Diagnostic Approach to TSH-Producing Pituitary Adenoma

177:4

A Tjörnstrand and Diagnostic approach to 177:4 R183–R197 Review H Filipsson Nyström pituitary adenoma

DIAGNOSIS OF ENDOCRINE DISEASE Diagnostic approach to TSH-producing pituitary adenoma

Axel Tjörnstrand1,2 and Helena Filipsson Nyström2,3 Correspondence 1 2 Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden, Institute of Medicine, should be addressed 3 Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and Department of Endocrinology, to A Tjörnstrand Sahlgrenska University Hospital, Gothenburg, Sweden Email [email protected]

Abstract

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition. p

European Journal of Endocrinology (2017) 177, R183–R197 European Journal of Endocrinology European

Introduction

In 1960, Jailer and Holub proposed that the pituitary pituitary adenomas has evolved substantially. This is due could be responsible for excessive production of to the following reasons: use of ultrasensitive TSH methods thyrotropin (TSH) and secondary hyperthyroidism (1). It since the late 1980s (9, 10); the introduction of the was later confirmed 2( ) that the underlying cause was a concept ‘syndrome of inappropriate TSH secretion’ (11); TSH-secreting pituitary adenoma (TSHoma). After that, advances in imaging procedures, moving from computed TSHoma reports were scarce in the literature. It was not tomography (CT) to magnetic resonance imaging (MRI) until the 1980s that a few limited reports on the diagnosis with superior visualization of the pituitary area (12); of TSHomas were published (3, 4, 5, 6, 7, 8). Subsequently, and the use of somatostatin analogs in the therapeutic the diagnostic and therapeutic management of these rare management of these patients (13, 14).

Invited Author’s profile Helena Filipsson Nyström is a senior consultant within thyroidology at Sahlgrenska University Hospital in Göteborg, Sweden, and the leader of the largest thyroid unit in the country. Her research currently focuses on mental consequences in two groups of patients: women with Graves’ disease and children whose mothers have had mild iodine deficiency during pregnancy. She is the national representative for the Iodine Global Network and is part of the EUthyroid collaboration.

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10.1530/EJE-16-1029 Review A Tjörnstrand and Diagnostic approach to 177:4 R184 H Filipsson Nyström pituitary adenoma (%) c c c c d c c d d d c c d c c c c c c c c 0 5 N/A 28 20 33 79 84 50 42 60 40 50 20 29 24 38 50 36 17 46 100 50 (mean) Plurihormonal Neurosurgery Neurosurgery/pathology Endocrine Neurosurgery Neurosurgery Neurosurgery – Cohort Neurosurgery Endocrine Endocrine Endocrine Neurosurgery Neurosurgery Neurosurgery Endocrine Endocrine/neurosurgery Neurosurgery Endocrine Neurosurgery Endocrine Endocrine Endocrine Neurosurgery , years plurihormonal activity is reported from clinical manifestation c 42 (11–74) 47 (19–71) 42 (27–61) 47 (28–75) 41 (24–57) 53 (20–75) 44 (11–84) 45 (25–72) 44 (15–80) 45 (18–80) 38 (20–62) 50 (18–84) 44 (N/A) 35 (N/A) 37 (24–51) 42 (22–63) 44 (N/A) 41 (23–60) 43 (20–58) 46 (26–73) 48 (N/A) 56 (16–81) 43 (14–76) Mean age (range)

b 23 60 38 56 58 83 58 72 63 67 80 54 38 50 28 91 72 28 29 N/A N/A N/A N/A Invasive (%) (%) n p 5 (83) 5 (83) 6 (86) 7 (78) 5 (83) 74 (82) 10 (100) 10 (77) 14 (100) 28 (87) 25 (92) 10 (91) 11 (92) 34 (83) 19 (100) 14 (82) 49 (70) 14 (88) 16 (89) 13 (72) 16 (59) 45 (73) mm), 435 (81)

10 ≥ Macroadenoma Macroadenoma ( European Journal of Endocrinology European (%)

n 7 (50) 4 (67) 8 (32) 6 (55) 5 (50) 9 (69) 5 (83) 4 (33) 3 (43) 7 (37) 2 (22) 4 (25) 3 (50) 43 (48) 16 (50) 23 (53) 10 (59) 34 (49) 15 (71) 12 (67) 11 (39) 30 (48) 261 (49) Men, 6 6 7 9 6 14 25 11 90 10 13 32 12 43 19 17 70 16 21 18 28 62 ) 535 n Cases ( invasive includes extrasellar extension and/or invasion to the cavernous sinus; b

