Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma).

BACKGROUND Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism. Somatostatin analogs have proved to be effective for inhibiting pituitary hormones secretion, working via interactions with somatostatin receptors (SSTRs). Moreover, antiproliferative activity of somatostatin analog is now demonstrated in several studies. In the present study, we determined the relative predominance of SSTR2 and SSTR5 subtypes among the different types of adenomas, especially TSHoma, and investigated the relationship between efficacy of short-term octreotide (OCT) treatment and SSTR expression. MATERIAL AND METHODS Serum hormone determinations and histological findings in resected tissue resulted in 5 diagnoses: 16 TSHomas, 8 acromegaly, 3 prolactinomas, 3 corticotropinomas, 4 clinically nonfunctioning adenomas (NFPAs), and 4 normal pituitary specimens. IHC was performed on formalin-fixed and paraffin-embedded tissue in tissue microarrays. RESULTS IHC of SSTR subtypes in the different cohorts showed SSTR2 staining intensity scores higher than SSTR5 in TSHoma, acromegaly and prolactinoma, whereas the expression of SSTR5 was stronger than SSTR2 in corticotropinoma and NFPA. SSTR2 and SSTR5 expressions were significantly higher in TSHoma than in other pituitary adenomas. OCT treatment for a median of 8.4 days (range: 3-18 days) and with a total median dose of 1.9 mg (range: 0.9-4.2 mg) showed a significant decrease of thyroid hormone levels (TSH [μIU/ml] in all patients. Patients with low SSTR5 expression presented a significantly higher TSH suppression rate (P values <0.05). CONCLUSIONS The present data confirm that somatostatin analogs should be considered as a medical alternative to surgical treatment, especially in patients with TSHoma, and short-term response to OCT therapy may be related to the expression of SSTR5.

Background

Pituitary adenomas (PA) are among the most common central nervous system tumors. They are a diverse group of neoplasms that may or may not secrete hormones based on their cell of origin. In general, pituitary adenomas are frequently an invasive adenoma, which grows with invasion into the floor of the sella turcica, parasellar dura, and/or cavernous sinuses [1]. Existing therapeutic methods, including surgical removal, chemotherapy, and radiotherapy, have limited effectiveness, largely caused by the limited understanding of the molecular pathogenesis of PA. The feasibility of targeting specific pituitary cell types in vivo makes the cell-specific therapeutic approach a useful tool to treat different pituitary disorders. Recombinant adenoviruses containing the GH promoter [2], the glycoprotein hormone α-subunit promoter [2], the POMC promoter [3], and the prolactin promoter [4] were used to selectively drive transgene expression in specific endocrine pituitary cell populations in animal models.

Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of all pituitary tumors [5,6]. Discovered in 1973, somatostatin (SS) is a native inhibitory peptide hormone distributed throughout the central nervous system and peripheral tissues of the body [7]. Medical treatment of endocrine pituitary tumors with somatostatin analogs depends on somatostatin receptor (SSTR) expression [8,9]. SSTR is expressed in both normal and neoplastic human pituitary cells, and SSTR2 and SSTR5 predominate [10,11], but the characteristic expression pattern of SSTR subtypes in pituitary adenomas is tissue-specific and subtype-specific [12]. The therapeutic effects on pituitary adenomas of somatostatin analogs like octreotide and lanreotide depends on the expression of specific somatostatin receptors on the target cells [13,14]. Both antihormonal and antiproliferative activity of SSTRs are induced in pituitary adenomas by somatostatin analogs [15], and their effectiveness is limited by the development of tumor resistance. Possible mechanisms of resistance include impairment or heterogeneity of SSTR expression, SSTR gene mutations, and decreased sensitivity of SSTRs owing to uncoupling of signaling pathways [16]. The most accepted hypothesis is the absence or reduced density of specific SSTRs in the tumors, especially SSTR2 and SSTR5. Therefore, it would be helpful to know the expression profile of SSTR subtypes in pituitary adenomas.

Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) are rare, accounting for 0.5% to 3% of all functioning pituitary adenomas [17]. Studies indicate that somatostatin analogs may control TSH secretion by interacting with SSTR2, and restrain cell proliferation by interacting with SSTR5 [17-19]. However, these results were acquired from a limited number of patients and will require further validation. Gatto et al. has recently found that a high sst(5)/sst(2) ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogs in TSHomas. Moreover, combined somatostatin and D(2) receptor targeting might be a potential tool to improve the response rate in octreotide-resistant tumors [20]. To the best of our knowledge, the expression of SSTR2 and SSTR5 in TSHoma has been demonstrated by IHC in only a few patients [21]. Highly specific antibodies can confirm the expression of SSTR subtype proteins, but heterogeneity of tumors and the use of different detection methods often lead to inconsistency in the reported expression of SSTR subtypes in different types of pituitary tumors [12,21-26]. Because it is clinically meaningful to identify the expression profiles of SSTR subtypes in pituitary adenomas, we investigated the expression of SSTR2 and SSTR5 in a series of patients with TSHoma and other pituitary adenomas, as well as the association of SSTRs expression with efficacy of short-term OCT treatment.

Material and Methods

Patients

We enrolled TSHoma patients enrolled who were newly diagnosed and previously untreated, while those with primary hyperthyroidism or resistance to thyroid hormone syndrome were excluded. All patients had undergone surgery at Yuhuangding Hospital, between January 1999 and June 2015. The diagnosis was based on a combination of clinical manifestations, biochemical assessments of pituitary function, findings of pituitary imaging, and pathological evaluation. On this basis, 16 patients with TSHoma were identified and enrolled in the study. Those with acromegaly, corticotropinoma, prolactinoma, or nonfunctioning pituitary adenomas (NFPA) were randomly sampled and 4 normal pituitary specimens collected from the donor’s head. The sex, age at diagnosis, pathological diagnosis, tumor size, and date of the last follow-up of each participant were collected from medical records. Informed consent was obtained from all participants.

Short-term preoperative octreotide therapy for TSH-secreting pituitary adenoma

Octreotide used in this investigation came from Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA). Each patient received an initial dose of 100 μg, injected subcutaneously at 8: 00 a.m. If the patient showed no obvious side effects (such as nausea, vomiting, stomach ache and diarrhea), their dosages were increased to 100 μg 2 or 3 times/day. Serum TSH, FT3, FT4, TT3, and TT4 concentrations were measured by chemiluminescent enzyme assays using commercially available kits. We used the formula: TSH suppression rate (%)=[(before treatment TSH value-after treatment TSH value)/before treatment TSH value]×100.

Pathological diagnosis of pituitary adenoma

All tissue specimens of the patients were obtained during pituitary surgery, fixed in 4% paraformaldehyde overnight, routinely processed, and embedded in paraffin. For adenoma classification, the specimens were cut into 4-μm-thick sections and stained with hematoxylin and eosin and periodic acid Schiff (PAS) staining protocol. ICH staining with monoclonal antibodies against the specific pituitary hormones, including TSH, growth hormone (GH), prolactin (PRL), ACTH (adrenocorticotropic hormone), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), were also carried out on the tumor tissues. The pathological diagnoses were verified by experienced pathologists following the 2004 World Health Organization classification [20].

Immunohistochemical staining of SSTR subtypes

Formalin-fixed slides were prepared in unstained 3-μm sections and a 48-dot core (diameter 2.0 mm) matrix chip template. Immunohistochemical staining was performed with a Leica BOND-III, automatic IHC and ISH stainer (Leica Biosystems, Nussloch, Germany), which is an automatic and continuous access slide-staining system that simultaneously processes IHC protocols, with a 10-min heat-induced epitope retrieval and a 15-min antibody incubation. The primary SSTR2 antibody was ab13120 (1: 100), and the primary SSTR5 antibody was ab13121 (1: 100; Abcam, Cambridge, UK). The preparation and evaluation of the tissues were performed at the Department of Neuropathology, Beijing Tiantan Hospital, Capital Medical University.

Quantification of immunostaining

The sections were assessed independently by 2 experienced pathologists who were blinded to both the clinical and the pathology data. The scoring of each section was determined by consensus and followed the immunoreactive score (IRS) method described by Remmele et al. [20]. The IRS was calculated by multiplying the staining intensity (0=no staining, 1=weak staining, 2=moderate staining, 3=strong staining) by the percentage of positively stained cells (0=0%, 1=1% to 33%, 2=33% to 66%, and 3 ≥66%). The resulting IRS scores ranged from 0 (no staining) to 9 (maximum staining). IRS scores of 0 were negative, 1–2 were low, 3–4 were intermediate, 5–7 were high-intermediate, and 8–9 were high.

