DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20211860

Increased thyroglobulin and receptor activator of nuclear factor kappa B ligand expression is a risk factor of bone metastasis on patients with thyroid cancer

Gede Ketut Alit Satria Nugraha, Putu Astawa, Made Bramantya Karna, I. Gede Eka Wiratnaya, I. Wayan Juli Sumadi

Abstract


Background: Metastatic bone disease (MBD) of thyroid cancer poses increased risk of morbidity and mortality and significant decrease of quality of life of the patient, with 10 years survival rate of 40-70%. This study aims to find correlation between increased expression of thyroglobulin and receptor activator of nuclear factor kappa B ligand (RANKL) on thyroid cancer biopsy and increased risk of bony metastasis.

Methods: This study use case control design to analyze the histopathologic preparation taken from biopsy of the patients with thyroid cancer from 2015 until 2020. The histopathology preparation was cut with 4 µm thickness, then analyzed through immunohistochemistry assay using thyroglobulin antibody cocktail and anti-RANKL polyclonal antibody by a pathologic anatomy consultant. Analysis and correlation between the high thyroglobulin and RANKL expression with the incidence of bony metastasis using chi-squared test and odd ratio calculation.

Results: There is a significant difference of thyroglobulin and RANKL expression between the group with metastasis and without metastasis (p=0.05 and p=0.02, respectively). ROC curve analysis of thyroglobulin and RANKL expression resulted in the optimal cutoff value of both parameters. Thyroglobulin cutoff value was 1.70 and RANKL cutoff value was 1.95. The analysis showed significant correlation between high expression of thyroglobulin with the incidence of bony metastasis (p=0.044). Similar result was also found in the high expression of RANKL (p=0.02).

Conclusions: Increased thyroglobulin and RANKL expression are a risk factor of bone metastasis on patients with thyroid cancer.


Keywords


Thyroid cancer, Metastatic bone disease, Thyroglobulin, RANKL

Full Text:

PDF

References


Wexler JA, Sharretts J. Thyroid and Bone. Endocrinol Metab Clin North Am. 2007;36(3):673-705.

Wu K, Hou SM, Huang TS, Yang RS. Thyroid carcinoma with bone metastases: A prognostic factor study. Clin Med Oncol. 2008;2:129-34.

Iñiguez-Ariza NM, Bible KC, Clarke BL. Bone metastases in thyroid cancer. J Bone Oncol. 2020;21:100282.

Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L ,et al. Bone metastases: an overview. Oncol Rev. 2017;11(1):321.

Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M, Strauss HW, et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[ 18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab. 2006;91(2):498-505.

Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, et al. Serum thyroglobulin autoantibodies: Prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 1998;83(4):1121-7.

Arai A, Mizoguchi T, Harada S, Kobayashi Y, Nakamichi Y, Yasuda H, et al. Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment. J Cell Sci. 2012;125:2910-7.

Franchi A, Taverna C, Simoni A, Pepi M, Mannelli G, Fasolati M, et al. RANK and RANK ligand expression in parotid gland carcinomas. Appl Immunohistochem Mol Morphol. 2018;26(7):478-82.

Indrasena BSH. Use of thyroglobulin as a tumour marker. World J Biol Chem. 2017;8(1):81-5.

Heymann MF, Riet A, Le-Goff B, Battaglia S, Paineau J, Heymann D. OPG, RANK and RANK ligand expression in thyroid lesions. Regul Pept. 2008;148(1-3):46-53.

Pilling AM, Jones SA, Endersby-Wood HJ, McCormack NAM, Turton JA. Expression of Thyroglobulin and Calcitonin in Spontaneous Thyroid Gland Tumors in the Han Wistar Rat. Toxicol Pathol. 2007;35(3):348-55.

Baloch ZW, Livolsi VA. Encapsulated follicular variant of papillary thyroid carcinoma with bone metastases. Mod Pathol. 2000;13(8):861-5.

Luo Y, Kawashima A, Ishido Y, Yoshihara A, Oda K, Hiroi N, et al. Iodine excess as an environmental risk factor for autoimmune thyroid disease. Int J Mol Sci. 2014;15(7):12895-912.

Whitley RJ, Ain KB. Thyroglobulin: A specific serum marker for the management of thyroid carcinoma. Clin Lab Med. 2004;24(1):29-47.

Kim LD, Bueno FT, Yonamine ES, Prospero JS, Pozzan G. Bone metastasis as the first symptom of tumors: role of an immunohistochemistry study in establishing primary tumor. Rev Bras Ortop. 2018;53(4):467-71.

Ramos-Vara JA, Miller MA, Johnson GC, Pace LW. Immunohistochemical detection of thyroid transcription factor-1, thyroglobulin, and calcitonin in canine normal, hyperplastic, and neoplastic thyroid gland. Vet Pathol. 2002;39(4):480-7.

Zakavi SR, Ayati N, Farahati J, Davachi B. Diffuse skeletal metastasis and low thyroglobulin level in a pediatric patient with papillary thyroid carcinoma. Indian J Nucl Med. 2015;30(3):283-5.

Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006;12(1):17-25.

Osorio M, Moubayed SP, Su H, Urken ML. Systematic review of site distribution of bone metastases in differentiated thyroid cancer. Head Neck. 2017;39(4):812-8.

Azim HA, Kamal NS, Azim HA. Bone metastasis in breast cancer: The story of RANK-Ligand. J Egypt Nat Cancer Inst. 2012;24(3):107-14.

Göktaş SS. Bone Metastasis in thyroid cancer: A Literature Review. Otolaryngol Open Access J. 2018;3(1):1-7.

D’Oronzo S, Brown J, Coleman R. The value of biomarkers in bone metastasis. Eur J Cancer Care. 2017;26(6).

Luparello C. Parathyroid hormone-related protein (PTHrP): a key regulator of life/death decisions by tumor cells with potential clinical applications. Cancer. 2011;3:396-407.

Renema N, Navet B, Heymann MF, Lezot F, Heymann D. RANK-RANKL signalling in cancer. Biosci Rep. 2016;36(4):00366.

Takegami N, Akeda K, Yamada J, Sano T, Murata K, Huang J, et al. RANK/RANKL/OPG system in the intervertebral disc. Arthritis Res Ther. 2017;19(1):121.

Deligiorgi M V., Mahaira H, Eftychiadis C, Kafiri G, Georgiou G, Theodoropoulus G, et al. RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma. J BUON. 2018;23(4):1029-40.

Ma R, Morshed S, Latif R, Zaidi M, Davies TF. The influence of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on osteoclastogenesis. Thyroid. 2011;21(8):897-906.

Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D, et al. Expression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol. 2011;226(3):780-4.