Thyrotrophin-Secreting Pituitary Tumors

C H A P T E R

18 Thyrotrophin-Secreting Pituitary Tumors Yona Greenman

INTRODUCTION The coexistence of hyperthyroidism, a pituitary mass, and excessive thyrotrophin production are hallmarks of thyrotrophin-secreting adenomas (TSPAs) [1]. The diagnosis of these tumors was compromised in the era of early radioimmunoassays that did not distinguish between normal and suppressed thyroidstimulating hormone (TSH) levels. In patients with primary thyroid disease, which is by far the most common cause of hyperthyroidism, TSH levels are suppressed by the elevated peripheral thyroid hormones, and are thus undetectable in serum. When TSH itself is responsible for thyroid hyperstimulation, it is readily detected, being either inappropriately in the normal range or actually elevated. Because of the past laboratory limitations, patients were often misdiagnosed as having primary hyperthyroidism, leading to erroneous therapeutic decisions. Introduction of sensitive TSH immunoassays led to increased detection, as demonstrated in a recent epidemiological report from Sweden: the incidence rate rose from 0.05 per million per year in 1991 94 to 0.26 per million per year in 2005 09 [2]. Nevertheless, they remain a rare disorder, being the least prevalent among all pituitary adenomas, accounting for 0.7%, 0.6%, and 2.7% of pituitary adenomas in epidemiological [3], postmortem pathological [4], and surgical [5] series, respectively.

PATHOGENESIS The role of disordered hypothalamic or peripheral endocrine function versus the presence of intrinsic lesions in the pituitary cell in the pathogenesis of pituitary adenomas has been the focus of intense investigations [6]. TSH-secreting tumors, as other types of pituitary adenomas, were found to be monoclonal in

The Pituitary. DOI: http://dx.doi.org/10.1016/B978-0-12-804169-7.00018-0

origin [7]. Several mechanisms are involved and probably interact to initiate transformation and promote proliferation of pituitary cells, including mutations in pituitary tumor-susceptibility genes, overactivation of proliferative cell-signaling pathways, under-expression of tumor suppressor genes, and alterations in hormone-regulatory pathways [8].

Hormone-Regulatory Pathways The secretion of TSH, a glycoprotein hormone composed of α- and β-subunits, is controlled by the integrated thyrotroph response to thyrotrophin-releasing hormone (TRH) stimulation and the negative feedback inhibition by thyroid hormones. TRH secreted by neurons in the paraventricular nucleus of the hypothalamus is the major stimulator of pituitary TSH synthesis and secretion [9]. TRH also modulates biologic activity of TSH by controlling its posttranslational glycosylation [9]. Thyroid hormones mediate the negative feedback regulation of both TSH and TRH genes, for which normal thyroid hormone receptors are essential. Thyroxine (T4) is converted to triiodothyronine (T3) by a type II 5’-deiodinase (D2). It then binds to thyroid hormone nuclear receptors (TR) that interact with thyroid-hormone-responsive elements on the promoter regions of TRH and TSH subunit genes, inhibiting their transcription rate [9]. Pituitary Hyperplasia in Long-Standing Hypothyroidism Loss of thyroid hormone feedback inhibition leads not only to TRH and TSH hypersecretion, but also to proliferation of TSH-secreting cells with compensatory hyperplasia. Thyrotroph hyperplasia may be associated with prolactin cell hyperplasia and hyperprolactinemia, probably as a result of sustained TRH stimulation [10]. Histology reveals the preserved

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18. THYROTROPHIN-SECRETING PITUITARY TUMORS

anterior pituitary acinar pattern surrounded by a reticulin-fiber network, but individual acini are larger, and contain many “thyroidectomy cells.” These are large pale cells with eccentric nuclei and abundant vacuolated cytoplasm characteristically present in the pituitaries of experimentally induced hypothyroid rats, as well as in patients with untreated protracted hypothyroidism [10]. The hyperplasic cells probably originate from division of preexisting thyrotrophs and differentiation of stem cells into mature TSH-secreting cells. In addition, growth hormone (GH) and TSH bihormonal cells or “thyrosomatotrophs” have been identified in the pituitary of patients with protracted primary hypothyroidism, supporting the notion of transdifferentiation of somatotrophs to thyrotrophs contributing to the generation of thyroid cell hyperplasia [11]. Enlargement of the pituitary gland due to long-standing hypothyroidism is a well-recognized disorder [12]. Pituitary enlargement is sometimes prominent, with growth into the suprasellar space, mimicking a neoplastic process. Recognition of this entity has important clinical implications, as thyroxine replacement therapy fully resolves these “pseudotumors” of the pituitary, avoiding inadvertent surgery. Rarely, hyperplasia to adenoma transition may occur, and monoclonal TSPAs arising in the background of hyperplasia have been reported in a few patients with long-standing untreated hypothyroidism [7]. However, most TSPAs are primary pituitary lesions unassociated with thyroid failure and without underlying thyrotroph hyperplasia, suggesting that TRH stimulation does not play a central role in tumorigenesis, although it may act as a growth promoter of transformed cells. Impaired Thyroid Hormone Negative Feedback Defective negative feedback of thyroid hormones on TRH or TSH secretion could also be involved in the pathogenesis of TSH-secreting tumors. In most patients harboring TSPA, TSH levels do not suppress after administration of thyroid hormones [1]. One possible explanation could be alterations in expression or activity of deiodinase enzymes, leading to decreased T3 concentration in the tumoral tissue. Indeed, type 3 deiodinase (D3), that catalyzes the inactivation of biologically active T3 to diiodothyronine and of T4 to inactive reverse T3 (rT3), has been found to have a 6.5-fold increased expression in pituitary tumors, in comparison to normal pituitary tissue. In particular, the TSH-secreting tumor examined in that series expressed a 13.1-fold excess of D3 mRNA and reduced D2 mRNA (0.1-fold of normal pituitaries), suggesting that this pattern of deiodinase expression may contribute to the tumor resistance to thyroid hormone feedback [13]. Another mechanism for impaired thyroid hormone feedback on TSH secretion could involve