Statistical analysis

The data were statistically analyzed using SPSS software version 20.0 for Windows (SPSS, Chicago, IL). Data of normal distribution were reported as means ± standard error (SE). Otherwise, the data are reported as medians and ranges (minimum–maximum). Multiple linear regression was used for analyzing factors for efficacy of short-term preoperative OCT treatment, and the Wilcoxon rank sum test was used to compare the 2 groups. P<0.05 was considered a statistically significant difference.

Results

Patient characteristics

As shown in Table 1, in addition to the 16 patients with TSHoma, we also included 8 with acromegaly, 3with prolactinoma, 3 with corticotropinoma, and 4 with clinical NFPA. Characteristics of the 34 patients included in our study are shown in Table 1. Tumors over 10 mm were defined as macroadenomas, and those smaller than 10 mm as microadenomas. We identified 16 TSHoma patients (11 men and 5 women) with a mean age of 33 years (range: 17–51 years). Three TSHomas were microadenomas and 13 were macroadenomas. Eight were acromegalic patients (4 men and 4 women) with a mean age of 33 years (range: 12–39 years); 1 with microadenoma and 7 with macroadenomas. Three patients had Cushing disease, who were all women, with a mean age of 45 years (range: 38–53 years); 1 had a microadenoma and 2 had macroadenomas. Three patients had prolactinomas, who were all women, with a mean age of 47 years (range: 31–64 years), and all had macroadenomas. Four patients had NFPAs (3 men and 1 woman), with a mean age of 45 years (range: 31–65 years), and all had macroadenomas. The diagnosis of functional pituitary adenoma was based on clinical manifestations, hormone levels, and imaging results, and confirmed by pathological evidence (Figure 1).

Table 1

Patient demographics in the five cohorts.

Case	Sex	Age (years)	SSTR2		SSTR5		Tumor size (mm)
			Staining intensity	Percent positivity (%)	Staining intensity	Percent positivity (%)
T 1	M	24	3	90	1	75	30×20×30
T 2	M	40	3	90	2	95	8×6×6
T 3	M	25	3	90	2	85	48×44×29
T 4	F	40	3	90	2	30	5×7×8
T 5	M	33	3	90	1	50	17×12×13
T 6	M	24	3	90	1	90	24×13×34
T 7	F	27	3	90	2	80	16×15×20
T 8	M	26	3	60	2	50	24×14×31
T 9	M	31	3	90	2	70	9×6×8
T 10	M	52	3	90	2	90	11×12×10
T 11	M	33	3	90	2	90	32×28×25
T 12	M	51	3	90	2	90	16×14×18
T 13	F	45	3	90	2	90	21×16×33
T 14	F	25	3	90	1	55	15×21×17
T 15	M	17	3	90	1	80	24×36×53
T16	F	39	3	90	1	50	41×25×38
S1	M	39	3	90	1	60	32×36×17
S2	M	39	3	90	1	40	14×13×15
S3	M	12	3	90	1	50	64×39×39
S4	F	26	3	90	1	80	24×27×14
S5	M	29	1	90	2	80	36×25×26
S6	F	32	1	50	1	70	6×8×7
S7	F	44	3	90	2	60	16×10×9
S8	F	43	3	90	2	80	17×24×17
C1	F	53	0	100	2	70	8×5×6
C2	F	38	3	80	1	60	12×12×16
C3	F	61	0	100	1	80	22×22×32
P1	F	64	1	60	1	35	27×35×22
P2	F	46	1	80	1	70	38×28×22
P3	F	31	3	90	2	90	15×16×19
N1	M	61	0	100	1	40	19×20×28
N2	M	39	0	100	1	60	29×28×41
N3	F	31	0	100	1	60	10×12×14
N4	M	65	0	100	2	60	30×35×29

F – female; M – male; T – thyrotropinoma; S – somatotrophinoma; C – corticotropinoma; P – prolactinoma; N – nonfunctioning pituitary adenoma.

