two ectopic TSH-producing adenomas have been documented in the pharyngeal hypophysis.20,21

At morphologic and histopathologic analysis, most TSH-omas are macroadenomas (87%), frequently with fibrous consistency, even in the absence of prior surgery or radiotherapy, and high local invasiveness.22 However, previous thyroid ablation by surgery or radioiodine has deleterious effects on the size and invasiveness of the tumor (Fig. 10-3).4 In fact, invasive macroadenomas were found in 49% of patients who had undergone thyroid ablation versus 27% in those who were untreated, whereas the figure was reversed in patients with microadenomas (diameter <1 cm) or intrasellar macroadenomas. Therefore, previous thyroid ablation may induce an aggressive transformation of the tumor, as is observed in Nelson’s syndrome after adrenalectomy for Cushing’s disease.

Light microscopy shows that adenoma cells are chromophobic, although they occasionally stain with basic or acid dyes. Ultrastructurally, adenomatous cells frequently appear monomorphous, even if they hypersecrete TSH, α subunit, and other pituitary tropins.23-26 Cells with abnormal morphologic features or mitoses,27 which may be misinterpreted as pituitary malignancy or metastases from distant carcinomas, are present in poorly differentiated adenomas that are characterized by the presence of fusiform cells with sparse and small secretory granules (80 to 200 nm). Indeed, there are no clear criteria of malignancy for TSH-omas except for the presence of metastases. It is worth noting that the first carcinoma reported in the literature exhibited a progressive malignant transformation accompanied by a decline in TSH and α subunit secretion.18

Immunostaining studies show the presence of TSH-β, either free or combined with the α subunit. In very few cases, a negative TSH-β immunostaining has been reported, possibly due to the extremely fast secretion rate of newly synthesized TSH molecules.4,34 With the use of double immunostaining, the existence of mixed TSH-α subunit adenomas composed of one cell type secreting α subunit alone and another cosecreting α subunit and TSH has been documented.28 In addition to α subunit, TSH frequently colocalizes with other pituitary hormones in the same tumoral cell29 or even in the same secretory granule.24,28,30,31 Nonetheless, positive immunohistochemistry panels for one or more pituitary hormones do not necessarily correlate with hypersecretion in vivo.32 Indeed, positive immunostaining for ACTH and gonadotropins without evidence of in vivo hypersecretion has been reported.3337

TSH-omas have been shown to be monoclonal in origin,38 and several studies have screened a substantial number of adenomas for proto-oncogene activation32,33,3941 or loss of antioncogenes,40,42 yielding negative results.4 A highly variable expression of thyrotropin-releasing hormone (TRH) and dopamine receptors was documented in several adenomas,4345 whereas functional somatostatin receptors were detected constantly in TSH-omas,4648 thus providing the rationale for their medical treatment with somatostatin analogues. Indeed, loss of heterozygosity at the locus of the somatostatin receptor type 5 gene appears to be associated with resistance to somatostatin analogues and a more aggressive phenotype.49

Recently, somatic mutations50 and aberrant alternative splicing51 of thyroid hormone receptor β have been reported, along with dysregulation of iodothyronine deiodinase enzyme expression and function.52,53 These findings at least in part may explain the defects in negative regulation of TSH secretion by thyroid hormones in some tumors.

Clinical Features

Patients with TSH-oma present with the signs and symptoms of either hyperthyroidism or the mass effect of an expanding intracranial tumor (Table 10-1). TSH-omas may occur at any age (range, 11 to 84 years), although most patients are in the third to sixth decade of life. Unlike the female predominance seen with other common thyroid disorders, TSH-omas occur with equal frequency in males and females. Goiter and clinical thyrotoxicosis are the most common presenting symptoms. Most patients presented with a long history of thyroid dysfunction, often mistakenly diagnosed as Graves’ disease, and one third had inappropriate thyroidectomy, radioiodine thyroid ablation, or both. Thus, patients with TSH-omas may present to the specialist with hyperthyroidism that has been refractory to previous therapeutic attempts. In general, clinical features of hyperthyroidism are milder than expected on the basis of circulating thyroid hormone levels. Moreover, individual patients with untreated TSH-oma were reported to be clinically euthyroid.10,5456 This emphasizes the importance of systematic measurement of TSH and FT4 in all patients with pituitary tumor, to disclose those with central hyperthyroidism or central hypothyroidism. In some acromegalic patients, signs or symptoms of hyperthyroidism are missed, as they are overshadowed by those of acromegaly.24,57 Severe thyrotoxic features, such as atrial fibrillation, cardiac failure, and episodes of periodic paralysis,5860 are observed in about one fourth of cases.

Table 10-1

Clinical Characteristics of Patients With Pituitary Thyrotropin (TSH-oma) (Data from reports published until December 2007)

  Patients With TSH-oma % (n/total)*
Age, years 40.9 ± 14.5 (312)
Sex, female 55 (180/325)
Previous thyroid ablation 33 (95/290)
Severe thyrotoxicosis 29 (60/204)
Goiter 93 (219/235)
Thyroid nodule(s) 72 (46/64)
Macroadenomas 87 (227/261)
Visual field defect 40 (61/154)
Headache 20 (23/117)
Menstrual disorders 33 (27/81)

*n/total refers to the number of patients for whom the information was available.