alterations in TR function. Human TR isoforms are encoded by two genes, THRA and THRB, located on chromosomes 17 and 3, respectively [14]. Through different promoter usage and alternative splicing, these genes generate several isoforms, with distinct tissue expression and ligand-binding properties. THRA encodes three isoforms, of which only TRα1, predominantly expressed in the heart and brain, binds T3, while the truncated forms TRα2 and TRα3 are unliganded and exert a dominant-negative effect on TR-mediated transcription. THRB encodes two T3-binding receptor isoforms: TRβ1, expressed mainly in skeletal muscle, kidney, and liver, and TR β2, expressed mainly in thyrotrophs and in TRH neurons, thus being pivotal for thyroid hormone axis regulation [15]. TRβ3, found only in rats, and TRβ4 [16] are unable to bind T3. TRβ2 germline mutations are the main cause of RTH syndromes and similarly to the unliganded TR isoforms, resistance to thyroid hormone (RTH)-related TRβ2 mutants have impaired feedback action on TSH secretion. The notion that impaired thyroid hormone feedback due to TR mutations may play a role in TSPA pathogenesis is supported by the finding that knock-in mice harboring a mutated TRβ (TRβPV/PV mouse) spontaneously developed TSPAs [17]. Unlike normal TRβ, the mutant TRβ does not bind the cyclic AMP response element-binding protein situated on the cyclin D1 promoter, thus leading to constitutive activation of this gene. Interestingly, mice deficient in all TRs, with similar loss of thyroid hormone feedback regulation, did not show pituitary cyclin D1 overexpression, nor did they develop TSPAs, suggesting that the presence of unliganded TRβ was required for tumorigenesis in the TRβPV/PV mouse model [17]. AKT and its downstream effectors mTOR and p70S6K are activated in these mice, causing increased pituitary cell proliferation and decreased apoptosis [18]. The possibility that altered TR expression or structure may be involved in TSPA pathogenesis has been explored in humans. Sequencing of TRα1 and TRβ1 from six tumors has been reported as normal, whereas no TRα1, TRα2, and TRβ1 mRNA expression was detected in one tumor [19]. In another study, normal expression levels of TRα and TRβ mRNA were detected in two TSH-secreting tumors, but the nuclear proteins were undetectable, suggesting a posttranscriptional defect in RNA processing [20]. Higher relative expression of TRβ4, an unliganded isoform, in three TSPAs relative to normal pituitary was hypothesized as a contributing factor to inappropriate TSH secretion by these tumors through disruption of the negative TSH regulation by TRβ1 or TRβ2 [16]. Somatic mutations in TRβ have been found in two TSH-secreting adenomas. In the first case, alternative

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PATHOGENESIS

splicing caused a 135-bp deletion within the ligandbinding domain of TRβ2 [21]. In the second case, a somatic mutation was identified in the ligand-binding domain of TRβ, that caused a His to Tyr substitution at codon 435 of TRβ1 corresponding to codon 450 of TRβ2 [22]. Both TRβ variants had impaired thyroid hormone binding, impaired T3-dependent negative regulation of TSHβ and glycoprotein α-subunit genes, and showed dominant-negative activity on the wildtype TRβ, accounting for the defective negative regulation of TSH in these tumors. Interestingly, the mutation found in the second case occurred in the same codon in which mutations causing RTHβ have been previously identified. Nevertheless, TSH-secreting tumors have been rarely reported [23,24] in the several hundred patients diagnosed with RTH, suggesting that germline mutations in TRβ are not sufficient to induce tumor formation. Altered Hypothalamic Signaling Increased hypothalamic hormone stimulation or, alternatively, defective action of inhibitory hypothalamic hormones could be involved in increased thyrotroph proliferation and TSH secretion. THYROTROPHIN-RELEASING HORMONE (TRH)

As already mentioned, TRH is the major stimulatory factor in TSH secretion. Mutations leading to constitutive activation of the TRH receptor or components of its signal transduction pathway could also be potentially involved in TSPA pathogenesis. Nevertheless, no mutations on the TRH receptor, Gαq, Gα11, or Gαs were detected in the tumors screened [25,26]. DOPAMINE

Dopamine (DA) and its agonists inhibit TSH secretion, while DA-receptor-blocking agents such as metoclopramide and domperidone increase TSH concentration both in euthyroid and hypothyroid subjects. The description of TSH-secreting tumors in two patients receiving long-term phenothiazine treatment raised the possibility of a facilitatory effect of this DAreceptor-blocking drug in the development of these tumors [27]. It should be noted, however, that longterm phenothiazine treatment does not enhance plasma TSH levels. Although impaired DA receptor function could potentially be associated with TSH-secreting tumors, no mutations on the dopamine type 2 receptor gene were detected in three TSPAs tested [28]. SOMATOSTATIN

Somatostatin lowers serum TSH concentrations in normal and hypothyroid patients, and also reduces the serum TSH response to TRH. TSH-secreting tumors express somatostatin receptors (SSTRs), mainly subtypes

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2 and 5, and respond to treatment with somatostatin analogues with decreased TSH secretion, in vitro inhibition of tumor cell proliferation, and clinical tumor shrinkage [29,30]. Loss of heterozygosity at the SSTR5 locus has been described in one TSH-secreting adenoma that was associated with unusual tumor aggressiveness and resistance to treatment with somatostatin analogues [31], but SSTR mutations have not been described in TSPAs. Hence, the somatostatin inhibitory pathway seems to be intact and not involved in the pathogenesis of these tumors.

Alterations in Pituitary Transcription Factors The β-TSH gene is under transcriptional control of Pit-1, a transcription factor restricted to the anterior pituitary gland, and specifically expressed in thyrotrophs, lactotrophs, and somatotrophs. Although Pit-1 is critical for the survival and proliferation of these cells, no mutations on Pit-1 were detected, but overexpression of the gene was found in most cases investigated [19].

Oncogenes, Tumor Suppressor Genes, and Growth Factors Amplified, mutated or overexpressed oncogenes, or inactivated tumor suppressor genes prevalent in other neoplasms are rarely involved in the development of pituitary tumors. Loss of heterozygosity on 11q13 was found in three of 13 TSPA, but none had mutations on the menin gene located in this region [32]. The gsp oncogene detected in 40% of GH-secreting tumors is not expressed in thyrotrophinomas [26]. Basic 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 [33]. bFGF may induce pituitary tumor transforming gene (PTTG) expression [34], an oncogene found to be overexpressed in pituitary tumors. PTTG-targeted overexpression using the α-glycoprotein subunit promoter was associated with the development of plurihormonal hyperplasia and microadenomas, secreting TSH, luteinizing hormone (LH), and GH in a transgenic mouse model [35].

Familial/Genetic Syndromes Pituitary tumors may develop as a consequence of germline mutations causing familial syndromes. The multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1. Forty percent of patients with the MEN1 syndrome develop pituitary adenomas, with a predominance of macroprolactinomas [36].

