Protein Expression Heterogeneity of Glucose Metabolism and Somatostatin Receptor between Primary Tumor and Distant Metastasis in Differentiated Thyroid Cancer

Protein Expression Heterogeneity of Glucose Metabolism and Somatostatin Receptor between Primary Tumor and Distant Metastasis in Differentiated Thyroid Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Protein Expression Heterogeneity of Glucose Metabolism and Somatostatin Receptor between Primary Tumor and Distant Metastasis in Differentiated Thyroid Cancer Joon Ho Choi, Jae Kyung Myung, Ji Eun Moon, Joon-Seog Kong, Byung Hyun Byun, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9194234/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective This study investigated the heterogeneity of protein expression between primary tumors and distant metastatic lesions in DTC, focusing on markers of glucose metabolism and somatostatin receptor (SSTR) expression. Methods We retrospectively analyzed 18 patients with DTC (mean age 56 ± 10 years) who had bone or soft tissue metastases. Immunohistochemical staining of surgical specimens was performed to assess the expression of glucose transporter 1 (GLUT-1), hexokinase-2 (HK-2), and somatostatin receptor subtype 2 (SSTR-2). Protein expression was classified as negative, weakly positive, or strongly positive. Correlations between primary and metastatic lesions were evaluated using Spearman analysis. FDG SUVmax values were compared according to protein expression using the Mann–Whitney U test, and the association between iodine avidity and SSTR-2 expression was assessed using Fisher’s exact test. Results GLUT-1 expression was more frequent in metastatic lesions than in primary tumors (65% vs. 50%). HK-2 expression was high in both primary and metastatic lesions (94% each). SSTR-2 expression was similar between primary (50%) and metastatic lesions (41%). GLUT-1 expression demonstrated a marginal positive correlation between primary tumors and bone metastases (r = 0.462, p = 0.062). After excluding primary tumors smaller than 1 cm, significant correlations were observed for both GLUT-1 (r = 0.624, p = 0.023) and HK-2 (r = 0.695, p = 0.008), whereas SSTR-2 showed no significant correlation. Among patients who underwent surgery and 18 F-FDG PET/CT within one year, GLUT-1–positive metastatic lesions demonstrated significantly higher FDG SUVmax values than GLUT-1–negative lesions (p = 0.046). SSTR-2 expression was not significantly associated with iodine avidity. Conclusion GLUT-1 expression showed partial concordance between primary and metastatic DTC lesions and was associated with increased FDG uptake, supporting its role as a marker of tumor aggressiveness. Although SSTR-2 expression was not correlated with iodine avidity, its presence in iodine-refractory metastases suggests potential utility for SSTR-targeted imaging or radionuclide therapy in selected patients with advanced DTC. Protein expression DTC glucose metabolism somatostain receptor iodine avidity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Although differentiated thyroid carcinoma (DTC), which comprises papillary thyroid carcinoma and follicular thyroid carcinoma, is among the most curable cancers and favorable outcomes, distant metastatic spread remains the leading cause of thyroid cancer–related mortality [ 1 , 2 ]. The most common sites of distant metastasis are the lungs and bones [ 3 – 5 ]. In patients with DTC and bone metastases, overall survival rates were reported to be 42% at 10 years, and 23% at 20 years [ 6 ]. Several studies have investigated prognostic factors in metastatic DTC, including iodine avidity, primary tumor size, age, sex, and tumor histology [ 3 , 7 – 10 ]. Further analyses of primary and metastatic lesions are clinically important, because such information can be applied to individual patients prior to systemic treatment. Previous studies have demonstrated that the genetic characteristics of metastatic lesions can often be predicted from primary tumors in several cancer types, including colorectal cancer [ 11 , 12 ], breast cancer [ 13 , 14 ], and pancreatic neuroendocrine tumor [ 15 ]. In papillary thyroid cancer, the intra-tumor heterogeneity between primary and metastasis sites has also been reported [ 16 – 18 ]. In thyroid cancer, sodium/iodide symporter (NIS) and hexokinases (HK) show similar staining intensity between primary tumors and cervical lymph nodes, whereas glucose transporter–1 (GLUT − 1) expression tends to be lower in cervical lymph nodes [ 19 ]. However, the contribution of intra-tumor heterogeneity to differences between primary lesion and distant metastasis in DTC remains poorly understood. Radioactive isotopes play a central role in the treatment of DTC, and once tumors lose the ability to concentrate radioiodine, therapeutic options become limited [ 9 , 20 ]. Several studies have demonstrated the expression of somatostatin receptors (SSTR) in human thyroid tissues and thyroid carcinoma cell lines [ 21 ], as well as the feasibility of SSTR-targeted imaging in thyroid tumor [ 22 , 23 ]. Based on these findings, the use of somatostatin analogs for both diagnostic and therapeutic purposes in patients with non-radioiodine-avid DTC has been proposed [ 24 – 26 ]. Evaluation of glucose transporter and SSTR expression in metastatic lesions may therefore allow the application of alternative therapeutic approaches in DTC patients with distant metastases. As far as we know, no prior study has comprehensively reported iodine avidity and protein expression patterns in distant metastases of patients with DTC. The primary aim of this study was to investigate the heterogeneity of protein expression between primary tumors and distant metastases in patients with DTC, focusing on markers of glucose metabolism and SSTR expression. The secondary aim was to evaluate SSTR expression in metastases lacking iodine avidity. MATERIALS AND METHODS Patients We retrospectively reviewed 9,235 patients who were diagnosed with differentiated thyroid cancer at the Korea Cancer Center Hospital from January 1983 to August 2013. The inclusion criteria for this study were: (i) patients who had metastasis in distant sites, and (ii) tissue material available for pathological review and immunohistochemistry. Eighteen patients met the criteria. Distant metastasis was diagnosed based on pathologic and/or radiologic findings. Paraffin tissue blocks from primary tumors and distant metastasis were obtained from the archives of the Pathology Department. The study was approved by the Institutional Review Board of Korea Cancer Center Hospital (IRB No.: KIRAMS 2019 − 02−008). All procedures were conducted in accordance with the ethical standards of the institutional review committee and with the Declaration of Helsinki as revised in 2013. The institutional review board waived the need to obtain informed consent. Immunohistochemistry Tissue microarray was generated by obtaining a 2 mm diameter core from each donor block, and transferring them to a recipient block using a trephine apparatus (Superbiochips Laboratories, Seoul, Republic of Korea). The tissue microarray (TMA) consisted of 18 metastatic carcinoma and normal thyroid tissues. Sections of 4 µm thickness were obtained from the TMA blocks. Table 1 summarizes the primary antibodies used in the immunohistochemical study of formalin-fixed, paraffin-embedded sections. Immunohistochemical staining was conducted using the horseradish peroxidase (HRP) polymer method and the Bond Polymer Refine Detection system. Protein expressions were classified as negative, weak positive, and strong positive by a pathologist with 10 years experience (Fig. 1 ). Table 1. Summary of the Antibodies used in this study. Name Manufacturer Antigen retrieval Dilution GLUT − 1 Abcam, Cambridge, UK microwave 1:500 HK − 2 Chemicon International, Temecula microwave 1:500 SSTR − 2 Abcam, Cambridge, UK microwave 1:500 GLUT−1, glucose transporter-1; HK−2, hexokinase-2; SSTR−2, somatostatin receptor-2. Iodine Whole-body Scan protocols A whole-body scan (WBS) was performed after total or near-total thyroidectomy was conducted. This was usually performed several months after the thyroid surgery. Therefore, patients were placed on l–thyroxine after thyroidectomy, which was then stopped before the WBS. The WBS was performed with high-dose 131 I (≥ 100 mCi) in all patients who were adequately prepared, as confirmed by a serum thyrotropin level above 30 mU/L at 4 to 6 weeks after l–thyroxine was withdrawn. After the WBS was performed, l–thyroxine treatment was resumed. Iodine avidity was visually determined at the known site of metastatic disease by two experienced nuclear medicine physicians under TSH-stimulated conditions. 