Mean ± SD (n).

Data include women with or without associated prolactin (PRL) hypersecretion.

The presence of a goiter is the rule (93%), even in patients who have undergone previous partial thyroidectomy. Because the thyroid is intrinsically normal in this disorder, it may regrow even after near total resection as a consequence of TSH hyperstimulation. Occurrence of multinodular goiter has been reported in several patients,61 and differentiated thyroid carcinoma has been reported in other patients.6265 Progression toward functional autonomy seems to be infrequent.66,67 In contrast to Graves’ disease, the occurrence of circulating antithyroid autoantibodies is similar to that found in the general population. Unilateral exophthalmos due to orbital invasion by pituitary tumor was reported in three patients with TSH-omas, whereas Graves’-associated bilateral ophthalmopathy was reported in five patients.4

Most patients bearing a TSH-producing macroadenoma seek medical attention with signs and symptoms of an expanding intracranial tumor. Indeed, as a consequence of tumor suprasellar extension or invasiveness, signs and symptoms of tumor mass prevail over those of thyroid hyperfunction in many patients. Visual field defects are present in 40% of patients and headache in one fifth. Moreover, partial hypopituitarism is common, and loss of gonadal function is present in about one third of patients.22,68 Galactorrhea was recorded in almost all patients with mixed TSH- and PRL-secreting tumors.69,70

Finally, TSH-omas may occur in families with multiple endocrine neoplasia type I71-73 and in McCune-Albright syndrome.74

Biochemical Findings

TSH and Thyroid Hormone Levels

High concentrations of thyroid hormones in the presence of detectable TSH levels typically are present in patients with hyperthyroidism due to a TSH-oma or with resistance to thyroid hormone. In the case of replacement therapy for prior thyroidectomy or thyroid ablation, it is crucial to assess patients in steady state, as TSH levels need 4 to 6 weeks to adjust to a change in LT4 dose. Thus, the diagnosis of TSH-producing adenoma may be difficult to establish in any patient who has had a dramatic change in thyroid hormone replacement therapy resulting from physician instruction or poor compliance. Conversely, the finding of elevated TSH levels in patients who have undergone thyroid ablation and have been overtreated with LT4 should be regarded as a possible sign of previously undiagnosed TSH-oma.75

Various abnormalities in the pituitary-thyroid axis, as well as laboratory artifacts, may cause a biochemical profile similar to that of central hyperthyroidism. These different conditions are more common than are TSH-omas and resistance to thyroid hormone and should be excluded before an extensive clinical assessment of the possible presence of central hyperthyroidism is conducted. Familial or drug- or estrogen-induced increases in circulating thyroxine-binding globulin (TBG) or variants of albumin or transthyretin have led to increases in the levels of total serum thyroid hormone, particularly T4, thus producing a biochemical profile that may be confused with that of TSH-omas. Therefore, measurement of free thyroid hormones is mandatory in these conditions and should be performed by means of direct “two-step” methods (i.e., techniques by which contact between serum proteins and tracer can be avoided at the time of assay).76,77 Indeed, normal levels of total T4 were recorded in several patients with TSH-oma, and only the measurement of FT4 allowed the right diagnosis of central hyperthyroidism. Furthermore, inhibition of T4 to T3 conversion induced by iodine-containing drugs or nonthyroidal illness may cause hyperthyroxinemia and nonsuppressed TSH that are, however, associated with normal or low-normal T3. In clinically ambiguous situations, the differential diagnosis rests on recognition of the underlying disorder, as well as on documentation of normalization of thyroid function test results at a later stage or after recovery of drug withdrawal.

Several laboratory artifacts may cause falsely high serum levels of TSH or thyroid hormones (Table 10-2). The more common factors that interfere with TSH measurement are heterophilic antibodies directed against mouse gamma globulins78 or anti-TSH antibodies. However, preventing formation of the “sandwich” anti-TSH antibodies usually leads to an underestimation of the actual levels of TSH and rarely to an overestimation. The presence of anti-T4 or anti-T3 autoantibodies or both may cause FT4, FT3, or both to be overestimated, particularly when “one-step” analog methods are employed.77 Finally, because patients with a TSH-oma may have T3 toxicosis, as in other forms of hyperthyroidism, there is a need to measure T3, in particular, free T3, when T4 levels are normal.

In TSH-omas, extremely variable levels of serum TSH and thyroid hormones have been reported (Table 10-3). It is interesting to note that in patients who were treated previously with thyroid ablation, TSH levels were dramatically higher than in untreated patients, although free thyroid hormone levels were still in the hyperthyroid range and the reduction of total thyroid hormone levels was minimal. The conserved sensitivity of tumoral thyrotroph cells to even small reductions in circulating free thyroid hormone levels is confirmed by the rapidly increased rate of TSH secretion during antithyroid drug administration.57

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