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TSPA associated with the MEN1 syndrome has been reported in very few cases [37 39]. The McCune Albright syndrome is caused by mosaicism for an activating mutation of GNAS, the gene encoding Gs-α. Pituitary hormone hypersecretion in this syndrome is usually secondary to somatotroph hyperplasia or GHsecreting tumors, but one patient with a plurihormonal tumor secreting GH, TSH, and prolactin has been reported [40]. Finally, thyrotrophinomas represent 0.5% of pituitary tumors in the familial isolated pituitary adenoma syndrome, which is caused by mutations in the aryl hydrocarbon receptor interacting protein gene [41].

PATHOLOGY Thyrotrophs represent approximately 5% of adenohypophyseal cells. Thyrotroph cell adenomas are composed of chromophobic cells that immunostain positively for TSHβ, α-subunit, and Pit-1. On electron microscopy, thyrotroph cell adenomas consist of elongated angular cells with long cytoplasmic processes containing small sparse, spherical secretory granules (50 200 nm), usually lining up along the cell membrane [42]. An interesting feature of TSH-secreting tumors is that many are plurihormonal, producing α-subunits, prolactin (PRL), GH, LH, and folliclestimulating hormone (FSH), in different combinations, in addition to TSH [19]. Most frequently GH and PRL are cosecreted with TSH, in line with the common transcription regulation by Pit-1 shared by these hormones. TSPAs may be monomorphous, consisting of one morphologically distinct cell type that produces two or more hormones, or plurimorphous, being composed of two or more morphologically distinct cell types each producing different hormones, sometimes in the same secretory granule [19]. Despite positive immunostaining in the cell cytoplasm, hormone production may not always be manifest clinically, or by increased serum TSH levels. This discrepancy could be due to synthesis of TSH molecules that are either not being secreted or are not detected by routine assay methods. Secretion of uncombined α- and β-subunits that are biologically inactive could explain the lack of clinical expression of these tumors. TSH-secreting tumors are usually invasive macroadenomas that tend to have a very fibrous consistency, possibly due to increased expression of bFGF [33]. In a recent series, three of 10 TSH-secreting tumors were classified as atypical adenomas according to the World Health Organization criteria (invasive growth, increased mitotic activity, and positive staining for p53 and Ki67 in greater than 3% of cells) [43]. Nevertheless, these three tumors did not recur or metastasize, indicating a lack of relationship between

the morphological features and the biological behavior in these cases. Thus far, three TSH-secreting carcinoma cases have been described [44 46]. Besides being locally invasive, there was also evidence of tumor metastasis to lung, liver, bone and the abdominal cavity [44], brain tissue [45], and intrathecal space [46].

CLINICAL FEATURES The mean age at diagnosis is approximately 45 years, ranging from 8 to 84, with a female-to-male ratio of 1:1.12 (Table 18.1). The clinical presentation is related to the pattern of hormone hypersecretion by the adenoma, as well as to the presence of compression of neighboring structures by the tumor, depending on its size.

Hyperthyroidism Most patients with TSH-secreting tumors present with classic symptoms and signs of hyperthyroidism of variable severity, indistinguishable from those caused by primary thyroid disease. Unlike Graves’ disease, however, the female preponderance characteristic of autoimmune thyroid disease is not apparent, pretibial myxedema and acropachy are absent, and ophthalmopathy is rare. Bilateral exophthalmos was present in a few patients with concurrent Grave’s disease [66], or that subsequently developed autoimmune thyroiditis. Unilateral exophthalmos due to orbital invasion by the pituitary tumor has been reported in three patients with TSPAs [67]. The history of thyroid dysfunction is often long, with a diagnosis delay that may reach several years, particularly when patients are misdiagnosed and treated as for primary hyperthyroidism [59]. The mean delay between documentation of hyperthyroidism and diagnosis of a TSH adenoma was 6 6 2 years in patients with intact thyroid, as opposed to 12 6 3 years in those with previously treated thyroids [64]. Nevertheless, more recent series report a significantly shorter mean latency time of 4.5 months between onset of symptoms and diagnosis [47]. However, the diagnosis of TSPA may be delayed by the association with Hashimoto’s thyroiditis [68], because of the absence of hyperthyroidism in these patients. The inadequate suppression of TSH during Lthyroxine replacement therapy in these cases should suggest the presence of autonomous TSH secretion. Inappropriate thyroidectomy or radio-iodine thyroid ablation were reported in 30% of patients in earlier series [19], but in only 5% in a recent report [5]. Cardiovascular symptoms related to thyrotoxicosis such

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CLINICAL FEATURES

TABLE 18.1

Clinical Characteristics of Patients With TSH-Secreting Pituitary Tumors Mean age (years)

n

F/M ratio

Goiter

Visual impairment

Acromegaly Hyperprolactinemia Macroadenomas

Gatto [47]

13

42

4/9

7/13

3/13

0/13

0/13

10/13

Yamada [5]

90

42

47/43

44/52

13/90

14/90

11/90

74/90

70

44.1

36/34

14/70

2/70

49/70

Kirkman, 2014

32

53

16/16

2/32

28/32

Van Varsseveld [49]

18

48

6/12

Onnestam [2]

28

56

17/11

Elston, 2010

6

40.8

3/3

Macchia [50]

26

45

Marucci [43]

10

Clarke [51]

21

Roelfsema [52]

5

1/4

Yoshihara [53]

8

1/7

Kienitz [54]

5

58.6

5/0

Ness-Abramof [55]

11

44.8

5/6

Bogazzi [56]

8

45

6/2

Mannavola [57]

8

Teramoto [58]

20

41.2

16/4

Socin [59]

43

44

Wu [60]

7

48

Sarlis [61]

21

Caron [62]

11

Kuhn [63]

18

Malchiodi [48] a

b

Brucker-Davis [64] c

Losa, 1999 Losa [65]

4/18

2/18

2/18

13/18

8/28

4/28

9/28

16/28

6/6

2/6

3/6

0/6

5/6

15/11

21/26

3/26

1/26

0/26

11/26

46.5

5/5

1/10

46

6/15

4/18

8/21

1/10

10/10

1/21

16/21

5/5

4/5

4/5

1/5 6/11

2/11

3/5 10/11

5/3

5/8 16/20

3/20

3/20

18/20

20/23

8/43

9/43

34/41

6/1

1/7

6/7 20/21

43

6/5

1/11

9/9

5/18

2/18

20/25

9/25

25

44

17/8

24

40.1

11/13

5 d

11/32

9/11 11/16

1/25

3/25

23/25

5/24

2/24

18/24

3/2

4/5

Persani, 1997

10

Beck-Peccoz [19]

280 41

140/115 166/177

53/126

Total

823 44.7

1.12

29.5% (122/416)

78% (299/381)

15% (103/695)

9/30

172/243

11.5% (80/685)

77.4% (397/513)

a

Kirkman et al. World Neurosurg 2014;82:1224 31. Elston et al. Intern Med J 2010;40:214 9. c Losa et al. Pituitary 1999;2:127 31. d Persani et al. Clin Endocrinol (Oxf) 1997;47:207 14. b

as tachycardia, atrial fibrillation, and heart failure are not frequently described, and episodes of periodic paralysis have been rarely reported [67].