1993–2013 1970–1990 1982–1996 1989–2007 1991–2013 1992–2006 1993–2011 1993–2013 2002–2012 1970–2013 1971–1996 1976–1989 1976–2001 1978–1991 1982–1986 1982–1996 1982–2012 1983–1999 1983–2003 1987–2003 1989–2011 1990–2010 1990–2013 Study period 5 TSHoma cases is presented with demographic and radiologic data including the plurihormonal activity from biochemical ) 6 > ) ) ( ) ) 130 130 ) 127 ) 20 ) et al. ) 8 ( ) ) ) ( ( ) 7 ) 16 ) 128 19 98 ) 125 ) . ( plurihormonal activity is reported from immunohistochemic analysis. ( ) ( ( ( ) ) d a 18 ) a 15 119 et al. ) 5 et al. ( 4 et al. ( 126 ( 124 . ( (silent) ( (overt) ( ( 129 17 123 et al ( ( ( et al. et al. ( ( et al. a et al. Case series with et al. et al et al. et al. et al. et al.

et al. et al. et al. et al. et al. (reference no) et al. Cases have to some extent been previously reported; Azzalin a and biochemistry; N/A, not available. Study Wynne Brucker-Davis Ness-Abramof Yamada Marucci Gatto Azzalin Kirkman Total Table 1 Table immunohistochemical evaluation. Bertholon-Gregoire Beckers Socin Mindermann Gesundheit Losa Malchiodi Sanno Elton-Conaglen ( Clarke Varsseveld Onnestam Perticone

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Although a rare disease, noteworthy cohorts have been published. The six largest patient cohorts reported are from Japan (N = 90) (15), Italy (N = 70) (16), Belgium and France (N = 43) (17), England (N = 32) (18), Sweden (N = 28) (19) and the United States (N = 25) (20) (Table 1). These series and other reports have contributed to the collation of substantial knowledge on TSHomas over 50 years. In 2013, a comprehensive guideline from the European Thyroid Association (ETA) on diagnosis and treatment of TSHomas was published (21). The aims of this review are to put TSHoma diagnosing into a practical perspective and present up-to-date information on the differential diagnoses, concurrent diseases, and highlight on recent advances and indicate future areas of research in the imaging area. In this review, the reader

will approach the diagnosis step by step. In the majority Figure 1 of cases, TSHomas are located in the pituitary, but a few Time trend in national incidence of TSH-secreting pituitary cases of ectopic TSH production have been described adenoma (TSHoma) in Sweden 1990–2009, and number of with suprasellar localization (22) or in the nasopharynx TSHoma micro- and macroadenomas (<1 cm/≥1 cm) 1990–1994, (23, 24, 25, 26, 27). This review will also cover the 1995–1999, 2000–2004 and 2005–2010 (17). Republished with possibility of these rare cases. the permission from Journal of Clinical Endocrinology and Metabolism.

Epidemiology adenomas, which may be attributed to more sensitive diagnostic methods and the more widespread use of MRI Pituitary adenomas are the most common type of p scanners. abnormal cell growth in the pituitary (28) with a high Before the 1990s, when the diagnosis of secondary prevalence in the normal population. In a meta-analysis hyperthyroidism was facilitated by modern ultrasensitive from 2004, the authors found an overall prevalence of European Journal of Endocrinology European TSH methods (9, 10, 37), tumor size was often large at 16.7% (29) (14.4% in autopsy studies and 22.5% in time of diagnosis (17, 20). Since the introduction of the radiologic studies). Clinical manifestations of pituitary ultrasensitive TSH methods, TSH-producing adenomas adenomas imply a much lower prevalence. A series of are more frequently found at the stage of microadenomas studies on well-defined populations report a prevalence of (17, 19, 38, 39, 40). However, macroadenomas ( 10 mm in 75.7–94/100 000 inhabitants of clinically overt cases (30, > any dimension) still represent approximately 80–85% of 31, 32), and the reported incidence is 3.9–4.1 cases/100 000 all newly discovered TSHomas (Table 1). An inappropriate inhabitants per year (31, 33, 34). Pituitary adenomas thyroid ablation seems also to promote the development are one of the most frequently occurring intracranial of macroadenomas (17), suggesting a similar mechanism tumors, and the occurrence of pituitary adenomas seems to the Nelson syndrome in ACTH-producing tumors to be similar despite geographic or ethnic differences when cortisol (or T4/T3) feedback is removed. Therefore, (29, 35, 36). a prompt and proper diagnosis is highly warranted. TSHomas are the rarest among the pituitary adenomas, TSHomas are predominantly diagnosed in middle age, only representing 0.7–0.94% of all pituitary adenomas but there are cases reported in the range of 11–84 years of (31, 33, 34). A comprehensive study of the Swedish age (Table 1). national Pituitary Registry found a national prevalence of 2.8 clinically overt cases per million inhabitants and an incidence rate of 0.15 cases per million inhabitants per Histopathology of TSHomas year (19). Moreover, during the study period 1991–2011, the detection rate increased fivefold (Fig. 1). This follows TSH-secreting pituitary tumors are presumed to a general trend of higher detection rate for all pituitary represent a clonal expansion of abnormal cells.