18 F − FDG−PET/CT imaging protocols 18 F − FDG−PET/CT imaging was performed after a fast of at least 6 h. 18 F − FDG was injected at a dose of 7.4 MBq/kg intravenously, and scanning was begun 60 min after injection. Positive FDG uptake was defined as FDG uptake greater than that of the adjacent normal tissue. Areas of positive FDG uptake were identified, and intensities of FDG uptake were also quantified by calculating SUVs from the amounts of FDG injected and total body weight. Two board-certified nuclear medicine physicians interpreted all FDG − PET/CT images. Statistical analysis For statistical analysis, continuous variables were presented as the median (range) and frequency (percentage) for categorical variables. The correlation between primary tumor and distant metastasis was obtained by Spearman’s correlation. Sign test was used to compare staining intensity between primary tumors and distant metastasis. Fisher’s exact test was performed to examine the relationships between pathologic types (i.e., papillary, follicular) and the protein expressions of the biological markers (i.e., GLUT − 1, HK − 2, SSTR − 2), as well as to assess the correlation between iodine avidity and SSTR − 2 expression. Also, the difference between FDG SUV max based on biological markers was tested by Mann–Whitney test. All statistical analysis was performed using MedClac (version 16.8.4, MedCalc software, Mariakerke, Belgium) and R 3.2.3 software ( http://www.r-project.org/ ). P values < .05 were considered statistically significant. RESULTS Patient characteristics Table 2 summarizes the patient characteristics. The median patient age was 55 years (mean, (55.3 ± 9.4) years; range, (41 − 73) years) and 11 patients (61%, 11/18) were women. The mean follow-up duration was (102 ± 73) months. The histological characteristics consisted of 9 (50%) papillary, and 9 (50%) follicular thyroid cancer. The median value of the initial thyroglobulin was 365 (0.5 to 18,600) ng/mL. The sites of metastases were found in bones (extremities (6), spine (4), pelvis (3), clavicle (1), skull (1)), followed by lung (2) and soft tissue (1). The patients were managed by radioactive iodine (RAI), external radiotherapy (RT), and surgical treatment. Ten patients underwent both surgery and RT. The study cohort of 13 patients was diagnosed with primary cancer with synchronous distant metastases. The other five patients showed 930 (513 to 3,113) days of median time interval between the diagnosis of primary cancer and distant metastases Table 2 Patient characteristics. No. GLUT − 1 HK − 2 SSTR − 2 Age Sex Pathology Primary Metastasis Primary Metastasis Primary Metastasis Treatment Sites of metastasis 1 62 M follicular 2 1 1 1 0 1 RT sacrum 2 70 F follicular 0 0 1 1 0 0 OP, RT left tibia 3 53 F follicular 0 2 0 2 0 1 OP T spine 4 58 M papillary 2 1 2 1 0 0 OP, RT left pelvis 5 64 F follicular 0 0 1 0 1 1 OP, RT T3, T4 6 44 F papillary 0 0 2 2 0 2 OP lung 7 61 M papillary 0 1 1 1 2 0 OP lung 8 73 F papillary 0 0 1 1 0 0 OP right scapula & right humerus 9 47 F follicular 1 0 1 1 2 0 RT right femur 10 56 F papillary 1 1 2 2 1 1 OP, RT spine 11 54 F papillary 1 2 1 1 1 1 RT left femur 12 41 M follicular 0 0 2 1 1 0 OP, RT right humerus 13 54 M insular 0 1 1 1 0 0 OP, RT left femur 14 64 M follicular 0 1 1 1 0 0 OP, RT right buttock & left femur 15 44 M papillary 1 2 1 1 2 1 OP, RT right clavicle 16 42 F follicular 1 N/A 2 N/A 1 N/A RT right pubis 17 51 F papillary 2 2 1 1 0 0 OP, RT retroesophageal/ soft tissue 18 58 F papillary 1 1 1 1 1 0 OP, RT skull The scores are protein expressions, as follows: negative (0), weak positive (1), strong positive (2) by immunohistochemistry. GLUT − 1, glucose transporter-1; HK − 2, hexokinase-2; SSTR − 2, somatostatin receptor-2; RT, radiation therapy; OP, operation. Pattern of protein expression in primary tumor and distant metastasis according to pathologic type Thirty-five specimens were obtained from primary tumors (n = 18) and distant metastasis (n = 17). Table 3 shows the distribution of protein expression based on pathologic type. Fisher’s exact test revealed no significant difference between the biomarker and pathologic type. The categorical variables of protein expressions were dichotomized as negative (score 0) or positive expression (scores 1 or 2). Metastatic lesions showed slightly higher GLUT − 1 expression (65%, 11/17) than primary lesions (50%, 9/18). HK − 2 was highly expressed in both primary (94%, 17/18) and metastatic (94%, 16/17) sites. Primary lesions revealed similar SSTR − 2 expression (50%, 9/18) to metastatic lesions (41%, 7/17) (Fig. 2 ). Table 3 Distribution of Positive and Negative Biologic Markers on Primary tumor and Distant metastasis According to Pathologic Type (n = 18). Pathologic type GLUT − 1 HK − 2 SSTR − 2 Negative Positive Negative Positive Negative Positive Primary tumor (n = 18) Papillary (9) 3 6 0 9 4 5 Follicular (9) 6 3 1 8 5 4 P value a 0.347 > 0.999 > 0.999 Distant metastasis (n = 17) Papillary (9) 2 7 0 9 5 4 Follicular (8) 4 4 1 7 5 3 P value a 0.335 0.471 > 0.999 a Fisher’s exact test is used for statistical analysis GLUT − 1, glucose transporter-1; HK − 2, hexokinase-2; SSTR − 2, somatostatin receptor-2. Correlation of protein expression between primary tumor and distant metastasis Figure 3 shows the results of a correlation of protein expressions between primary tumor and distant metastasis. While the GLUT − 1 expression tended to show marginally positive correlation between primary and distant metastasis (r = 0.462, p = 0.062), the expression of HK − 2 and SSTR − 2 did not show such correlation (HK − 2: r = 0.209, p = 0.420; SSTR − 2: r = 0.056, p = 0.831). Upon exclusion of primary tumors smaller than 1 cm (n = 5), significant correlations were identified for both GLUT-1 (r = 0.624, p = 0.023) and HK-2 (r = 0.695, p = 0.008), whereas SSTR-2 showed no significant association (r = 0.371, p = 0.212). Table 4 compares the staining intensity between primary tumor and distant metastasis. The primary tumor and distant metastasis had the same expression for GLUT − 1 in 8 of 17 cases (47%). Distant metastasis showed a stronger expression than primary tumors in 6 cases (35%) for GLUT − 1, while the opposite results were shown in 3 cases (17%). For HK − 2, 13 cases (76%) represented the same expressions of primary and metastasis. For SSTR − 2, 5 cases (29%) showed stronger expressions in primary tumor, while 3 cases showed stronger expressions in distant metastasis (18%). There were no significant differences between primary and metastasis groups for GLUT − 1, HK − 2, and SSTR − 2 (p = 0.508, p = 0.625, and p = 0.727, respectively, Table 4 ). Table 4 Comparison of Staining Intensity between Primary Tumors and Distant Metastasis. Biological marker Primary tumor > Distant metastasis Primary tumor = Distant metastasis Primary tumor < Distant metastasis P value a GLUT − 1 3 8 6 0.508 HK − 2 3 13 1 0.625 SSTR − 2 5 9 3 0.727 a Sign test is used for statistical analysis GLUT − 1, glucose transporter–1; HK − 2, hexokinase–2; SSTR − 2, somatostatin receptor–2. Correlation between protein expression and FDG avidity We examined the patients who underwent FDG − PET/CT and surgical resection within 1 year. Eight of 18 (44%) patients met the criteria. Figure 4 shows the results of the FDG/PET-CT with the protein expressions of metastatic lesions. The patients consisted of 6 positive and 2 negative for GLUT − 1 expression. The difference of FDG SUV max was estimated according to GLUT − 1, HK − 2, and SSTR − 2. Significant difference in FDG SUV max was shown between the GLUT − 1 positive (weak positive (1) or strong positive (2)) and GLUT − 1 negative groups (8.15 [4.0 to 18.8], 2.2 [2.1 to 2.3], p = 0.046), while there was no difference in FDG SUV max between the HK − 2 positive and HK − 2 negative groups (6.0 [2.3 to 9.8], 6.3 [2.1 to 18.8], p > 0.999), or between the SSTR − 2 positive and SSTR − 2 negative groups (8.0 [2.3 to 9.8], 4.5 [2.1 to 18.8], p = 0.882, Fig. 5 ). Correlation between Iodine avidity and SSTR − 2 expression We also investigate the correlation between Iodine avidity and SSTR − 2 expression of metastasis sites. Among the 18 patients, 10 patients were excluded (scans from six patients were no longer available, while scans from four patients were deemed inappropriate because they had been acquired after surgery), while the remaining 8 patients were examined. SSTR2 expression was observed in both iodine non-avid patients (2/2) and in three of the six iodine-avid patients (3/6). For iodine avidity and SSTR − 2 expression, no significant difference was observed in terms of SSTR − 2 expression between the iodine avid and iodine non-avid patients (p = 0.464; Table 5 ). Table 5 Correlation between Iodine avidity and SSTR − 2 expression in metastasis. SSTR − 2 expression Iodine non-avid Iodine avid negative 0 3 positive 2 3 SSTR − 2, somatostatin receptor-2. DISCUSSION This study demonstrates the heterogeneity of protein expression between primary and metastatic lesions in differentiated thyroid cancer (DTC), focusing on glucose metabolism and somatostatin receptor 2 (SSTR − 2). We observed that GLUT − 1 expression was higher in metastatic sites compared with primary lesions, whereas HK − 2 was highly expressed in both. SSTR − 2 expression showed no significant difference between primary and metastatic sites, but was detected in some iodine non-avid patients. These findings indicate that molecular phenotypes of DTC may vary across disease progression, particularly with respect to metabolic adaptation and receptor expression. Also, positive SSTR − 2 expression was observed in all patients with iodine non-avid metastases, indicating that SSTR − 2-targeted therapy may be a viable treatment option for iodine-refractory disease. Our results revealed the significant role of the Warburg effect in DTC