Goiter The thyroid gland is enlarged as assessed by physical examination in about 80% of patients (Table 18.1).

Thyroid nodules are frequently reported, but differentiated thyroid carcinomas were documented in only a few cases [69]. Goiters are frequent even in patients who had previously undergone thyroidectomy, since the thyroid remnant may enlarge as a consequence of persistent TSH stimulation. In fact, regrowth of the thyroid gland after thyroidectomy in patients inappropriately treated

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for primary thyroid disease may alert the physician to the presence of excess TSH production.

Pituitary Tumor Mass Effect TSH-secreting tumors are usually large, with a 77% rate of macroadenomas at the time of diagnosis (Table 18.1). The high frequency of invasive macroadenomas in this tumor subtype has often been attributed to delayed diagnosis that was common before the era of sensitive TSH immunoassays. Increased incidence of invasive macroadenomas in patients previously undergoing thyroid ablation has been reported, as compared to intrasellar tumors more frequent in patients not having received primary treatment directed to the thyroid gland [19]. Tumor invasiveness in patients with a history of previous thyroid ablation may be synonymous with that described in patients developing Nelson syndrome after bilateral adrenalectomy for Cushing disease [67]. In view of the high rate of macroadenomas, signs and symptoms secondary to compression of surrounding anatomic structures are common. Visual field defects and impaired vision are reported in approximately 30% of patients and complaints of headaches are not uncommon. Studies of anterior pituitary hormone function are not reported in detail in most series, impairing the accurate assessment of the prevalence of hypopituitarism. Symptoms indicative of hypogonadism such as amenorrhea, impotence, and decrease libido are reported in 15 20% of cases, but they may often be secondary to coexistent hyperprolactinemia. In a recent large series 12.8% of patients (9/70) were diagnosed with hypopituitarism (five patients had hypogonadism, one had hypoadrenalism and three had both) [48]. With the considerable evolution of the diagnosis of TSPA in the last decades due to the widespread availability of ultrasensitive methods for TSH measurement, and improved pituitary imaging, it could be anticipated that tumors would be diagnosed at an earlier stage. Indeed, there are reports of increased relative incidence of microadenoma [5,59] in the more recent period of large case series, but this finding is not universal, with the high ratio between macro- and microadenomas remaining stable over time in other cohorts [48,50]. Moreover, the latency in diagnosis was significantly shorter over time in macroadenomas, suggesting that TSPAs tend to be large and invasive in nature, and not as a consequence of diagnosis delay [47,50].

Hormone Cosecretion Cosecretion of GH occurs commonly, being reported in approximately 15% of patients (Table 18.1). In some patients with acromegaly, signs and symptoms of

hyperthyroidism may be overlooked, as the clinical picture related to GH hypersecretion may predominate. Hyperprolactinemia has been reported in almost 12% of patients, mostly manifesting with amenorrhea, galactorrhea, impotence, or decreased libido in addition to TSH-induced hyperthyroidism (Table 18.1). Although cosecretion of prolactin by the tumor itself is common, in some of the patients hyperprolactinemia may be secondary to stalk compression by the large TSPA. Cosecretion of FSH and/or LH is uncommon, being found in up to 6% of cases [48]. LH hypersecretion may rarely manifest with elevated androgen levels [70]. Immunohistochemical reports of a higher incidence of hormonal coexpression, suggest that these hormones may not be secreted in sufficient quantities to lead to clinical disease [51]. Positive immunostaining for adrenocorticotrophic hormone has been reported in eight cases, with no clinical evidence of hypercortisolism [51,55,60,70].

DIAGNOSIS Laboratory Studies The presence of elevated, inappropriately normal, or barely detectable TSH levels, measured by a reliable and sensitive assay, concurrently with elevated peripheral thyroid hormones is essential for the diagnosis of a TSH-secreting tumor. Nevertheless, many patients initially misdiagnosed and treated for primary hyperthyroidism were rendered euthyroid or hypothyroid by thyroid ablation and were no longer hyperthyroid at the time of diagnosis. Currently available sensitive TSH immunometric assays clearly distinguish the markedly suppressed TSH levels found in primary hyperthyroidism from conditions in which the thyrotroph is not suppressed to such a degree. The importance of early diagnosis should be emphasized, as it may increase the chances of identifying smaller tumors with a more favorable outcome [59]. TSH levels vary widely, being several-fold higher in patients previously treated with thyroid ablation (89 6 33 mU/L), compared to those with intact thyroid (6.2 6 1.9 mU/L), despite peripheral thyroid hormone levels still in the hyperthyroid range [64]. TSH levels were within the normal range in 33% of patients with intact thyroid, in comparison with 11% of patients who underwent previous thyroid ablation [19]. In a more recent series [5], TSH levels were normal in 70% of patients. There was no correlation between TSH levels and tumor volume [5], or between the severity of clinical hyperthyroidism and TSH levels, suggesting the existence of TSH molecules with variable biologic activity [71]. Although TSH molecules secreted by these

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DIAGNOSIS

tumors are immunologically identical to native TSH, the biologic/immunologic (B/I) ratio of serum or tumor-derived TSH from patients with thyrotrophinomas is usually increased [72], secondary to variant or aberrant glycosylation of TSH [71,73]. Glycoprotein α-subunit levels are increased in about 63% of patients with TSH-secreting tumors (Table 18.2). Normal α-subunit levels seem to be found more TABLE 18.2

frequently in microadenomas than in macroadenomas [74]. Furthermore, caution should be exercised when evaluating α-subunit levels in menopausal women or in men with primary hypogonadism, as the elevated gonadotrophins could contribute to the observed elevated α-subunit level, which is common to the glycoprotein hormones. In these patients, different normal criteria have been suggested [1].