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The TSH-producing cells represent <5% of all pituitary connected to hormonal hyperproduction, or on suspicion cells (41). This may explain why TSHomas are so of visual symptoms. Clinically silent TSHomas or TSHomas rare (19, 33, 34). Chromophobic polygonal or short- that present with active hormone production have similar spindled tumor cells are often seen in a diffuse pattern. prognosis and outcome (18). Only a quarter of surgically Also globoid or whorl-like appearance with intertwined treated patients with a positive histopathological TSH- cytoplasmic processes, stromal fibrosis, and calcification immunostaining present clinically (18). In clinically active are often noted (42). This has been attributed to an expression of the basic fibroblast growth factor (bFGF) (43) and corresponds well with clinical findings of fibrotic characteristics (41), seen in approximately 40% of TSHomas (17). In TSHomas, co-secretion of PIT-1 factor-dependent hormones (growth hormone (GH) and prolactin (PRL)) is common (Table 1). The frequency seems to vary considerably depending on clinical or histopathological classification. In the largest case series of TSHoma patients (15), clinical manifestations of acromegaly and hyperprolactinemia were observed in 14 (16%) and 11 cases (12%), respectively. Microscopically, however, positive immunostaining for GH was found in 36%, GH and PRL in 27% and PRL in 10% of cases (15). In this study, KI-67 was low; in only two patients, KI-67 was >3%. Pituitary cells express several regulatory receptors. Somatostatin analogs (SSA) have inhibitory effect on the hormone production in TSH-, ACTH- and p GH-secreting pituitary tumors (44), which is mediated by somatostatin receptors (SSTR), of which six subtypes have been characterized. TSHomas express SSTR 1, 2, European Journal of Endocrinology European 3, and 5, where SSTR 2 (with subtype 2A and 2B) is most frequent (45). Endogenous somatostatin binds with high affinity to all its receptors, SSTR 1–5, and the activation of SSTR 1, 2, 4 and 5 appears to induce cell-cycle arrest (44, 46). First-generation SSAs, such as octreotide and lanreotide, show preferential affinity for SSTR2 and moderate affinity for SSTR5. The newly available SSA, pasireotide, shows a preferential binding affinity for SSTR5 > SSTR2 > SSTR1 > SSTR3. Recent clinical studies have shown the efficacy of pasireotide in acromegaly and Cushing’s disease, respectively (47, 48).

Clinical presentation Figure 2 Although TSHomas are rare, they are an important entity TSH (A) and FT4 (B) at diagnosis of 28 TSH-secreting pituitary with a spectrum of clinical manifestations. Pituitary adenoma (TSHoma) patients with intact or treated thyroid adenomas can be discovered accidentally in the workup gland. Hormone levels are related to upper limit of normal with CT/MRI that is done for other reasons, such as in the (dotted line) (17). Republished with the permission from diagnostic procedure for a headache, through symptoms Journal of Clinical Endocrinology and Metabolism.