progression, indicated by high expression levels of both GLUT − 1 and HK − 2. The finding that metastatic lesions exhibited a higher frequency of GLUT − 1 expression (65%), compared to primary tumors (50%), aligns with established knowledge that de-differentiated and aggressive thyroid cancer cells upregulate glucose transporters to support rapid proliferation [ 27 ]. This metabolic shift towards glycolysis is a hallmark of malignancy, and is strongly associated with the loss of radioiodine avidity [ 28 , 29 ]. The observed marginal positive correlation for GLUT − 1 expression between primary tumors and distant metastases (Fig. 3 A) suggests that while metabolic profiling may be partially shared, considerable intratumoral and inter-lesional heterogeneity exists. This heterogeneity is a known factor limiting the efficacy of systemic therapies in advanced DTC, and underscores the necessity of obtaining biopsies from metastatic sites for accurate molecular characterization, rather than relying solely on the primary tumor profile [ 30 ]. Our analysis further validated the clinical utility of GLUT − 1 as a predictive biomarker for imaging. The GLUT − 1 positive group showed a significantly higher 18 FDG PET/CT SUV max value (p = 0.046), which confirms that GLUT − 1 is the primary cellular determinant of FDG avidity in DTC, consistent with findings in other solid tumors [ 31 ]. In contrast, HK − 2 showed consistently high expression across all lesions (primary 94%, metastatic 96.4%), and no correlation with 18 F − FDG SUVmax or location. This suggests HK − 2 is a general marker of active tumor metabolism, whereas GLUT − 1 expression levels may be more reflective of the degree of de-differentiation and aggressiveness. In a similar study, Jung showed that the staining intensity of GLUT − 1 at primary tumor was higher than or equal to that of the cervical metastases (19/19, 100%). In this study, all patients were synchronous, suggesting that the metastatic lesion was early in the de-differentiation state, so that the GLUT − 1 staining intensity in the cervical metastasis sites was low. Our outcome included 5 metachronous patients. Another reason for this difference is Jung included all metastatic sites in cervical lymph node metastasis, while our study mainly included various lesions, such as distant metastasis to bone (15 patients), lung (2 patients), and soft tissue (1 patient). There are heterogenous biological characteristics in the regional lymph nodes metastasis and distant metastases of thyroid cancer [ 32 ]. The most impactful finding of this study is the presence of SSTR − 2 expression in the distant metastatic sites of all three iodine non-avid patients tested. Given the poor prognosis associated with iodine-refractory disease—especially those that are also FDG–avid—the identification of an alternative druggable target is critical [ 33 ]. SSTR − 2 is the primary target for Peptide Receptor Radionuclide Therapy (PRRT), a highly effective treatment utilized in neuroendocrine tumors (NETs). The observation that SSTR − 2 expression occurred in iodine non-avid lesions suggests a viable therapeutic strategy for a previously un-targetable subgroup. While the overall SSTR − 2 expression showed poor correlation between primary and metastatic sites (r = 0.056, p = 0.831), its presence in the metastatic lesions themselves provides the direct rationale for clinical intervention. This supports the growing body of evidence that SSTR − 2 expression, independent of classical thyroid markers, can be induced in de-differentiated thyroid cancer, opening the door for the application of 177 Lu–DOTATATE or related somatostatin analogues [ 34 ]. We also found that SSTR − 2-targeted therapy could be applicable for certain iodine non-avid patients, although no significant difference was observed between iodine avidity and SSTR − 2 expression. In this study, both iodine non-avid patients (2/2, 100%) exhibited SSTR − 2 expression, suggesting that SSTR-based approaches may provide therapeutic opportunities for iodine-refractory thyroid cancer [ 25 , 26 ]. A similar study investigated SSTR expression in paired samples of primary tumors and recurrent cervical lymph nodes [ 35 ]. That study demonstrated a positive correlation between SSTR1/SSTR2A expression and iodine avidity; however, approximately (40 − 50) % of iodine-negative cases also showed strong SSTR1 and SSTR2A expression, indicating that SSTR-targeted imaging could still be considered for selected non-avid lesions. Nevertheless, their imaging analysis included both diagnostic and post-therapeutic 131 I scans, and their specimens were confined to cervical lymph node recurrences, limiting generalization to distant metastatic disease. In contrast, our study evaluated SSTR − 2 expression in distant metastases, providing a broader perspective on the potential applicability of SSTR-targeted imaging and therapy in advanced and iodine-refractory DTC. Currently available SSTR-based radiotracers, such as 111 In-DTPA-octreotide, 99m Tc-depreotide, and 68 Ga-DOTATOC, could therefore be considered for functional assessment or therapeutic planning in this patient subgroup [ 36 – 38 ]. The present study includes several limitations. Firstly, the small sample size (n = 18) limits the statistical power, particularly evident in the marginal significance of the GLUT − 1 correlation. Secondly, the retrospective nature introduces the possibility of selection bias. Furthermore, immunohistochemistry provides a semi-quantitative measure of protein expression; future studies utilizing more quantitative methods, such as Western blotting or gene expression analysis, would provide a deeper mechanistic understanding. Despite these limitations, our findings carry significant translational potential. The observed SSTR − 2 positivity in iodine non-avid metastatic DTC patients warrants immediate investigation. Future directions must include prospective, larger-scale clinical trials specifically targeting SSTR − 2 in this refractory population, to evaluate the efficacy and safety of PRRT as a salvage therapy. Also, concurrent analysis of SSTR − 2 and GLUT − 1 could potentially stratify patients for optimal treatment sequencing (e.g., PRRT for SSTR − 2 positive disease vs. other systemic therapies for high GLUT − 1/FDG avid disease). Future studies should aim to validate these findings in larger, prospective cohorts to produce data useful for clinical treatment decisions, given the observed heterogeneity in protein expression between primary and metastatic lesions. Longitudinal analyses incorporating serial biopsies could elucidate temporal changes in GLUT − 1, HK − 2, and SSTR − 2 expression during disease progression and treatment. Functional imaging with SSTR-targeted PET tracers may help refine patient selection for SSTR − 2-directed therapies, particularly in iodine-refractory cases. As well, integrating molecular profiling with immunohistochemical assessment may clarify the underlying mechanisms driving differential protein expression, potentially informing personalized therapeutic strategies in advanced DTC. CONCLUSIONS This study demonstrated marked heterogeneity in protein expression between primary and metastatic differentiated thyroid cancer (DTC) lesions. GLUT − 1 expression was higher in metastases, suggesting metabolic adaptation during progression, while HK − 2 and SSTR − 2 showed no site correlation. Notably, all iodine non-avid patients expressed SSTR − 2 in metastases, indicating potential eligibility for SSTR-targeted radionuclide therapy. These findings highlight the need for molecular profiling of metastatic lesions to optimize theranostic strategies and support SSTR-based therapy as a promising option for iodine-refractory DTC. Declarations Acknowledgments Joon Ho Choi, Jae Kyung Myung, Ji Eun Moon, Joon-Seog Kong, Byung Hyun Byun, Byung Il Kim, Ilhan Lim declare that they have no conflict of interest. This study was supported by a grant from the Korea Institute of Radiological and Medical Science (KIRAMS), funded by the Ministry of Science and ICT of the Republic of Korea (Nos. 50547−2025, 2020R1A2C2102492), and by the Soonchunhyang University Research Fund (No. 20250049). Ethics Approval This study was approved by the Institutional Review Board at the Korea Cancer Center Hospital (IRB No. KIRAMS 2019−02−008). 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Trends Endocrinol Metab. 2006;17(1):19–25. Budiawan H, Salavati A, Kulkarni HR, Baum RP. Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using (90)Yttrium and (177)Lutetium labeled somatostatin analogs: toxicity, response and survival analysis. Am J Nucl Med Mol Imaging. 2013;4(1):39–52. Iten F, Muller B, Schindler C, Rasch H, Rochlitz C, Oertli D, et al. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer. 2009;115(10):2052–62. Zhang L, Feng Q, Wang J, Tan Z, Li Q, Ge M. Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities. Biochim Biophys Acta Rev Cancer. 2023;1878(4):188928. Zampella E, Klain M, Pace L, Cuocolo A. PET/CT in the management of differentiated thyroid cancer. Diagn Interv Imaging. 2021;102(9):515–23. Oh SW, Park S, Chong A, Kim K, Bang JI, Seo Y, et al. Nuclear Medicine Imaging in Differentiated Thyroid Cancer: Summary of the Korean Thyroid Association Guidelines 2024 from Nuclear Medicine Perspective, Part-I. Nucl Med Mol Imaging. 