Laboratory Characteristics of Patients With TSH-Secreting Pituitary Tumors n

Gatto [47]

13

Yamada [5]

90

Malchiodi [48]

Thyrotoxicosis

TSH range (mU/L)

Elevated α-SU

α-SU/TSH molar ratio .1

1.2 13.2 83/90

1.8 4.3f

44/58

70 a

Kirkman, 2014

32

8/32e

0.1 7.4

Van Varsseveld [49]

18

16/18

0.9 51.5

Onnestam [2]

28

b

7/11

6/11

1.3 55

Elston, 2010

6

6/6

2.7 18

4/3

4/4

Macchia [50]

26

18/26

1.4 9

18/26

25/26

Marucci [43]

10

8/10

Clarke [51]

21

10/21

Roelfsema [52]

5

5/5

1.4 5.8

3/5

Yoshihara [53]

8

8/8

0.4 8.2

Kienitz [54]

5

5/5

2 126

Ness-Abramof [55]

11

6/11

Bogazzi [56]

3/5

3/5

8

7/8

7/8

Mannavola [57]

8

1/5

1/5

Teramoto [58]

20

0.46 55

15/19

19/19

Socin [59]

43

0.1 12

13/43

Wu [60]

7

Sarlis [61]

21

Caron [62]

11

Kuhn [63]

18

18/18

25

22/25

Losa, 1999

24

20/24

Losa [65]

5

Brucker-Davis [64] c

d

Persani

10

Beck-Peccoz [19]

280

Total

823

32/43

1.1 393

1/3

3/3

8/14

12/14

93/142

108/135

62.6% (216/245)

80.6% (187/232)

1.1 7.8 2/10

76% (267/352)

0.1-126

a

Kirkman et al. World Neurosurg 2014;82:1224 31. Elston et al. Intern Med J 2010;40:214 9. Losa et al. Pituitary 1999;2:127 31. d Persani et al. Clin Endocrinol (Oxf) 1997;47:207 14. e Defined as clinical hyperthyroidism. f Interquartile range. b c

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An α-subunit/TSH molar ratio greater than 1 is found in about 80% of patients with documented TSPAs (Table 18.2). This ratio is helpful in the differential diagnosis between thyrotrophinomas and nontumorous TSH hypersecretion, where the ratio is usually less than unity.

Dynamic Tests Dynamic testing may be helpful for the differential diagnosis between TSPA and RTH. It is particularly important in patients in whom imaging does not reveal a defined pituitary mass or when only a microadenoma is apparent. In these cases, the association of RTH with a pituitary incidentaloma may be difficult to discern from a TSH-secreting tumor [24,75]. The combined use of the T3 suppression test and the TRH test has increased specificity and sensitivity for the diagnosis work-up in these situations [67]. TRH Test The absence of a TSH response to exogenous TRH stimulation was initially believed to be a universal finding in patients with TSPA, implying autonomous TSH hypersecretion by the tumor. Although this is true for most patients, over 20% do in fact respond normally to TRH, with a poststimulatory doubling of basal TSH levels [5,59,64]. Hence, a blunt TSH response to TRH stimulation supports the presence of a TSPA, but a normal test by no means excludes the diagnosis. The α-subunit and the TSH responses to TRH are usually parallel, but in some instances a TRH-induced rise in α-subunit values occurred despite an absent TSH response [74,76]. According to BruckerDavis et al. [64], in patients with intact thyroid, the most sensitive test to identify a TSH-secreting adenoma was an elevated α-subunit/TSH ratio (83%), followed by an elevated α-subunit level (75%), a flat or decreased response to TRH (71%), and an elevated baseline TSH (43%). A flat or decreased response to TRH was the most specific test for the diagnosis of TSPA (96%), followed by elevated α-subunit (90%), elevated baseline TSH (88%), and elevated α-subunit/ TSH ratio (65%). The TSH response to TRH had the best positive and negative predictive value. In patients with prior thyroid treatment, the TRH test was less sensitive (64%), but was highly specific (100%) [64]. T3 Suppression Test T3 administration (80 100 μg per day for 8 10 days) completely inhibits TSH secretion and suppresses TRH-stimulated TSH values in normal subjects, and brings to substantial inhibition of TSH secretion in patients with RTH [75], whereas patients

harboring TSH-secreting tumors do not suppress TSH levels normally after exogenous administration of T3 or T4 [1]. Notably, reduction of circulating T4 or T3 by antithyroid drugs results in elevation of TSH levels in the majority of TSPA patients, suggesting that endogenous elevated thyroid hormone levels have some inhibitory effect on tumor thyrotroph function [74]. Although T3 suppression seems to be the most accurate test to differentiate between TSPA and RTH syndromes, this test is contraindicated in elderly patients or in those with coronary heart disease. Octreotide Test Somatostatin and its analogues inhibit TSH secretion in physiological conditions and in most TSPA since they express functional SSTRs [29,30]. Acute subcutaneous administration of octreotide (50 100 μg) reduced TSH levels to less than 50% of basal levels in 70% of patients [5,58]. Patients with RTH respond with a similar degree of TSH reduction to the acute octreotide test [57]. However, continued treatment with octreotide-LAR for 2 months did not alter TSH and peripheral thyroid hormone levels in patients with RTH, whereas free thyroid hormones normalized or significantly decreased in 7/8 patients with TSPA [57]. Thus, a 2-month clinical trial with somatostatin analogues, but not the acute octreotide test, may assist in the differential diagnosis of difficult cases of central hyperthyroidism. Circadian Secretion of TSH The circadian rhythm of TSH secretion is lost in most patients with TSPA [77]. The TSH secretion pattern studied in five patients was characterized by increased pulse frequency, delayed diurnal rhythm, enhanced basal secretion, spikiness, and disorderliness [52].

Pituitary Imaging Most reported thyrotrophinomas are large macroadenomas which frequently invade surrounding structures such as the cavernous and sphenoid sinuses; they also extend suprasellarly, and may compress the optic chiasm. Delayed diagnosis and previous inadvertent ablative therapy to the thyroid gland, thereby reducing endogenous negative feedback on the thyrotroph, have been implicated as possible causes for this relatively aggressive tumor proliferation [67]. On the other hand, it is possible that the tumors display an inherently more invasive growth behavior irrespective of diagnosis delay [50]. CT and magnetic resonance imaging (MRI) are currently used for the evaluation of pituitary and parasellar abnormalities and masses, but MRI has the

III. PITUITARY TUMORS

DIFFERENTIAL DIAGNOSIS

additional advantage of better delineating the relationship of pituitary tumors to surrounding structures. In 80% of patients thyrotrophinomas were hypoenhancing with respect to the normal pituitary after gadolinium administration [61]. Approximately 20% of TSPAs are microadenomas (Table 18.1) mainly diagnosed by MRI, although in isolated cases explorative transsphenoidal surgery [72] or inferior petrosal sinus sampling [78] were necessary for tumor localization. One-quarter of patients harboring macroadenomas had minimal or no suprasellar extension, while the remainder had either marked suprasellar extension or invasion of sphenoidal and cavernous sinuses [19]. Some of these tumors were highly invasive, extending to the hypothalamus, brain stem, or orbit [67]. Thyrotrophinomas have been successfully imaged by means of indium-111 pentetreotide single-photon emission tomography, further confirming the presence of SSTRs in these tumors in vivo [65]. There was a trend for a direct correlation between the degree of TSH inhibition after acute octreotide administration and the degree of radioisotope uptake by the tumor, but larger series are necessary to confirm these findings. This imaging modality may also play a role in the identification of ectopic tumors, although so far only two cases of ectopic TSPA have been reported in the nasopharynx [79]. The presence of tumoral dopamine receptors has been demonstrated in vivo by iodine-123 iodobenzamine scanning in one patient [80].