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TSHomas, often mild-to-moderate classic hyperthyreotic Laboratory assessment symptoms are common (17, 19, 20), although the time to diagnosis may be long (17, 19, 20). As symptoms may be First step discrete and the diagnostic procedures are complicated, a Before conducting further investigations for central referral to tertiary referral centers is often needed. hyperthyroidism in the presentation as syndrome of Also, patients may present by symptoms from local inappropriate TSH secretion (SITSH) with unsuppressed compression, which is the reason for detection in 29–38% TSH and elevated thyroid hormone levels, interference of cases (19, 20). The clinical presentation of a TSHoma can from medications, like estrogens, pregnancy state, also be blurred by the co-production of other hormones non-thyroidal illness and subacute/silent autoimmune from the tumor, predominantly PRL and/or GH (6, 17, 19, thyroiditis, need to be excluded (54). The timing of the 20, 38) (Table 1). Clinically detectable co-production of sampling should not be underestimated, and repeated any of these PIT-1 factor-dependent hormones increases sampling at months’ interval is needed to exclude with tumor size, even if many tumors histopathologically transitory changes. To exclude thyroid disease, thyroid express all three hormones regardless of size (17, 49). autoantibodies (thyreoperoxidase (TPO) and TSH In TSHomas, TSH is characteristically unsuppressed, receptor-antibodies) are of value. Also, the euthyroid, and thyroid hormones are elevated above the upper hypothyroid and hyperthyroid states of the patient reference (19). A subgroup represents cases where an need to be assessed. Laboratory interference and genetic initial diagnosis has been missed and the patients causes are more common than TSHomas (see differential have been improperly treated with thyroidectomy or diagnoses below). Therefore, when a patient is referred radioactive iodine (RAI). In these cases, TSH increases with SITSH, the first diagnostic procedures include a blood to supranormal levels when l-thyroxin is administered test to evaluate pituitary function, thyroid hormone (19, 20, 27) (Fig. 2A and B). The patient may be referred evaluation through testing with several laboratory due to an inability to normalize TSH with increasing methods and to take thyroid hormone function tests l-thyroxin doses without causing supranormal FT4 in first-degree relatives (Fig. 3). Although patients with levels. In these cases, an undiagnosed TSHoma must TSHomas and resistance to thyroid hormones (RTH) be considered. p have increased production of thyroid hormones in common, the peripheral response differs because of the insensitive TR in RTH. To distinguish hyperthyroidism Diagnostic approach β from RTH, carboxy-terminal cross-linked telopeptide of European Journal of Endocrinology European TSH secretion in the pituitary is regulated by thyrotropin- type-I collagen (ITCP) may be used (55). Patients with releasing hormone (TRH), somatostatin, dopamine and hyperthyroidism have significantly higher ITCP levels thyroid hormones and is characterized by a diurnal than RTH patients, illustrating the hypermetabolic state pattern with small bursts (50). In the abnormal cells in in the bone in hyperthyroidism, whereas in RTH, the a TSHoma, TSH secretion is disorganized, which may resistance in the TRβ influences bone resorption markers be explained by altered functional properties within (56). Furthermore, sex hormone-binding globulin (SHBG) the tumor. An increased pulse frequency is seen with is usually elevated in thyrotoxicosis and is reported to be enhanced non-pulsatile release (51). In TSHomas, the TSH normal in RTH (57, 58). Therefore, SHBG and ITCP may level varies from normal to elevated that can be explained be used in the first diagnostic workup. by a change in glycosylation of TSH molecules with higher bioactivity (52): TSHomas also secrete a mixture of Second step isoforms, where the alpha subunit of the glycoprotein is the major component (53). If there are no indications of laboratory error and if first- As mentioned earlier, guidelines for the diagnosis degree relatives do not demonstrate a similar laboratory of TSHoma were published in 2013 by the ETA (21). picture, then a TRH test is done regardless if pituitary Clinicians are used to work in an evidence-based manner. function tests do indicate a pituitary origin or not. This However, predictive values are not available for different may also be the step of choice for heredity indications diagnostic tests as TSHomas are rare and there is a lack in parallel with mutation tests for RTH and/or familial of power. The frequency of abnormal tests in TSHoma dysalbuminemic hyperthyroxinemia. The normal patients is described below. response in TSH from TRH stimulation is defined as an

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Figure 3 Flowchart on the diagnosis of thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) when it is presented as the syndrome of inappropriate TSH secretion.

increase of >50% and/or an increase of >4 IU/L (17). feedback mechanism from the thyroid hormones and According to this definition of a normal response, 81% of react on small changes. The thyroid hormone regulatory TSHomas have an abnormal response to the TRH test (17), feedback mechanism is superior to that of somatostatin whereas in the ETA guidelines Beck-Peccoz et al. reported p regulation. In TSHomas, the TSH production is 90% with an abnormal TRH test (21, 59). autonomous, and the negative feedback is redundant.