2025;59(1):1–7. McGranahan N, Swanton C. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. 2017;168(4):613–28. Higashi T, Tamaki N, Torizuka T, Nakamoto Y, Sakahara H, Kimura T, et al. FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors. J Nucl Med. 1998;39(10):1727–35. Sugino K, Kure Y, Iwasaki H, Ozaki O, Mimura T, Matsumoto A, et al. Metastases to the regional lymph nodes, lymph node recurrence, and distant metastases in nonadvanced papillary thyroid carcinoma. Surg Today. 1995;25(4):324–8. Aashiq M, Silverman DA, Na'ara S, Takahashi H, Amit M. Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. Cancers (Basel) 2019; 11 (9). Enke JS, Bundschuh RA, Wienand G, Reitsam NG, Kircher M, Pfob CH et al. Somatostatin Receptor Antagonists as a Theranostic Option in Iodine-Refractory Thyroid Carcinoma. J Nuclear Med 2023:jnumed.123.265639. Lee JW, Min HS, Lee SM, Kwon HW, Chung JK. Relations Between Pathological Markers and Radioiodine Scan and (18)F-FDG PET/CT Findings in Papillary Thyroid Cancer Patients With Recurrent Cervical Nodal Metastases. Nucl Med Mol Imaging. 2015;49(2):127–34. Middendorp M, Selkinski I, Happel C, Kranert WT, Grunwald F. Comparison of positron emission tomography with [(18)F]FDG and [(68)Ga]DOTATOC in recurrent differentiated thyroid cancer: preliminary data. Q J Nucl Med Mol Imaging. 2010;54(1):76–83. Kurdziel K, Ravizzini G, Croft B, Tatum J, Choyke P, Kobayashi H. The evolving role of nuclear molecular imaging in cancer. Expert Opin Med Diagn. 2008;2(7):829–42. Rodrigues M, Li S, Gabriel M, Heute D, Greifeneder M, Virgolini I. 99mTc-depreotide scintigraphy versus 18F-FDG-PET in the diagnosis of radioiodine-negative thyroid cancer. J Clin Endocrinol Metab. 2006;91(10):3997–4000. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 23 Mar, 2026 Reviewers invited by journal 23 Mar, 2026 Editor assigned by journal 22 Mar, 2026 First submitted to journal 22 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9194234","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":610502006,"identity":"1bc7ecf5-ae7e-4d3c-8760-9513f0b14142","order_by":0,"name":"Joon Ho Choi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIie3OMQuCQBTA8SeCLZeuJ4J9BdtDv8qJYJO7Q1twS1HriV+iEJovgiarNbDBj3Au0RQZtbR0tjXcb3uP94cHoCh/yNBhfBPeCAC/N/jrfcvsQW2zNP4hcS2tdlC5+yExdJ0MM3oKrHwWCpj4YOdclhiENLQK2eVQYNhH4JhEliCyzWhFPJxs2pGDi6SPWc20T4/BK7l3SiDSUcm11TPRKAenQxJrLI1Cdk4KHC4iZM8lyWDJYxCeH1gsWQtx9V1cSpJPBED2lqIoitLFA2u4Os3QDCmKAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7735-761X","institution":"Soonchunhyang University Bucheon Hospital","correspondingAuthor":true,"prefix":"","firstName":"Joon","middleName":"Ho","lastName":"Choi","suffix":""},{"id":610502007,"identity":"e4f1ca0d-179f-4220-acd2-1e8dec066896","order_by":1,"name":"Jae Kyung Myung","email":"","orcid":"","institution":"Hanyang University","correspondingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Kyung","lastName":"Myung","suffix":""},{"id":610502008,"identity":"84631a8d-9e4a-4b16-9ba4-9ff68b137ae2","order_by":2,"name":"Ji Eun Moon","email":"","orcid":"","institution":"Cheongun University","correspondingAuthor":false,"prefix":"","firstName":"Ji","middleName":"Eun","lastName":"Moon","suffix":""},{"id":610502009,"identity":"839fe585-6e71-48d3-8a40-07c505117f59","order_by":3,"name":"Joon-Seog Kong","email":"","orcid":"","institution":"Korea Institute of Radiological and Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Joon-Seog","middleName":"","lastName":"Kong","suffix":""},{"id":610502010,"identity":"78af4ade-67bf-405a-b72b-e21fdd2d68c0","order_by":4,"name":"Byung Hyun Byun","email":"","orcid":"","institution":"Korea Institute of Radiological and Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Byung","middleName":"Hyun","lastName":"Byun","suffix":""},{"id":610502011,"identity":"0ccd2dd2-2d78-41e7-9d76-d92c34c06faa","order_by":5,"name":"Byung Il Kim","email":"","orcid":"","institution":"Korea Institute of Radiological and Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Byung","middleName":"Il","lastName":"Kim","suffix":""},{"id":610502012,"identity":"8fef426b-ef61-4915-9a5f-66e7ba3fa62d","order_by":6,"name":"Ilhan Lim","email":"","orcid":"https://orcid.org/0000-0002-5903-1659","institution":"Korea Institute of Radiological and Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ilhan","middleName":"","lastName":"Lim","suffix":""}],"badges":[],"createdAt":"2026-03-23 00:55:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9194234/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9194234/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105456781,"identity":"7891ca4a-c3b4-4837-990e-718dbf7a2866","added_by":"auto","created_at":"2026-03-26 09:15:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":139067,"visible":true,"origin":"","legend":"\u003cp\u003eAssessment of protein expression by immunohistochemistry. Protein expressions were categorized as negative of (A) GLUT-1, (B) HK-2, (C) SSTR-2, weak positive of (D) GLUT-1, (E) HK-2, (F) SSTR-2, strong positive of (G) GLUT-1, (H) HK-2, (I) SSTR-2.\u003c/p\u003e","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/e67ae0a2ea5db1017a78d44e.png"},{"id":105456778,"identity":"8b44b0be-357f-4502-b685-3c413b08b377","added_by":"auto","created_at":"2026-03-26 09:15:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10911,"visible":true,"origin":"","legend":"\u003cp\u003eProtein expressions by primary tumor and distant metastasis of (A) GLUT-1 (B) HK-2 (C) SSTR-2. The staining intensities were categorized as negative (0), weak positive (1), strong positive (2).\u003c/p\u003e","description":"","filename":"OnlineFIg2.png","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/af738d0a84e27efa00c47d2d.png"},{"id":105566154,"identity":"a55b9e53-a435-4565-ad45-f807e33abb81","added_by":"auto","created_at":"2026-03-27 12:55:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":10777,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation of protein expression between primary tumor and distant metastasis of (A) GLUT-1 (B) HK-2 (C) SSTR-2. The staining intensities were categorized as negative (0), weak positive (1), strong positive (2).\u003c/p\u003e","description":"","filename":"OnlineFIg3.png","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/65a91202a9b3c991a6170080.png"},{"id":105456796,"identity":"bfe977dc-3438-42b3-b992-a95bde85129d","added_by":"auto","created_at":"2026-03-26 09:15:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":31389,"visible":true,"origin":"","legend":"\u003cp\u003eFDG avidity and protein expressions of the 8 patients who underwent surgery and FDG-PET/CT within 1 year. The patients were categorized based on GLUT-1 expression. The arrows indicated the metastatic lesions of (A) sacrum, (B) T11 ,(C) left pelvis, (D) left lower lung, (E) left femur, (F) esophagus, (G) left upper long, (H) right scapular, respectively.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eThe scores are protein expressions as follows : negative (0), weak positive (1) , strong positive (2) by immunohistochemistry.\u003c/p\u003e","description":"","filename":"OnlineFIg4.png","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/960f9bf9d3f46524d53842a6.png"},{"id":105456779,"identity":"3c394113-ae29-4baf-a480-e5c9465bb73b","added_by":"auto","created_at":"2026-03-26 09:15:41","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":12142,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in FDG SUVmax at metastatic sites according to the expression levels of (a) GLUT-1, (b) HK-2, and (c) SSTR-2.\u003c/p\u003e","description":"","filename":"OnlineFIg5.png","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/cdec66a0eebc14b18b1bea52.png"},{"id":105569612,"identity":"737d3b6a-7b37-430b-b68a-f9beaad3462b","added_by":"auto","created_at":"2026-03-27 13:12:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1234007,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9194234/v1/a1dc77c6-5420-485d-adf9-92f93f672e84.pdf"}],"financialInterests":"","formattedTitle":"Protein Expression Heterogeneity of Glucose Metabolism and Somatostatin Receptor between Primary Tumor and Distant Metastasis in Differentiated Thyroid Cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAlthough differentiated thyroid carcinoma (DTC), which comprises papillary thyroid carcinoma and follicular thyroid carcinoma, is among the most curable cancers and favorable outcomes, distant metastatic spread remains the leading cause of thyroid cancer\u0026ndash;related mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The most common sites of distant metastasis are the lungs and bones [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In patients with DTC and bone metastases, overall survival rates were reported to be 42% at 10 years, and 23% at 20 years [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Several studies have investigated prognostic factors in metastatic DTC, including iodine avidity, primary tumor size, age, sex, and tumor histology [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurther analyses of primary and metastatic lesions are clinically important, because such information can be applied to individual patients prior to systemic treatment. Previous studies have demonstrated that the genetic characteristics of metastatic lesions can often be predicted from primary tumors in several cancer types, including colorectal cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], breast cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and pancreatic neuroendocrine tumor [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In papillary thyroid cancer, the intra-tumor heterogeneity between primary and metastasis sites has also been reported [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In thyroid cancer, sodium/iodide symporter (NIS) and hexokinases (HK) show similar staining intensity between primary tumors and cervical lymph nodes, whereas glucose transporter\u0026ndash;1 (GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1) expression tends to be lower in cervical lymph nodes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, the contribution of intra-tumor heterogeneity to differences between primary lesion and distant metastasis in DTC remains poorly understood.