DIFFERENTIAL DIAGNOSIS In the differential diagnosis of patients presenting with elevated thyroid hormone levels and normal or elevated circulating TSH, a series of conditions need to be considered, including methodological assay interference, abnormalities in thyroid hormones binding proteins, and rare syndromes of impaired sensitivity to thyroid hormone. The term “inappropriate TSH secretion” has been used to describe two entities: (1) neoplastic TSH secretion and (2) nonneoplastic pituitary hypersecretion of TSH due to RTH. In fact, this is a misnomer, as the increased TSH secretion in RTH is appropriate and compensatory to the reduced tissue sensitivity to thyroid hormones. In recent years, in addition to the first described RTH syndrome secondary to mutations in THRB, other inheritable forms of impaired sensitivity to thyroid hormone were identified, including defects in thyroid hormone cell membrane transport, thyroid hormone metabolism defects, and RTH due to mutations in THRA [81]. In contrast with RTHβ, which presents a challenge in the differential diagnosis of TSPA, these disorders are usually

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discernible by their distinct clinical features and will be presented only briefly.

Impaired Sensitivity to Thyroid Hormones Resistance to Thyroid Hormone β (RTHβ) RTHβ is a rare inherited autosomal dominant disease, most commonly caused by heterozygous point mutations in THRB. Most mutations affect the Cterminal ligand-binding domain, reducing TRβ affinity for T3 or impairing the interaction with corepressors or coactivators involved in the regulation of target genes transcription. The defective TRβ exerts a dominantnegative effect by interfering with the function of the normal allele [82]. THRB gene deletions have a recessive inheritance, are rare, and result in a more severe phenotype. Most patients with RTHβ are asymptomatic and normo-metabolic as elevated thyroid hormone levels compensate for the reduced affinity of the mutant TRβ for T3. However, clinical manifestations are variable, depending on the degree of sensitivity and TR expression in different tissues. Hence, symptoms of hypo- and hyperthyroidism may coexist in the same individual, due to a combination of low thyroid hormone action in organs predominantly expressing TRβ and high thyroid hormone action in TRα-expressing tissues. The same mutation may manifest with different phenotypes in the same family and across families, but the molecular basis of this heterogeneity is not well understood [82]. Common clinical manifestations include goiter and tachycardia in up to 95% and 75% of patients, respectively. Learning disabilities, hearing loss, and delayed bone maturation with short stature are characteristic of patients diagnosed at an early age. The differentiation between a TSPA and RTHβ may sometimes be challenging. Although the finding of a clear adenoma on MRI strongly supports the diagnosis of TSPA, the possible association between an unrelated pituitary adenoma in the background of RTHβ should be kept in mind [1]. Further, patients with TSHsecreting microadenoma not demonstrable by imaging techniques may be difficult to distinguish from patients with RTHβ [83]. In these cases, screening family members for thyroid function abnormalities may be helpful. Alternatively, direct screening for TRβ mutations may be required, with the caveat that in 15% of patients with RTH no thyroid hormone action defects were identified (non-TR-RTH), raising the possibility that deficiency/mutations in cofactors may be involved in the etiology of these cases. Biochemically, mean free T4 and TSH levels are slightly higher in patients with TSPA compared to

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those with RTHβ, but there is a large overlap [83]. Normal α-subunit levels and α-subunit/TSH molar ratios support the diagnosis of RTHβ but are not specific, as normal values may also be found in TSPA. When dynamically tested, RTHβ patients usually display an exaggerated TSH stimulation by TRH, and often TSH levels are suppressible by thyroid hormones, in contrast to patients harboring thyrotrophinomas [83]. The response to long-acting somatostatin analogues may also be useful in this differential diagnosis as patients with TSPA usually display a marked decrease in thyroid hormone levels, while patients with RTH do not respond [57]. Peripheral markers of thyroid hormone action may also assist in the differential diagnosis of these two entities. Circulating sex-hormone-binding globulin is elevated in over 90% of TSPA patients, reflecting clinical hyperthyroidism, whereas levels are usually normal in generalized thyroid hormone resistance [19]. Similarly, markers of bone turnover such as carboxyterminal crosslinked telopeptide of type I collagen are elevated in the hyperthyroid state caused by TSHsecreting tumors and are in the normal range in thyroid resistance syndrome. Thyroid color flow Doppler sonography (CFDS) has been suggested as an adjunctive tool for differentiating patients with TSPA versus RTHβ. Baseline CFDS pattern and peak systolic velocity were elevated in both conditions at baseline; after the T3 suppression test, these parameters normalized in most patients with RTHβ, but not in those with TSPA [56]. Resistance to Thyroid Hormone α (TRHα) This rare disorder is caused by heterozygous loss of function mutations in THRA, and manifests with symptoms of hypothyroidism at birth or in childhood. Free T4 levels are low or low-normal, free T3 is high or high-normal resulting in abnormally low T4/T3 ratio concurrent with normal TSH levels [84]. Monocarboxylate Transporter 8 (MCT8) Defect A defect in the active transport of T3 into cells is caused by mutations in the monocarboxylate transporter 8 gene located on the X chromosome [82]. Affected males present with severe psychomotor disorders and a combination of low levels of T4, high concentrations of T3, and low levels of reverse T3, with slightly elevated TSH levels. Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Defect Another cause of impaired biological activity of thyroid hormone is decreased generation of deiodinase 2. This is caused by mutations in sequence-binding protein 2 (SBP2), thus producing a variable decrease in several

selenoproteins [82]. The characteristic laboratory findings in subjects with SBP2 mutations are high T4, low T3, high rT3, and slightly elevated levels of TSH.