Table 2 Comparison of the clinical presentation and European Journal of Endocrinology European Third step laboratory findings in TSH-secreting adenomas (TSHomas) and Alpha subunit (αSU) may also be used as a diagnostic resistance to thyroid hormones (RTH). tool and is elevated in 30% of cases with a TSHoma (17). TSHoma RTH Stimulated αSU, defined as a 100% increase after TRH Goiter (%) 94 80 administration, is positive in 44% of cases (17). The molar Pituitary over/under + − ratio between αSU and TSH is no longer recommended (21) production of other (Table 2). To possibly confirm or discard the hypothesis of hormones TSHoma requires a thorough detective work. Increased α subunit + − Increase in TSH after a TRH Negative Positive A somatostatin test may also be used in order to test distinguish between a TSHoma and RTH. The patient Increase in α subunit after Positive Negative is given somatostatin subcutaneously and thyroid TRH test MRI pituitary + – hormones are checked after 6 h. If this is well tolerated, Visual field disturbances Maybe + 20 mg of the somatostatin analog octreotide long-acting T3 suppression test No TSH Suppression release (LAR) may be given intramuscularly every fourth suppression of TSH DNA mutation analysis − + week. After 8 weeks, thyroid hormones are measured. In Somatostatin test FT4 ↓ >30% FT4 is not RTH, there is no reduction in thyroid hormones, whereas affected in 6 out of 8 cases, TSHomas normalize thyroid hormone Sinus petrosus + − levels despite minor changes in immunoreactive TSH catheterization

levels (13). The thyreotropic cells and TRH-producing MR, magnetic resonance imaging; RTH, resistance to thyroid hormone; hypothalamic cells are regulated through the negative TRH, thyrotropin releasing hormone; TSH, thyroid-stimulating hormone.

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Figure 4 T3 test used at our institution, this version is modified from Dare et al. (99) and from personal communication with the last author of that publication. The autonomous TSH production is proven by an inability of T3 to suppress TSH.

Hence, in most cases of TSHomas, thyroid hormone long-term primary hypothyreosis, there is hyperplasia of levels will be lower. the pituitary (62, 63), and sporadic reports on TSHomas in RTH (64, 65, 66). The T3 suppression test should not be done in cases Fourth step of severe pulmonary or cardiovascular disease or any A difficulty in the diagnosis of TSHomas is that disease that may decompensate from a short period of incidentalomas (non-functioning pituitary adenomas hyperthyroidism, such as heart disease or psychiatric (NFPA)) are more common and occur in 10–20% of the p disease. An example of the T3 test used at our institution, at normal population (29). There is also a special diagnostic Sahlgrenska University Hospital Gothenburg, is presented dilemma in differentiating a TSHoma from RTH in in Fig. 4; this version is modified from Dare et al. (67) combination with a pituitary incidentaloma (60). If the and from personal communication with the last author European Journal of Endocrinology European suspicion of a TSHoma arises from a pituitary tumor of that publication. The autonomous TSH production is during MRI and the classical laboratory test results are proven by an inability of T3 to suppress TSH. This test is in accordance with SITSH, the occurrences of a NFPA abnormal in 100% of TSHomas (21, 59). are more frequent than a TSHoma and autonomous TSH If MRI does not reveal an adenoma despite laboratory production needs to be established (38). findings indicative of a TSHoma, there are some reports The T3 suppression test, the liothyronine test, is only on sinus petrosus catheterization with TRH stimulation used if doubts are raised during diagnosis or a NFPA needs used in order to evaluate the presence of a TSHoma to be excluded. When a MRI scan is performed due to (17, 68), but its performance and validity are not described. symptoms of an expansive process in the pituitary gland Perhaps functional imaging may play a future role in and an adenoma is found in combination with high these cases. Although less common, an ectopic TSHoma FT4 and normal TSH and the TRH test is abnormal, the may also be considered (17). patient could be referred directly for surgery without a T3 suppression test. However, there are situations when Imaging assessment results are contradictory, such as in cases of an abnormal TRH test when the MRI does not reveal a pituitary Imaging of the pituitary has developed rapidly. Earlier, adenoma, or if there is a normal response to TRH in evaluation with plain skull radiographs was the modality the presence of a pituitary adenoma, or if the patient of choice; however, this technique was poor in delineating is thyroidectomized. Also, it has been reported that the the soft tissue. The technique focused mainly on secondary frequency of hyperplasia/adenomas in the pituitary findings of pathology in the sella, i.e. calcifications and from RTH is approximately 20% (61). In cases with enlargement. These findings are not considered sensitive