\u003c/p\u003e \u003cp\u003eRadioactive isotopes play a central role in the treatment of DTC, and once tumors lose the ability to concentrate radioiodine, therapeutic options become limited [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Several studies have demonstrated the expression of somatostatin receptors (SSTR) in human thyroid tissues and thyroid carcinoma cell lines [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], as well as the feasibility of SSTR-targeted imaging in thyroid tumor [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Based on these findings, the use of somatostatin analogs for both diagnostic and therapeutic purposes in patients with non-radioiodine-avid DTC has been proposed [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Evaluation of glucose transporter and SSTR expression in metastatic lesions may therefore allow the application of alternative therapeutic approaches in DTC patients with distant metastases. As far as we know, no prior study has comprehensively reported iodine avidity and protein expression patterns in distant metastases of patients with DTC.\u003c/p\u003e \u003cp\u003eThe primary aim of this study was to investigate the heterogeneity of protein expression between primary tumors and distant metastases in patients with DTC, focusing on markers of glucose metabolism and SSTR expression. The secondary aim was to evaluate SSTR expression in metastases lacking iodine avidity.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed 9,235 patients who were diagnosed with differentiated thyroid cancer at the Korea Cancer Center Hospital from January 1983 to August 2013. The inclusion criteria for this study were: (i) patients who had metastasis in distant sites, and (ii) tissue material available for pathological review and immunohistochemistry. Eighteen patients met the criteria. Distant metastasis was diagnosed based on pathologic and/or radiologic findings. Paraffin tissue blocks from primary tumors and distant metastasis were obtained from the archives of the Pathology Department. The study was approved by the Institutional Review Board of Korea Cancer Center Hospital (IRB No.: KIRAMS 2019\u0026thinsp;\u0026minus;\u0026thinsp;02\u0026minus;008). All procedures were conducted in accordance with the ethical standards of the institutional review committee and with the Declaration of Helsinki as revised in 2013. The institutional review board waived the need to obtain informed consent.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImmunohistochemistry\u003c/h3\u003e\n\u003cp\u003eTissue microarray was generated by obtaining a 2 mm diameter core from each donor block, and transferring them to a recipient block using a trephine apparatus (Superbiochips Laboratories, Seoul, Republic of Korea). The tissue microarray (TMA) consisted of 18 metastatic carcinoma and normal thyroid tissues. Sections of 4 \u0026micro;m thickness were obtained from the TMA blocks. Table\u0026nbsp;1 summarizes the primary antibodies used in the immunohistochemical study of formalin-fixed, paraffin-embedded sections. Immunohistochemical staining was conducted using the horseradish peroxidase (HRP) polymer method and the Bond Polymer Refine Detection system. Protein expressions were classified as negative, weak positive, and strong positive by a pathologist with 10 years experience (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTable\u0026nbsp;1. Summary of the Antibodies used in this study.\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eName\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eManufacturer\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eAntigen retrieval\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eDilution\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eAbcam, Cambridge, UK\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003emicrowave\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1:500\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHK\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eChemicon International, Temecula\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003emicrowave\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1:500\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eAbcam, Cambridge, UK\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003emicrowave\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e1:500\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e\u003cp\u003eGLUT−1, glucose transporter-1; HK−2, hexokinase-2; SSTR−2, somatostatin receptor-2.\u003c/p\u003e\n\u003ch3\u003eIodine Whole-body Scan protocols\u003c/h3\u003e\n\u003cp\u003eA whole-body scan (WBS) was performed after total or near-total thyroidectomy was conducted. This was usually performed several months after the thyroid surgery. Therefore, patients were placed on l\u0026ndash;thyroxine after thyroidectomy, which was then stopped before the WBS. The WBS was performed with high-dose \u003csup\u003e131\u003c/sup\u003eI (\u0026ge;\u0026thinsp;100 mCi) in all patients who were adequately prepared, as confirmed by a serum thyrotropin level above 30 mU/L at 4 to 6 weeks after l\u0026ndash;thyroxine was withdrawn. After the WBS was performed, l\u0026ndash;thyroxine treatment was resumed. Iodine avidity was visually determined at the known site of metastatic disease by two experienced nuclear medicine physicians under TSH-stimulated conditions.\u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cb\u003e18\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eF\u0026thinsp;\u0026minus;\u0026thinsp;FDG\u0026minus;PET/CT imaging protocols\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e18\u003c/sup\u003eF\u0026thinsp;\u0026minus;\u0026thinsp;FDG\u0026minus;PET/CT imaging was performed after a fast of at least 6 h. \u003csup\u003e18\u003c/sup\u003eF\u0026thinsp;\u0026minus;\u0026thinsp;FDG was injected at a dose of 7.4 MBq/kg intravenously, and scanning was begun 60 min after injection. Positive FDG uptake was defined as FDG uptake greater than that of the adjacent normal tissue. Areas of positive FDG uptake were identified, and intensities of FDG uptake were also quantified by calculating SUVs from the amounts of FDG injected and total body weight. Two board-certified nuclear medicine physicians interpreted all FDG\u0026thinsp;\u0026minus;\u0026thinsp;PET/CT images.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor statistical analysis, continuous variables were presented as the median (range) and frequency (percentage) for categorical variables. The correlation between primary tumor and distant metastasis was obtained by Spearman\u0026rsquo;s correlation. Sign test was used to compare staining intensity between primary tumors and distant metastasis. Fisher\u0026rsquo;s exact test was performed to examine the relationships between pathologic types (i.e., papillary, follicular) and the protein expressions of the biological markers (i.e., GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, HK\u0026thinsp;\u0026minus;\u0026thinsp;2, SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2), as well as to assess the correlation between iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression. Also, the difference between FDG SUV\u003csub\u003emax\u003c/sub\u003e based on biological markers was tested by Mann\u0026ndash;Whitney test. All statistical analysis was performed using MedClac (version 16.8.4, MedCalc software, Mariakerke, Belgium) and R 3.2.3 software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.r-project.org/\u003c/span\u003e\u003cspan address=\"http://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). \u003cem\u003eP\u003c/em\u003e values \u0026lt; .05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the patient characteristics. The median patient age was 55 years (mean, (55.