Euthyroid Hyperthyroxinemia Several conditions may cause euthyroid hyperthyroxinemia. They are not uncommon and should be excluded before considering an extensive work-up for TSPA or RTHβ [85]. 1. Assay interference a. TSH measurement: TSH levels may be spuriously elevated in some assays due to the presence of anti-TSH immunoglobulins, human antianimal antibodies (HAA), or heterophile antibodies [85]. b. Free (F)T4/FT3 measurement: Artifactual high FT4 or FT3 levels can be caused by thyroxinebinding antibodies, HAA, or heterophile antibodies that interact with the assay antibody. This type of interference is assay-dependent and is less common with current assays [86]. 2. Abnormalities in circulating thyroid-binding proteins a. Increased thyroid-binding globulin levels, either congenital or secondary to drugs (oral estrogen, raloxifene, tamoxifen, mitotane, fluorouracil, methadone, heroin), or liver disease, are not uncommon. In these patients total thyroid hormones are elevated but free thyroid hormone levels are normal. Increased affinity binding to transthyretin may cause a similar biochemical profile [87]. b. Increased affinity binding of T4 and/or T3 to mutant albumin molecules, as occurs in familial dysalbuminemic hyperthyroxinemia, is associated with elevated total thyroid hormone concentrations. Free thyroid hormones may also be falsely increased on routine commercial assays, but are normal when measured by equilibrium dialysis [87]. 3. Drugs: Amiodarone may cause persistent elevation of FT4 with normal FT3 levels due to inhibition of type 1 deiodinase. High-dose intravenous furosemide, aspirin, and heparin can lead to increased FT4 and FT3 due to T4 and T3 displacement from thyroid hormone-binding proteins [88]. 4. Nonthyroidal illness (NTI): A variety of abnormal patterns of thyroid function tests may be found in NTI, depending on the progression and the type of the underlying condition. Although total T4 and T3 are typically low, T4 levels may also be elevated, mainly in acute major psychiatric illness [85].

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TREATMENT

TABLE 18.3 Secretion

Differential Diagnosis of Inappropriate TSH Total T4

Free T4

T3

TSH

TSPA

m

m

m

mor N

THRβ

m

m

m

mor N

THRα

kor N

kor N

m or N

N

MCT8 mutation

k

k

m

m or N

SBP2 mutation

m

m

k

m or N

EUTHYROID HYPERTHYROXINEMIA Increase in TBG

m

N

m

N

Familial dysalbuminemia

m

m

m

N

Assay interference

m or N

m or N m or N

m

m

Inhibition of T4 to T3 conversion Acute nonthyroidal illness

mkor N mkor N

m kor N

kor N N k

kor N

N, normal; m, increased; k, decreased; TSPA, TSH-secreting pituitary adenoma; RTH, resistance to thyroid hormone; MCT8, monocarboxylate transporter 8; SBP2, selenocysteine insertion sequence-binding protein 2; TBG, thyroid-binding globulin; TH, thyroid hormone.

5. Thyroxine treatment: Mildly elevated FT4 levels, possibly reflecting inefficient deiodination, may occur in patients receiving levothyroxine dosages to achieve TSH normalization. Another situation in which free T4 levels may be inappropriately elevated in the presence of normal or elevated TSH levels is poor compliance, or TSH measurements prior to achievement of steady-state levels. This “disequilibrium” situation also occurs physiologically during the neonatal period. Conditions to be considered when evaluating a patient for a TSH-secreting tumor are summarized in Table 18.3.

TREATMENT Surgery The goal of therapy in patients with TSH-secreting adenomas is to restore euthyroidism in hyperthyroid patients and eliminate the symptoms of mass effect in patients with large tumors. Selective transsphenoidal pituitary surgery is the preferred initial therapy for these patients, as it provides the possibility of complete removal of neoplastic tissue and definitive cure, thus controlling hyperthyroidism, while preserving anterior pituitary function [1]. Surgical cure, defined as

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absence of residual mass on pituitary imaging, normalization of thyroid hormone and TSH levels as well as of cosecreted hormones, has been documented in about 40% of patients after surgery [19]. More recent and larger series report better outcomes, with cure rates of 58% [48,59] and 84% [5], respectively. Remarkably, normalization of thyroid function despite the presence of residual tumor on imaging studies was noted in up to 41% of patients [48]. Not surprisingly, patients harboring microadenomas had a more favorable surgical outcome, with cure rates reaching 80% [48] to 100% [5] as compared to patients with macroadenomas in whom cure rates were 44% [48] and 81% [5], respectively. Presurgical treatment with somatostatin analogues [48], age, gender, fibrotic tumor consistency, and levels of thyroid hormones and TSH did not affect surgical outcome [5]. Although GH cosecretion, presence of visual disturbance, maximal tumor diameter, Knosp grade, and cavernous sinus invasion were associated with negative surgical outcomes by univariate analysis, only cavernous sinus invasion (RR 72.4, 95% CI, 10.5 1546) and maximal tumor diameter (RR 1.1 per mm, 95% CI, 1 1.3), remained significant independent predictors after multivariate analysis [5]. Following complete tumor resection, TSH levels may decrease below the normal range with a parallel decrease in FT4 levels for several months. Thyroid hormone replacement therapy for transient postoperative central hypothyroidism was necessary in 12% of 76 patients after surgical cure [5].

Medical Treatment Preoperative medical therapy is indicated to restore euthyroidism to reduce thyrotoxicosis-associated complications and prevent thyroid storm [89]. This can be achieved with short-term treatment with antithyroid drugs or somatostatin analogues [90]. Therapy directed at the thyroid gland level was previously used either because the patients were initially diagnosed as having primary thyroid disease, or as an attempt to control hyperthyroidism until the pituitary tumor could be targeted. Antithyroid drugs reduced thyroid hormone levels, at least temporarily, in most patients. In old series, about one-third of patients underwent partial or total thyroidectomy, or radioactive iodine ablation, sometimes on multiple occasions because of the recurrence of goiter and hyperthyroidism [19]. 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