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indicators of pituitary gland abnormalities. Thus, plain scanners, i.e. 3.0 T, was superior to low-field scanners radiographs were replaced by cross-sectional imaging of 1.0 T or 1.5 T in predicting local invasion of adjacent techniques such as the CT scan and MRI. structures. They also showed that the use of a 3.0 T scanner improved surgical planning of sellar lesions (74). Lee et al. evaluated the technique of simultaneous Structural imaging acquisition of contrast-enhanced coronal and sagittal images on a 3.0 T MRI and found a detection rate of more MRI than 92% for microadenomas in the pituitary region MRI techniques for diagnosing pituitary lesions have (75). In comparison, the detection rate was only 82% witnessed a rapid evolution since it first came to use in for uniplanar coronal and 75% for uniplanar sagittal the early 1980s. The resolution and sensitivity of these projections (75). The multiplanar combination of sagittal techniques were until the early 1990s comparable to those and coronal projections in gadolinium-enhanced MRI are of CT-scans, but presented a superior soft-tissue resolution now the preferred tools for visualization and is considered and a greater delineation to adjacent structures. With the the modality of choice for pituitary imaging (71, 72). introduction of dynamic contrast-enhanced MRI in the There are however some disadvantages that comes with early 1990s (69), the sensitivity for diagnosing pituitary the use of MRI at 3.0 T. Prolonged T1 relaxation time, microadenomas increased vastly (70). radiofrequency magnetic field inhomogeneity and MRI is usually the only method needed for the increased susceptibility artifacts have been proposed (76). morphological investigation of endocrine active pituitary The spoiled gradient recalled acquisition in the steady-state adenomas. Radiologic evaluations differ in regard to the (SPGR) sequence and fast SPGR (fSPGR) are relatively new size of the lesion, i.e. macroadenomas (>10 mm) and sequencing techniques that challenge these disadvantages. microadenomas (<10 mm). Pituitary macroadenomas Kakite et al. demonstrated that vascular pulsation artifacts are usually located in the center of the sella turcica with and partial volume effect were significantly reduced on the extra sellar extension, growing upward toward the third SPGR sequence (77). SPGR and fSPGR also demonstrate ventricle and sometimes the foramen of Monro (71, 72). superior soft-tissue contrast compared with the spin echo Studies on TSH-producing adenomas using MRI, p technique and can be performed in notably thin-slice describe macroadenomas in the majority of cases and sections (78). As SPGR can be performed in sections of usually hypoechoic appearance in respect to normal 1 mm, the risk of missing small lesions in the pituitary is pituitary tissue after gadolinium administration (73). In far less. SPGR has primarily been used in the evaluation European Journal of Endocrinology European comparison to other similar, and more common, pituitary of suspected adenomas in Cushing’s disease, since they adenomas (such as GH- and PRL-producing adenomas), often manifest as microadenomas (usually <2 mm) and TSH-producing adenomas tend to have a higher degree of are notoriously difficult to detect with the standard T1 microscopic invasion and intra- and peritumoral fibrosis, spin echo MRI sequence. Currently, modern pituitary MRI which correlate with the findings in surgical material (15). sequences fail to detect approximately 40% of Cushing’s In this regard, a protocol with several sequences (such disease cases (79). In these patients, SPGR has increased as dynamic, contrast enhanced, spin echo T1 and T2) is the detection rate by 10–15%. Masopust et al. achieved preferable to not just detect elusive lesions but also to a remarkable sensitivity of 100% in 41 Cushing’s disease delineate tumor tissue to adjacent structures and normal patients by combining three MR sequences: spin echo, pituitary tissue. Such signs of microscopic invasion can SPGR and fSPGR (80). contribute with important prognostic information before To our knowledge, SPGR sequences have not been surgical treatment (73). studied on TSH-producing adenomas. SPGR seems to Microadenomas are more difficult to detect, but provide higher sensitivity in the MRI evaluations in have often a hypoechoic signal on contrast-enhanced ACTH-producing adenomas, but these results cannot be T1 sequences. Microadenomas are now reported with generalized to TSHomas. TSHomas usually manifest as an increased frequency in TSHomas, accounting for macroadenomas and with a fibrous consistency, and thus about 20% of all recorded cases (Table 1). Smaller lesions the sensitivity of the spin echo sequence is, in most cases, require more complex methods and high-field scanners. sufficient. A diagnostic imaging with higher specificity Different methods and approaches have been assessed in would be a better contribution in the current diagnostic regard to optimize the detection rate of microadenomas. workup. In this regard, functional imaging seems to Pinker et al. demonstrated that the use of high-field MRI have the potential to provide a better detection rate with