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4) years; range, (41\u0026thinsp;\u0026minus;\u0026thinsp;73) years) and 11 patients (61%, 11/18) were women. The mean follow-up duration was (102\u0026thinsp;\u0026plusmn;\u0026thinsp;73) months. The histological characteristics consisted of 9 (50%) papillary, and 9 (50%) follicular thyroid cancer. The median value of the initial thyroglobulin was 365 (0.5 to 18,600) ng/mL. The sites of metastases were found in bones (extremities (6), spine (4), pelvis (3), clavicle (1), skull (1)), followed by lung (2) and soft tissue (1). The patients were managed by radioactive iodine (RAI), external radiotherapy (RT), and surgical treatment. Ten patients underwent both surgery and RT. The study cohort of 13 patients was diagnosed with primary cancer with synchronous distant metastases. The other five patients showed 930 (513 to 3,113) days of median time interval between the diagnosis of primary cancer and distant metastases\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eHK\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePathology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSites of metastasis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003esacrum\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eleft tibia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eT spine\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eleft pelvis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eT3, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003elung\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003elung\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright scapula \u0026amp;\u003c/p\u003e \u003cp\u003eright humerus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright femur\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003espine\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eleft femur\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright humerus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003einsular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eleft femur\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright buttock\u003c/p\u003e \u003cp\u003e\u0026amp; left femur\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright clavicle\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eright pubis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eretroesophageal/ soft tissue\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epapillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOP, RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eskull\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eThe scores are protein expressions, as follows: negative (0), weak positive (1), strong positive (2) by immunohistochemistry.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, glucose transporter-1; HK\u0026thinsp;\u0026minus;\u0026thinsp;2, hexokinase-2; SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2, somatostatin receptor-2; RT, radiation therapy; OP, operation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePattern of protein expression in primary tumor and distant metastasis according to pathologic type\u003c/h3\u003e\n\u003cp\u003eThirty-five specimens were obtained from primary tumors (n\u0026thinsp;=\u0026thinsp;18) and distant metastasis (n\u0026thinsp;=\u0026thinsp;17). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the distribution of protein expression based on pathologic type. Fisher\u0026rsquo;s exact test revealed no significant difference between the biomarker and pathologic type. The categorical variables of protein expressions were dichotomized as negative (score 0) or positive expression (scores 1 or 2). Metastatic lesions showed slightly higher GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression (65%, 11/17) than primary lesions (50%, 9/18). HK\u0026thinsp;\u0026minus;\u0026thinsp;2 was highly expressed in both primary (94%, 17/18) and metastatic (94%, 16/17) sites. Primary lesions revealed similar SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression (50%, 9/18) to metastatic lesions (41%, 7/17) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of Positive and Negative Biologic Markers on Primary tumor and Distant metastasis According to Pathologic Type (n\u0026thinsp;=\u0026thinsp;18).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePathologic\u003c/p\u003e \u003cp\u003etype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eHK\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003ePrimary tumor (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapillary (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollicular (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eDistant metastasis (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapillary (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollicular (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003ea\u003c/sup\u003eFisher\u0026rsquo;s exact test is used for statistical analysis\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, glucose transporter-1; HK\u0026thinsp;\u0026minus;\u0026thinsp;2, hexokinase-2; SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2, somatostatin receptor-2.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eCorrelation of protein expression between primary tumor and distant metastasis\u003c/h3\u003e\n\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the results of a correlation of protein expressions between primary tumor and distant metastasis. While the GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression tended to show marginally positive correlation between primary and distant metastasis (r\u0026thinsp;=\u0026thinsp;0.462, p\u0026thinsp;=\u0026thinsp;0.062), the expression of HK\u0026thinsp;\u0026minus;\u0026thinsp;2 and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 did not show such correlation (HK\u0026thinsp;\u0026minus;\u0026thinsp;2: r\u0026thinsp;=\u0026thinsp;0.209, p\u0026thinsp;=\u0026thinsp;0.420; SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2: r\u0026thinsp;=\u0026thinsp;0.056, p\u0026thinsp;=\u0026thinsp;0.831). Upon exclusion of primary tumors smaller than 1 cm (n\u0026thinsp;=\u0026thinsp;5), significant correlations were identified for both GLUT-1 (r\u0026thinsp;=\u0026thinsp;0.624, p\u0026thinsp;=\u0026thinsp;0.023) and HK-2 (r\u0026thinsp;=\u0026thinsp;0.695, p\u0026thinsp;=\u0026thinsp;0.008), whereas SSTR-2 showed no significant association (r\u0026thinsp;=\u0026thinsp;0.371, p\u0026thinsp;=\u0026thinsp;0.212).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e compares the staining intensity between primary tumor and distant metastasis. The primary tumor and distant metastasis had the same expression for GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 in 8 of 17 cases (47%). Distant metastasis showed a stronger expression than primary tumors in 6 cases (35%) for GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, while the opposite results were shown in 3 cases (17%). For HK\u0026thinsp;\u0026minus;\u0026thinsp;2, 13 cases (76%) represented the same expressions of primary and metastasis. For SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2, 5 cases (29%) showed stronger expressions in primary tumor, while 3 cases showed stronger expressions in distant metastasis (18%). There were no significant differences between primary and metastasis groups for GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, HK\u0026thinsp;\u0026minus;\u0026thinsp;2, and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 (p\u0026thinsp;=\u0026thinsp;0.508, p\u0026thinsp;=\u0026thinsp;0.625, and p\u0026thinsp;=\u0026thinsp;0.727, respectively, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Staining Intensity between Primary Tumors and Distant Metastasis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiological\u003c/p\u003e \u003cp\u003emarker\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary tumor\u0026thinsp;\u0026gt;\u0026thinsp;Distant metastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrimary tumor\u0026thinsp;=\u0026thinsp;Distant metastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePrimary tumor\u0026thinsp;\u0026lt;\u0026thinsp;Distant metastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.508\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHK\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.625\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.727\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eSign test is used for statistical analysis\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, glucose transporter\u0026ndash;1; HK\u0026thinsp;\u0026minus;\u0026thinsp;2, hexokinase\u0026ndash;2; SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2, somatostatin receptor\u0026ndash;2.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between protein expression and FDG avidity\u003c/h2\u003e \u003cp\u003eWe examined the patients who underwent FDG\u0026thinsp;\u0026minus;\u0026thinsp;PET/CT and surgical resection within 1 year. Eight of 18 (44%) patients met the criteria. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the results of the FDG/PET-CT with the protein expressions of metastatic lesions. The patients consisted of 6 positive and 2 negative for GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression. The difference of FDG SUV\u003csub\u003emax\u003c/sub\u003e was estimated according to GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, HK\u0026thinsp;\u0026minus;\u0026thinsp;2, and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2. Significant difference in FDG SUV\u003csub\u003emax\u003c/sub\u003e was shown between the GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 positive (weak positive (1) or strong positive (2)) and GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 negative groups (8.15 [4.0 to 18.8], 2.2 [2.1 to 2.3], p\u0026thinsp;=\u0026thinsp;0.046), while there was no difference in FDG SUV\u003csub\u003emax\u003c/sub\u003e between the HK\u0026thinsp;\u0026minus;\u0026thinsp;2 positive and HK\u0026thinsp;\u0026minus;\u0026thinsp;2 negative groups (6.0 [2.3 to 9.8], 6.3 [2.1 to 18.8], p\u0026thinsp;\u0026gt;\u0026thinsp;0.999), or between the SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 positive and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 negative groups (8.0 [2.3 to 9.8], 4.5 [2.1 to 18.8], p\u0026thinsp;=\u0026thinsp;0.882, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between Iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression\u003c/h2\u003e \u003cp\u003eWe also investigate the correlation between Iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression of metastasis sites. Among the 18 patients, 10 patients were excluded (scans from six patients were no longer available, while scans from four patients were deemed inappropriate because they had been acquired after surgery), while the remaining 8 patients were examined. SSTR2 expression was observed in both iodine non-avid patients (2/2) and in three of the six iodine-avid patients (3/6). For iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression, no significant difference was observed in terms of SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression between the iodine avid and iodine non-avid patients (p\u0026thinsp;=\u0026thinsp;0.464; Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation between Iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression in metastasis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIodine non-avid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIodine avid\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eSSTR\u0026thinsp;\u0026minus;\u0026thinsp;2, somatostatin receptor-2.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study demonstrates the heterogeneity of protein expression between primary and metastatic lesions in differentiated thyroid cancer (DTC), focusing on glucose metabolism and somatostatin receptor 2 (SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2). We observed that GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression was higher in metastatic sites compared with primary lesions, whereas HK\u0026thinsp;\u0026minus;\u0026thinsp;2 was highly expressed in both. SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression showed no significant difference between primary and metastatic sites, but was detected in some iodine non-avid patients. These findings indicate that molecular phenotypes of DTC may vary across disease progression, particularly with respect to metabolic adaptation and receptor expression. Also, positive SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression was observed in all patients with iodine non-avid metastases, indicating that SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2-targeted therapy may be a viable treatment option for iodine-refractory disease.\u003c/p\u003e \u003cp\u003eOur results revealed the significant role of the Warburg effect in DTC progression, indicated by high expression levels of both GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 and HK\u0026thinsp;\u0026minus;\u0026thinsp;2. The finding that metastatic lesions exhibited a higher frequency of GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression (65%), compared to primary tumors (50%), aligns with established knowledge that de-differentiated and aggressive thyroid cancer cells upregulate glucose transporters to support rapid proliferation [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This metabolic shift towards glycolysis is a hallmark of malignancy, and is strongly associated with the loss of radioiodine avidity [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observed marginal positive correlation for GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression between primary tumors and distant metastases (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) suggests that while metabolic profiling may be partially shared, considerable intratumoral and inter-lesional heterogeneity exists. This heterogeneity is a known factor limiting the efficacy of systemic therapies in advanced DTC, and underscores the necessity of obtaining biopsies from metastatic sites for accurate molecular characterization, rather than relying solely on the primary tumor profile [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur analysis further validated the clinical utility of GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 as a predictive biomarker for imaging. The GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 positive group showed a significantly higher \u003csup\u003e18\u003c/sup\u003eFDG PET/CT SUV\u003csub\u003emax\u003c/sub\u003e value (p\u0026thinsp;=\u0026thinsp;0.046), which confirms that GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 is the primary cellular determinant of FDG avidity in DTC, consistent with findings in other solid tumors [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In contrast, HK\u0026thinsp;\u0026minus;\u0026thinsp;2 showed consistently high expression across all lesions (primary 94%, metastatic 96.4%), and no correlation with \u003csup\u003e18\u003c/sup\u003eF\u0026thinsp;\u0026minus;\u0026thinsp;FDG SUVmax or location. This suggests HK\u0026thinsp;\u0026minus;\u0026thinsp;2 is a general marker of active tumor metabolism, whereas GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression levels may be more reflective of the degree of de-differentiation and aggressiveness.\u003c/p\u003e \u003cp\u003eIn a similar study, Jung showed that the staining intensity of GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 at primary tumor was higher than or equal to that of the cervical metastases (19/19, 100%). In this study, all patients were synchronous, suggesting that the metastatic lesion was early in the de-differentiation state, so that the GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 staining intensity in the cervical metastasis sites was low. Our outcome included 5 metachronous patients. Another reason for this difference is Jung included all metastatic sites in cervical lymph node metastasis, while our study mainly included various lesions, such as distant metastasis to bone (15 patients), lung (2 patients), and soft tissue (1 patient). There are heterogenous biological characteristics in the regional lymph nodes metastasis and distant metastases of thyroid cancer [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most impactful finding of this study is the presence of SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression in the distant metastatic sites of all three iodine non-avid patients tested. Given the poor prognosis associated with iodine-refractory disease\u0026mdash;especially those that are also FDG\u0026ndash;avid\u0026mdash;the identification of an alternative druggable target is critical [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 is the primary target for Peptide Receptor Radionuclide Therapy (PRRT), a highly effective treatment utilized in neuroendocrine tumors (NETs).\u003c/p\u003e \u003cp\u003eThe observation that SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression occurred in iodine non-avid lesions suggests a viable therapeutic strategy for a previously un-targetable subgroup. While the overall SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression showed poor correlation between primary and metastatic sites (r\u0026thinsp;=\u0026thinsp;0.056, p\u0026thinsp;=\u0026thinsp;0.831), its presence in the metastatic lesions themselves provides the direct rationale for clinical intervention. This supports the growing body of evidence that SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression, independent of classical thyroid markers, can be induced in de-differentiated thyroid cancer, opening the door for the application of \u003csup\u003e177\u003c/sup\u003eLu\u0026ndash;DOTATATE or related somatostatin analogues [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e We also found that SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2-targeted therapy could be applicable for certain iodine non-avid patients, although no significant difference was observed between iodine avidity and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression. In this study, both iodine non-avid patients (2/2, 100%) exhibited SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression, suggesting that SSTR-based approaches may provide therapeutic opportunities for iodine-refractory thyroid cancer [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA similar study investigated SSTR expression in paired samples of primary tumors and recurrent cervical lymph nodes [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. That study demonstrated a positive correlation between SSTR1/SSTR2A expression and iodine avidity; however, approximately (40\u0026thinsp;\u0026minus;\u0026thinsp;50) % of iodine-negative cases also showed strong SSTR1 and SSTR2A expression, indicating that SSTR-targeted imaging could still be considered for selected non-avid lesions. Nevertheless, their imaging analysis included both diagnostic and post-therapeutic \u003csup\u003e131\u003c/sup\u003eI scans, and their specimens were confined to cervical lymph node recurrences, limiting generalization to distant metastatic disease.