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use of antithyroid drugs only for short-term preparation for pituitary surgery [1]. β-Adrenergic blocking agents such as propranolol provide temporary symptomatic relief and could be used as adjunct therapy. Somatostatin Analogues SSTR ligands are the most effective medical treatment for TSH-secreting tumors [1]. Expression analysis of SSTR subtypes has been conducted in very few tumors and found to be heterogeneous; in one case analyzed by qualitative RT-PCR the tumor expressed predominantly SSTR2, but all SSTR types except for SSTR1 mRNA were also expressed (Fig. 18.1) [91]. In other series using quantitative RT-PCR, SSTR2, and SSTR5 were the most abundantly expressed subtypes, although SSTR1 and SSTR3 were also significantly expressed in a few tumors [29,30,53]. 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 [30,53]. The clinical response sometimes can be dramatic, with marked tumor shrinkage occurring after just a few weeks of treatment [92] (Fig. 18.2). During short-term treatment (up to 2 weeks), shortacting octreotide induced a mean 74% decrease in TSH level in 90% of patients, with normalization of thyroid hormone levels in 73% [93]. A parallel decrease in α-subunits was reported in 78% of subjects. With treatment extension, the percentage of cases in which there was thyroid function normalization increased to 84 95%, tumor shrinkage was reported in 40 50%, improvement in visual fields occurred in 75% of patients, and goiter size reduction was reported in 20% [67,93]. An impressive improvement in visual field defects occurring just 3 hours after initiation of treatment has been reported [94]. Escape from short-acting octreotide treatment, manifesting with increased TSH

FIGURE 18.1 Expression of somatostatin receptor subtypes in a TSH-secreting tumor in comparison to expression in normal pituitary. Source: From Usui T, Izawa S, Sano T, Tagami T, Nagata D, Shimatsu A, et al. Clinical and molecular features of a TSH-secreting pituitary microadenoma. Pituitary 2005;8:127 34.

levels while thyroid hormone levels remained normal, was reported in 20% of 25 patients followed for 20 6 17 months [93]. Tachyphylaxis was successfully reversed by increasing the dose of octreotide. True escape from therapy occurred in 10 12% of patients, with complete resistance in 4% of cases [93]. The dose of octreotide required to achieve TSH normalization in patients with TSH-secreting adenomas was reported to be lower than that needed to suppress GH in GHsecreting adenomas [93,95]. Slow-release, long-acting preparations of octreotide and lanreotide are equally effective in the treatment of TSH-secreting tumors,

FIGURE 18.2 Marked tumor volume reduction of a mixed TSH/ GH-secreting tumor after 1 week of therapy with SC octreotide 50 μg TID and one IM injection of octreotide LAR 20 mg. (A) Baseline; (B) 2 months after diagnosis. Source: From Yoshihara A, Isozaki O, Hizuka N, Nozoe Y, Harada C, Ono M, et al. Expression of type 5 somatostatin receptor in TSH-secreting pituitary adenomas: a possible marker for predicting long-term response to octreotide therapy. Endocr J 2007;54:133 8.

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CONCLUSIONS

with thyroid function normalized in 80 90% of patients [62,63]. Primary medical treatment was given to few patients because of poor general condition, absence of a visible adenoma on MRI, or patient preference [55,59]. In a recent small series, primary therapy with SSTR ligands led to long-term (8.5 6 7 years) biochemical control in 6/7 patients [96]. One patient developed tachyphylaxis and required a dose increase after 3.7 years. This underscores the need for long-term follow-up of nonirradiated TSPA patients receiving primary or postoperative somatostatin analogue treatment, to accurately assess rates of remission and tachyphylaxis. Although the number of reported patients is small, primary treatment with somatostatin analogues has been advocated in view of its efficacy and safety record, and as a means to avoid or delay surgical/radiotherapy complications [47,49]. Cure of a TSPA by primary treatment with octreotideLAR has been reported [97]. Dopamine Agonists Dopamine agonists are seldom effective for the treatment of TSH-secreting adenomas [59]. Acute administration of bromocriptine reduced TSH levels in only 20% of patients tested [58]. However, normalization of thyroid function and tumor size stabilization have been reported in several patients receiving dopamine agonist therapy [54,55,98], one of which has been resistant to therapy with somatostatin analogues [99]. An acute paradoxical rise of TSH after L-dopa [100] and cabergoline administration [54] has been reported, but the mechanism and clinical significance of this finding remain unclear.

Radiotherapy Radiation therapy has been administered as an adjuvant treatment to patients not cured by surgery. In a recent single-center large series comprising 70 patients, 19 underwent radiation therapy (six conventional fractionated radiotherapy and 13 radiosurgery) [48]. After a mean follow-up of approximately 5 years, there was complete disappearance of the pituitary lesion in one patient, and a significant reduction of tumor size in five, whereas in the remaining patients tumor size remained unchanged. At last follow-up, 7/19 patients were still on medical treatment for the control of hormone hypersecretion. Thirty-two percent of irradiated subjects developed hypopituitarism. The risk of complications is potentially lower when stereotactic techniques are used, as radiation is delivered to the region of interest with less exposure of surrounding brain tissue. However, few long-term follow-up

studies have been reported, and specifically the small number of TSPA treated with these new techniques precludes accurate evaluation of efficacy and complication rates. The 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.

CRITERIA OF CURE AND FOLLOW-UP No single criterion is sufficient to define cure of TSPA patients. Normalization of thyroid hormone and TSH levels, albeit a clinical goal, does not necessarily reflect cure, as it may occur despite the presence of significant residual tumor mass. Undetectable TSH levels in the early postoperative period in patients who were hyperthyroid before surgery are predictive of complete tumor removal as all these patients were reported to have a normal postoperative MRI and normal TSH suppression after T3 administration [74]. Nevertheless, recurrence may also occur after apparent complete tumor surgical excision, especially in patients in whom dynamic stimulatory and suppressive tests of TSH secretion remain abnormal. Although these are rare tumors and treatment series are in general small and heterogeneous, it seems that multimodal therapy including surgery, somatostatin analogue treatment, and radiotherapy when indicated, are likely effective in controlling most patients [5,48,59]. There is still a lack of long-term follow-up data, precluding an accurate assessment of recurrence rates and escape from medical therapy, in particular for patients not undergoing radiation therapy. Careful long-term monitoring of these patients is indicated.

CONCLUSIONS With improved diagnostic techniques and increased awareness of the disease, TSH-secreting tumors are being more readily detected. It appears that diagnosis of the disease at an early stage of tumor growth may improve prognosis. As there are essentially few unique aspects of the clinical presentation of these hyperthyroid patients, their initial distinction from patients with primary thyroid disease is challenging, requiring the recommendation of routine TSH measurements for evaluation of hyperthyroid patients. Pituitary microsurgery is the cornerstone of treatment, providing a good chance of remission for small tumors, or improvement of symptoms by debulking larger tumors. Somatostatin analogues are recommended as

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second-line treatment after unsuccessful surgery, in light of their high effectiveness in controlling tumoral hypersecretion and sometimes tumor growth. Radiotherapy should be reserved for rare patients unresponsive to treatment with somatostatin analogues. With the availability of improved diagnostic and therapeutic tools, aggressive behavior characteristic of these rare tumors may be successfully controlled in many of these patients.

[17]

[18]

[19]

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