Figure 1

Immunohistochemistry of pituitary adenoma tissue. Immunohistochemical staining among the tumor cells. (A) Histopathology findings of TSHoma (hematoxylin-eosin staining); (B) Strong TSH staining of TSHoma; (C) Growth hormone-producing cells; (D) Prolactin-producing cells; (E) Adrenocorticotrophic-producing cells; (F) Nonfunctioning pituitary adenomas. (Magnification ×200).

Expression of SSTR2 and SSTR5 protein in pituitary tumor tissue

The immunohistochemistry of SSTR2 and SSTR5 was positive in the membrane staining, as shown in Figures 2 and 3. The immunostaining pattern in TSHoma was SSTR2>SSTR5, with 15 of 16 specimens (93.7%) having high SSTR2 IRC scores and only 1 specimen having a high-intermediate score. The SSTR5 IRS scores were high-intermediate in 8 specimens (50%), intermediate in 4 (25%), and low in 4 (25%). SSTR2 and SSTR5 expression were higher in TSHomas than in other pituitary adenomas.

Figure 2

Heterogeneous immunohistochemical expression of SSTR2 in TSHoma. Representative examples of SSTR2 expression. (A) Negative (IRS 0); (B) High-intermediate (IRS 5–7); (C) High (IRS 8–9). (Magnification 200×).

Figure 3

Heterogeneous immunohistochemical expression of SSTR5 in TSHoma. Representative examples of SSTR5 expression. (A) Low (IRS 1–2); (B) Intermediate (IRS 3–4); (C) High-intermediate (IRS 5–7). (Magnification 200×).

IHC staining (Table 2) demonstrated that, in acromegaly, SSTR2 expression was more frequent and stronger than SSTR5 expression. High IRC scores were seen for SSTR2 in 6 of the 8 acromegaly specimens (75%), with low and intermediate intensity staining in the remaining 2 specimens (12.5% each). High-intermediate SSTR5 staining intensity was seen in 2 of the 8 acromegaly specimens (25%); while low and intermediate staining intensity was found in 3 of the 8 (37.5% each). The 3 prolactinoma specimens had different SSTR2 (low, intermediate, and high-intermediate) and SSTR5 (low, intermediate, and high) staining intensities. High-intermediate SSTR2 staining intensity was seen in 1 of the 3 corticotropinoma specimens, while the remaining 2 were negative. SSTR5 staining was also found to be different in each of the corticotropinoma specimens (low, intermediate, and high-intermediate). All the 4 NFPA specimens were negative for SSTR2 expression; high-intermediate SSTR5 staining was observed in 1 (25.0%) and the remaining 3 were negative. In normal pituitary tissues, SSTR2 expression was high-intermediate in 2 of the 4 samples tested and intermediate in 2. Two of the specimens had high-intermediate SSTR5 expression, and the other 2 were negative.

Table 2

Expression of SSTR2 and SSTR5 as determined by immunohistochemistry (n=38).

Tumor type	SSTR2					SSTR5
	Negative	Low	Inter mediate	High-inter-mediate	High	Negative	Low	Inter-mediate	High-inter-mediate	High
TSHoma (n=16)	0 (0%)	0 (0%)	0 (0%)	1 (6.3%)	15 (93.7%)	0 (0%)	4 (25%)	4 (25%)	8 (50%)	0 (0%)
Acromegaly (n=8)	0 (0%)	1 (12.5%)	1 (12.5%)	0 (0%)	6 (75%)	0 (0%)	3 (37.5%)	3 (37.5%)	2 (25%)	0 (0%)
Prolactinoma (n=3)	0 (0%)	1 (33.3%)	1 (33.3%)	0 (0%)	1 (33.3%)	0 (0%)	1 (33.3%)	1 (33.3%)	1 (33.3%)	0 (0%)
Cortico-tropinoma (n=3)	2 (66.7%)	0 (0%)	0 (0%)	1 (33.3%)	0 (0%)	0 (0%)	1 (33.3%)	1 (33.3%)	1 (33.3%)	0 (0%)
NFPA (n=4)	4 (100%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	3 (75%)	1 (25%)	0 (0%)	0 (0%)
Normal pituitary specimen (n=4)	0 (0%)	0 (0%)	2 (50%)	2 (50%)	0 (0%)	2 (50%)	0 (0%)	0 (0%)	2 (50%)	0 (0%)

Negative (IRS=0), low (IRS=1–2), intermediate (IRS=3–4), high-intermediate (IRS=5–7), and high (IRS=8–9).