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higher specificity in pituitary adenomas in general and in workup of TSHomas. A study evaluating the uptake of TSHomas in particular. 68Ga-DOTATOC in pituitary adenomas is ongoing and will hopefully bring more clarity to the matter (clinicaltrials. gov identifier: NCT02419664). Functional imaging

Scintigraphy Differential diagnoses As pituitary gland and pituitary adenomas express In the workup of a patient’s syndrome of inappropriate somatostatin receptors, SSTR, as oppose to adjacent TSH secretion, diagnoses other than TSHomas must first structures and brain tissue, these receptors provide be considered, given the low incidence of TSHomas (19). excellent conditions for functional imaging. TSHomas The most important differential diagnoses are laboratory have a high expression density of somatostatin receptors interference and mutations resulting in a changed affinity compared to normal pituitary tissue, in particular SSTR 2 for the thyroid hormone receptor or to carrier molecules. and 5, which makes it a good candidate for scintigrahpic Also, rarely, thyroxin binding globulin (TBG) deficiency evaluation. Scintigraphy with radio-labeled octreotide can can result in decreased levels of total thyroid hormone successfully localize most hormone-producing adenomas and thereby increased free T4 (85), from lower binding due to high expression rate of somatostatin receptors (81). capacity, even if TBG deficiency is most commonly TSHomas are detectable with this technique (82); however, presented as central hypothyroidism. Another rare cause the specificity of this technique is low, as positive scans of SITSH is inadequate hydrocortisone replacement after can occur in the case of a pituitary mass of different types, surgery in Cushing’s syndrome (86). either secreting or non-secreting, and even in normal Laboratory interference is not a true increase in pituitary tissue. thyroid hormone production, but results from interfering substances in the laboratory method used, such as thyroid Position emission tomography (PET) hormone antibodies (87), heterophilic antibodies (88) or other method specific interferences 89( , 90), result in PET/CT has superior resolution and imaging quality over p falsely increased thyroid hormone levels (54). In clinical scintigraphy, and there have been promising results in practice, different forms of laboratory interference are identifying pituitary adenomas. In a case series with seven rarely diagnosed, as the important issue is to find a TSHoma patients examined with 111In-pentreotide- TSHoma. Laboratory interference can be suspected when European Journal of Endocrinology European SPECT (single-photon emission CT) and two patients thyroid hormone levels vary among different laboratory with 11C-l-methionine PET/CT, both SPECT and PET/CT methods: this can be detected through comparing imaging revealed positive uptake in patients with the results from one sample with several analytical microadenomas that was not detected by MRI (17). The platforms. The TRH- and α-subunit-tests are normal in PET/CT evaluation even detected 2 microadenomas in laboratory interference. cases where the 111In-pentreotide scan did not detect any When disturbances due to the laboratory method pathology (17). However, the study was unable to predict are excluded, the main differential diagnosis to TSHomas the response to somatostatin analog treatment. is mutation in the thyroid hormone receptor with the PET/CT technique has the advantages of better syndrome of RTH (91) (Table 2) or mutations in thyroid resolution and the ability to quantify, compared to SPECT. hormone transport proteins, familiar FDH (92). These The use of somatostatin receptor PET/CT for the detection conditions have a variety of mutations. In RTH, both TRH of TSHomas has not yet been widely evaluated. A new in the hypothalamus and TSH from the anterior pituitary is line of gallium-labeled somatostatin receptor analogs inappropriately increased in relation to thyroid hormone (68Ga-DOTANOC, DOTATATE, DOTATOC) has been levels. In RTH, both T4 and T3 are elevated, whereas in increasingly used in the evaluation of neuroendocrine the typical scenario, in FDH, only T4 levels are disturbed. tumors, NETs. This technique has only been evaluated However, practically, not only total T4 but also total T3 in a small number of case series with successful results or free T3 and free T4 are disturbed (elevated) in many in diagnosing an ectopic TSH-producing adenoma (83) patients with FDH. Individuals with genetic variations and pituitary carcinoma (84), thus implying a promising in thyroid hormone transport proteins are clinically prospect for better functional imaging in future diagnostic euthyroid, but present with altered thyroid function