\u003c/p\u003e \u003cp\u003eIn contrast, our study evaluated SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression in distant metastases, providing a broader perspective on the potential applicability of SSTR-targeted imaging and therapy in advanced and iodine-refractory DTC. Currently available SSTR-based radiotracers, such as \u003csup\u003e111\u003c/sup\u003eIn-DTPA-octreotide, \u003csup\u003e99m\u003c/sup\u003eTc-depreotide, and \u003csup\u003e68\u003c/sup\u003eGa-DOTATOC, could therefore be considered for functional assessment or therapeutic planning in this patient subgroup [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present study includes several limitations. Firstly, the small sample size (n\u0026thinsp;=\u0026thinsp;18) limits the statistical power, particularly evident in the marginal significance of the GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 correlation. Secondly, the retrospective nature introduces the possibility of selection bias. Furthermore, immunohistochemistry provides a semi-quantitative measure of protein expression; future studies utilizing more quantitative methods, such as Western blotting or gene expression analysis, would provide a deeper mechanistic understanding.\u003c/p\u003e \u003cp\u003eDespite these limitations, our findings carry significant translational potential. The observed SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 positivity in iodine non-avid metastatic DTC patients warrants immediate investigation. Future directions must include prospective, larger-scale clinical trials specifically targeting SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 in this refractory population, to evaluate the efficacy and safety of PRRT as a salvage therapy. Also, concurrent analysis of SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 and GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 could potentially stratify patients for optimal treatment sequencing (e.g., PRRT for SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 positive disease \u003cem\u003evs.\u003c/em\u003e other systemic therapies for high GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1/FDG avid disease).\u003c/p\u003e \u003cp\u003eFuture studies should aim to validate these findings in larger, prospective cohorts to produce data useful for clinical treatment decisions, given the observed heterogeneity in protein expression between primary and metastatic lesions. Longitudinal analyses incorporating serial biopsies could elucidate temporal changes in GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1, HK\u0026thinsp;\u0026minus;\u0026thinsp;2, and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 expression during disease progression and treatment. Functional imaging with SSTR-targeted PET tracers may help refine patient selection for SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2-directed therapies, particularly in iodine-refractory cases. As well, integrating molecular profiling with immunohistochemical assessment may clarify the underlying mechanisms driving differential protein expression, potentially informing personalized therapeutic strategies in advanced DTC.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis study demonstrated marked heterogeneity in protein expression between primary and metastatic differentiated thyroid cancer (DTC) lesions. GLUT\u0026thinsp;\u0026minus;\u0026thinsp;1 expression was higher in metastases, suggesting metabolic adaptation during progression, while HK\u0026thinsp;\u0026minus;\u0026thinsp;2 and SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 showed no site correlation. Notably, all iodine non-avid patients expressed SSTR\u0026thinsp;\u0026minus;\u0026thinsp;2 in metastases, indicating potential eligibility for SSTR-targeted radionuclide therapy. These findings highlight the need for molecular profiling of metastatic lesions to optimize theranostic strategies and support SSTR-based therapy as a promising option for iodine-refractory DTC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJoon Ho Choi, Jae Kyung Myung, Ji Eun Moon, Joon-Seog Kong, Byung Hyun Byun, Byung Il Kim, Ilhan Lim declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003eThis study was supported by a grant from the Korea Institute of Radiological and Medical Science (KIRAMS), funded by the Ministry of Science and ICT of the Republic of Korea (Nos. 50547\u0026minus;2025, 2020R1A2C2102492), and by the Soonchunhyang University Research Fund (No. 20250049).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board at the Korea Cancer Center Hospital (IRB No. KIRAMS 2019\u0026minus;02\u0026minus;008).\u003c/p\u003e\n\u003cp\u003eAll procedures of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe institutional review board of our institute approved this retrospective study, and the requirement to obtain informed consent was waived.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLang BH, Lo CY, Chan WF, Lam KY, Wan KY. 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J Clin Endocrinol Metab. 2006;91(10):3997\u0026ndash;4000.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Protein expression, DTC, glucose metabolism, somatostain receptor, iodine avidity","lastPublishedDoi":"10.21203/rs.3.rs-9194234/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9194234/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study investigated the heterogeneity of protein expression between primary tumors and distant metastatic lesions in DTC, focusing on markers of glucose metabolism and somatostatin receptor (SSTR) expression.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 18 patients with DTC (mean age 56\u0026thinsp;\u0026plusmn;\u0026thinsp;10 years) who had bone or soft tissue metastases. Immunohistochemical staining of surgical specimens was performed to assess the expression of glucose transporter 1 (GLUT-1), hexokinase-2 (HK-2), and somatostatin receptor subtype 2 (SSTR-2). Protein expression was classified as negative, weakly positive, or strongly positive. Correlations between primary and metastatic lesions were evaluated using Spearman analysis. FDG SUVmax values were compared according to protein expression using the Mann\u0026ndash;Whitney U test, and the association between iodine avidity and SSTR-2 expression was assessed using Fisher\u0026rsquo;s exact test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGLUT-1 expression was more frequent in metastatic lesions than in primary tumors (65% vs. 50%). HK-2 expression was high in both primary and metastatic lesions (94% each). SSTR-2 expression was similar between primary (50%) and metastatic lesions (41%). GLUT-1 expression demonstrated a marginal positive correlation between primary tumors and bone metastases (r\u0026thinsp;=\u0026thinsp;0.462, p\u0026thinsp;=\u0026thinsp;0.062). After excluding primary tumors smaller than 1 cm, significant correlations were observed for both GLUT-1 (r\u0026thinsp;=\u0026thinsp;0.624, p\u0026thinsp;=\u0026thinsp;0.023) and HK-2 (r\u0026thinsp;=\u0026thinsp;0.695, p\u0026thinsp;=\u0026thinsp;0.008), whereas SSTR-2 showed no significant correlation. Among patients who underwent surgery and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT within one year, GLUT-1\u0026ndash;positive metastatic lesions demonstrated significantly higher FDG SUVmax values than GLUT-1\u0026ndash;negative lesions (p\u0026thinsp;=\u0026thinsp;0.046). SSTR-2 expression was not significantly associated with iodine avidity.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eGLUT-1 expression showed partial concordance between primary and metastatic DTC lesions and was associated with increased FDG uptake, supporting its role as a marker of tumor aggressiveness. Although SSTR-2 expression was not correlated with iodine avidity, its presence in iodine-refractory metastases suggests potential utility for SSTR-targeted imaging or radionuclide therapy in selected patients with advanced DTC.\u003c/p\u003e","manuscriptTitle":"Protein Expression Heterogeneity of Glucose Metabolism and Somatostatin Receptor between Primary Tumor and Distant Metastasis in Differentiated Thyroid Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 09:15:25","doi":"10.21203/rs.3.rs-9194234/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-03-23T13:19:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-23T08:26:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-23T01:33:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2026-03-22T20:54:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"21e74f96-8b2f-42d0-a59b-b170193ece24","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T04:51:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 09:15:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9194234","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9194234","identity":"rs-9194234","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}