Efficacy of short-term OCT treatment

Short-term preoperative OCT administration was highly effective in normalizing excessive hormone concentrations, with tolerable adverse effects as well. Due to incomplete date, 1 TSHoma patient was excluded. Following OCT treatments for a median of 8.4 days (range: 3–18 days) and with a total median dose of 1.9 mg (range: 0.9–4.2 mg), all patients presented significant decreases of TSH and thyroid hormone levels (TSH [μIU/ml]: 4.95±3.59 to 0.92±1.55 [t=4.721, P=0.000]; FT3 [Pmol/L]: 11.77±8.69 to 4.17±0.88 [t=3.507, P=0.003]; FT4 [Pmol/L] 29.56±8.51 to 16.72±4.13 [t=6.662, P=0.000] (Table 3). Reference ranges are TSH: 0.35–4.94 μIU/ml; FT3: 2.63–5.7 Pmol/L; FT4: 9.00–19.04 Pmol/L. Safety of treatment with SST analogs was proven; no patients discontinued treatment due to unbearable adverse effects.

Table 3

Thyroid function before and after short-term octreotide treatment.

	Before	After	t-value	P
TT3 (nmol/l)	3.50±1.35	1.36±0.32	6.112	P=0.000
TT4 (nmol/l)	193.85±50.23	109.80±31.10	7.848	P=0.000
FT3 (Pmol/L)	11.77±8.69	4.17±0.88	3.507	P=0.003
FT4 (Pmol/L)	29.56±8.51	16.72±4.13	6.662	P=0.000
TSH (uIu/ml)	4.95±3.59	0.92±1.55	4.721	P=0.000

Relationship between TSH suppression rate and SSTR5 expression

Linear regression analysis found no statistically significant difference between the TSH suppression rate and general characteristics (age or sex), tumor size (micro-or macro adenoma), and SSTRs expression. With IRS scores categorized as low expression (0–4) and high expression (5–9), we analyzed the relationship between TSH suppression rate and SSTR5 expression with the 2 independent-samples Wilcoxon rank sum test. The results showed P value=0.002, which is statistically significant, suggesting that SSTR5 expression may be related to the efficacy of short-term OCT therapy.

Discussion

Quantitative real-time polymerase chain reaction (RT-PCR) and Western blot assays were used to describe the expression profiles of SSTR subtypes in pituitary adenomas [28,29]. Quantitative RT-PCR might overestimate the actual percentage of tumors expressing SSTR subtypes because immune, stromal, and normal tissue cells, as well as blood vessels that are present in or surrounding the tumors, might also express SSTR subtypes. Most reports publicly available focused on tumor types other than growth hormone-secreting adenomas, especially TSHoma, and many of these are case reports or are limited to assays of RNA expression.

Studies have reported that abnormal miR-26a, cold-inducible RNA-Binding Protein (CIRP), and cyclooxygenase-2 (COX-2) expression play a major role in pituitary tumorigenesis, recurrence, and invasiveness [30-32]. Somatostatin peptides bind to the SSTRs expressed on the cells of the target tissues, exerting a series of biological effects. In the central nervous system, somatostatin acts as a neuromodulator and neurotransmitter [33]. The immunohistochemical method performed on surgically removed tumor tissue reveals the expression of receptor proteins and demonstrates their cellular localization [29]. Although immunohistochemical methods can detect receptor proteins and show the subcellular localization of the receptors, they are rarely used to study the expression of SSTR subtypes because of a lack of well-characterized SSTR subtype-specific antibodies. Schmid et al. [34,35] developed a series of mouse monoclonal antibodies with high specificity for the 5 SSTR subtypes and no cross-reactivity with IHC staining. Few of these studies investigated IHC. In the present study, however, we assessed the expression profiles of SSTR2 and SSTR5 in pituitary adenomas by IHC technique, and found significant differences in the expression and distribution of SSTR subtypes in various adenomas. This finding could prove helpful in the selection of treatment strategies.