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tests, and do not require treatment. In FDH, laboratory Thus, a plausible relationship between TSH stimulation interference may occur as the change of binding affinity from the pituitary on the thyroid gland was established. to prealbumin interacts differently in different methods. A trophic hormone may cause autonomous secretion Unlike in TSHomas, in RTH and FDH, familial cases in the thyroid gland, which resembles what happens in are common. RTH is an autosomal dominant inherited other target glands. Patients exposed to unregulated and mutation in the β-isoform of the T3 receptor (93), and inappropriate TSH levels may have an increased risk for FDH is a familiar autosomal dominant disease caused well-differentiated thyroid cancer (97). In 62 patients with by a mutation in the albumin gene that results in a TSHomas, three cases with this thyroid cancer were found 10-fold higher affinity of T4 in homozygotic cases; in (97), and it is also reported in other case reports (98, 99, heterozygote people T4 affinity is doubled (94). FDH is 100, 101). A common disease can inevitably co-exist with the most common inherited cause of increased T4 (94). a more rare disorder without any causal relationship, but In cases of SITSH where the TRH- and α-subunit-tests are there may be a rationale for excluding neoplastic lesions normal, FDH may be suspected, especially if the results in the thyroid gland, e.g. with an ultrasound. vary depending on the methods used. There may also be an etiologic link between Graves’ Mutation analyses are costly compared to FT4 and TSH disease and TSHomas. Autoimmunity may be induced blood samples, thus, a first step may be to analyze thyroid when TSH levels rapidly decrease after surgical and/or hormones in first-degree relatives, in order to strengthen SSA treatment (102). Graves’ disease may also be triggered the suspicion of a heredity cause for the syndrome of through affected intrathyroidal lymphocytes harboring inappropriate TSH secretion. the same SSTR 2A as the TSHoma cells. The development As many patients approach health care with a of Graves’ disease after treatment for a TSHoma is reported laboratory constellation of unsuppressed TSH and (103, 104, 105), as is Graves’ disease before the detection of increased thyroid hormone levels, all differential a TSHoma (106, 107, 108, 109, 110). The combination of diagnoses need to be considered in parallel for an effective TSHoma and Graves’ disease may be further complicated clinical workup. by the coexistence of exophthalmia. Exophthalmos is In Italy, 99 patients were referred for SITSH, of these, reported in TSHoma because of tumor invasion in the 68 were determined as RTH and 31 as TSHomas (95). In p orbit (111). 24% of the RTH cases, no mutation was found, and there Autoimmune hypothyroidism may co-exist with were no familial cases; eventually three TSHomas were TSHoma, but any causality is yet unclear (112, 113, 114). detected, illustrating the difficulties of distinguishing Pituitary hyperplasia from increased TSH production European Journal of Endocrinology European between the etiologies. To support the investigation, in hypothyroidism may in some rare cases mimic a clinical presentation can be useful (Table 2). Goiter is macroadenoma (115). In the same way as TSHoma is common in patients with TSHomas and RTH, but the reported, in RTH, where longstanding stimulation may response to stimulatory tests differs due to the pituitary promote tertiary tumor evolvement (66, 116), a secondary involvement (Table 2). Diagnosing a patient with a hyperplasia may mimic a pituitary tumor (117). However, syndrome of inappropriate TSH secretion is complicated primary hypothyroidism in parallel may complicate the and requires special competences, especially in situations diagnosis of TSHoma and cause delay (118). where patients have received treatment for an assumed Even if most TSHomas are sporadic, there are primary hyperthyroidism (17, 19, 27) or in the rare cases reports that TSHomas may be the pituitary component where RTH is coexisting with a TSHoma (64). RTH is in multiple endocrine neoplasia type 1 (MEN-1). In a considered to predispose to both pituitary hyperplasia and report from six Belgian and French centers where 43 to the development of adenomas and, even in some rare patients with TSHoma were described, 2 patients were cases, ectopic TSHomas (22, 23, 24, 25, 26, 27), making diagnosed with clinical MEN-1, but no MEN-1 mutation regular monitoring of these patients a necessity. was found (17). In another cohort of 166 patients with pituitary tumors, including one TSHoma (119), patients with hyperparathyroidism (n = 8, 4.8%) were selected Concomitant diseases in association and screened for other manifestations of MEN-1: the with TSHomas TSHoma case was not found among the group of eight pituitary adenomas selected, and prolactinomas appeared In 1994, a case with autonomous functioning thyroid dominate in MEN-1. However, TSHoma cases are described nodules preceded by a TSHoma was first reported (96). in MEN-1 (120).

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Received 15 December 2016 Revised version received 27 March 2017 Accepted 30 May 2017

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