It was previously shown by RT-PCR in a single fetal pituitary (14 wk) that all 5 human SSTR subtype mRNAs were expressed [36]. Shimon et al. reported that using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 weeks [37]. In our study, 2 normal pituitaries collected from the donor’s head did not express SSTR5. This may be because the different detection methods that we used lead to disparate test results.

Previous studies enrolled patient cohorts with compositions different from ours, which might have resulted in different SSTR subtype expression profiles. Our immunohistochemical results differ from findings of previous molecular studies. For example, Pisarek et al. [35] found that the pattern of SSTR immunostaining in acromegaly was SSTR 5>SSTR 1>SSTR 2A=SSTR 3>SSTR 2B. Thodou et al. [33] used immunohistochemistry to study the expression of SSTR subtypes in TMAs and qPCR to compare absolute mRNA copy numbers for all 5 SSTR isoforms in 23 somatotrophinomas, and found that expression was SSTR5>SSTR2A>SSTR2B. Taboada et al. [23] found that in somatotrophinomas, expression of subtype SSTR5 mRNA was the highest, followed by SSTR2=SSTR3=SSTR1=SSTR4. Some previous IHC studies also found high SSTR2 and low SSTR5 immunoreactivity in Cushing’s disease [18,34]; others have reported low expression of SSTR2 mRNA in patients with Cushing’s disease [35-42]. Low expression of SSTR2 and SSTR5 mRNA was reported in a sample of 19 NFPAs, while SSTR3 expression was high and predominant in more than half of the tumors [23]. Some studies have also reported high expression of both SSTR3 and SSTR2 mRNA in NFPAs [25,43]. Tateno et al. [25] found that SSTR3 had the highest expression level followed by SSTR2 in a series of 15 NFPAs, and Pisarek et al. [22,35] reported an expression pattern of SSTR2B>SSTR2A>SSTR5 in a group of 22 NFPAs. Because most prolactinomas are responsive to treatment with dopamine agonists, specimens are seldom available. Pisarek et al. [22] reported an IHC staining pattern of SSTR 2B=SSTR 3=SSTR 5>SSTR 1=SSTR 2A in prolactinomas. Among the 3 prolactin secreting adenomas in our series, expression of SSTR2 was stronger than that of SSTR5.

TSHoma is a very rare disease, with few reports of the relative expression of SSTR subtypes. Horiguchi et al. [18] reported an mRNA expression pattern of SSTR2A>SSTR1>SSTR5>SSTR3 in a series of TSH-secreting adenomas compared with expression in normal pituitary tissue. No expression of SSTR2B or SSTR4 mRNA was observed in the TSHoma tissue. Overall, the results of the present study are not completely consistent with existing research findings. Possible explanations include the small sample size and population-related differences, as all the patients in our study were Chinese, while data of other studies were obtained from white patients. Most (80%) TSHoma patients have macro-adenomas, with microadenomas thus being exceptional [44]. TSHomas are often large and invasive lesions and highly fibrous, which hampers complete removal. As for medical therapy, somatostatin analogs are reported to inhibit TSH secretion in addition to tumor growth in combination with the surgical or radiological therapy [19]. Our study found short-term preoperative OCT can control TSH and thyroid hormone levels.

However, the relationship between the response to OCT and expression of subtype-specific SSTRs in tumor tissues has yet to be clarified. TSH secretion is mediated via interactions with SSTR2 and tumor size reduction via interactions with SSTR5 [18,19]. In our study, low SSTR5 expression shows a higher TSH suppression rate. First, SSTR2 expression alone might suppress TSH secretion in the short term. Second, SSTR 5 expression might be lost during the therapy. Short-term response to OCT therapy may be related to the expression of SSTR5. However, additional studies with larger numbers of cases are necessary to establish the SSTR5 expression spectrum in pituitary adenoma and the role of SSTRs in OCT therapy for TSHoma.

Conclusions

TSH-secreting pituitary adenomas preferentially express SSTR2, with higher SSTR2 IHC staining intensity scores as compared to SSTR5. In addition, the patients with TSHoma had stronger expression of SSTR2 and a higher prevalence of SSTR5 expression as compared to patients with the other types of pituitary adenomas. SSTR2 and SSTR5-preferring octreotide and lanreotide may be a useful treatment approach, especially in TSHoma or somatotropinoma patients. Therefore, immunohistochemical staining for detection of SSTR subtypes is recommended for all surgical specimens.