The Role of Insulin-Like Growth Factor 1 in the Development of Benign and Malignant Thyroid Nodules

Abstract

Objective: This study aims to investigate the role of IGF-1 in the development of nodular thyroid disease. Material and Methods: A total number of 100 consecutive patients operated for nodular thyroid disease in our institution were included in this prospective study. In addition to classical pathological examinations, nodules and extranodular healthy tissues were sampled and immunochemically stained for IGF-1. The materials were independently evaluated using an Allred Scoring System ranging from 0 to 8. If the score was ≥1, the tissue was accepted as IGF-1 positive. Results: IGF-1 positivity was observed in 88% and 58% of the samples obtained from nodules and extranodular healthy tissues, respectively. Allred 8-unit scores were higher in benign nodules (n=89; 4.1±2.3) and papillary carcinomas (n=7; 6.7±1.3), than in extranodular healthy tissues in the same patients (2.3±2.3 and 3.3±1.9, respectively); and higher in papillary carcinomas than in benign nodules, when the scores were compared to each other (p<0.01 for all comparisons). Conclusions: Allred 8-unit scores for IGF-1 increase in the presence of benign thyroid nodules, papillary cancer. The results of our study support the findings of previous studies demonstrating the role of IGF-1 in the development of thyroidal nodules. Turkish Başlık: Benign ve Malign Tiroid Nodüllerinin Gelişiminde Insulin-Like Growth Factor 1'in Rolü Anahtar Kelimeler: IGF-1, Tiroid nodülleri, Tiroid kanserleri Amaç: Bu çalışmanın amacı tiroid nodüllerinin gelişmesinde IGF-1'in rolünü araştırmaktır. Yöntem: Kliniğimizde nodüler tiroid hastalığı sebebiyle ameliyat edilen ardışık 100 hasta çalışmaya dahil edilmiştir. Bu hastalardan alınan tiroid dokuları rütin patolojik değerlendirmelerin yanısıra, nodüller ve nodül dışı alanlar ayrı ayrı olmak üzere IGF-1 için immünokimyasal olarak boyanmışlardır. Boyanan materyaller iki ayrı tecrübeli patolog tarafından Allred Skorlama Sistemi kullanılarak 0 dan 8'e kadar puanlanarak değerlendirilmiştir. Skor 1'in üzerindeki tüm dokular IGF-1 açısından pozitif kabül edilmişlerdir. Bulgular: IGF-1, nodüllerden alınan örneklerde %88 oranında pozitif çıkarken, nodül dışı tiroid dokularından alınan örneklerde %58 oranında pozitif çıkmıştır. Allred skoru gerek selim nodüllerde (n=89, 4.1±2.3) gerekse papiller kanser saptanan nodüllerde (n=7; 6.7±1.3), aynı hastaların nodül dışı dokularından alınan örneklere oranla anlamlı düzeyde yüksek çıkmıştır (sırasıyla 2.3±2.3 ve 3.3±1.9). Bunun yanında papiller kanser saptanan dokuların Allred skorları selim nodüllerin skorlarından anlamlı düzeyde yüksek çıkmıştır (bahsedilen tüm karşılaştırmalarda p<0.01). Sonuç: Çalışmamız gerek selim, gerekse papiller kanser içeren tiroid nodüllerinde IGF-1 tutulumunun nodül dışı çevre tiroid dokularına oranla daha yoğun olduğunu ortaya koymuştur. Bu bulgu ışığında IGF-1'in tiroid nodülleri patogenezinde rol oynayan önemli faktörlerden biri olabileceği söylenebilir.

Keywords

• IGF-1, thyroid nodules, thyroid cancer

The Role of Insulin-Like Growth Factor 1 in the Development of Benign and Malignant Thyroid Nodules

Öz

References

1. Gharib H, Papini E. Thyroid nodules: clinical importance, as- sessment, and treatment. Endocrinol Metab Clin North Am 2007;36:707-35 [CrossRef]
2. Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, et al. Molecular Pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 2005;26:504-24. [CrossRef]
3. Koh KB, Chang KW. Carcinoma in multinodular goiter. Brit J Surg 1992;79:266-7. [CrossRef]
4. Bradly DP, Reddy V, Prinz RA, Gattuso P. Incidental papillary car- cinoma in patients treated surgically for benign thyroid diseases. Surgery 2009;146:1099-104. [CrossRef]
5. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proin- sulin. J Biol Chem 1978;253:2769-76.
6. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3-34. [CrossRef]
7. Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE. Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer 2006;13:583-92. [CrossRef]
8. Van der Laan BF, Freeman JL, Asa SL. Expression of growth fac- tors and growth factor receptors in normal and tumorous human thyroid tissues. Thyroid 1995;5:67-73. [CrossRef]

9. Bechtner G, Schopohl D, Rafferzeder M, Gärtner R, Welsch U. Stimulation of thyroid cell proliferation by epidermal growth factor is different from cell growth induced by thyrotropin or insulin-like growth factor I. Eur J Endocrinol 1996;134:639-48. [CrossRef]
10. Nakahashi K, Kitahori Y, Konishi N, Ohnishi T, Sugimura M, Hiasa Y. Establishment of a rat thyroid carcinoma cell line in vitro dem- onstrating high DNA synthesis in response to insulin-like growth factor I. Cancer Letters 1996;101:247-55. [CrossRef]
11. Hsiao PJ, Tsai JH. Increased insulin-like growth factor-1 recep- tors in thyroid tissues of Graves’ disease. J Formos Med Assoc 1994;93:925-32.
12. Chakravarty G, Santillan AA, Galer C, Adams HP, El-Naggar AK, Jasser SA, et al. Phosphorylated insulin like growth factor-I re- ceptor expression and its clinico-pathological significance in his- tologic subtypes of human thyroid cancer. Exp Biol Med (May- wood) 2009;234:372-86. [CrossRef]
13. Maiorano E, Ambrosi A, Giorgino R, Fersini M, Pollice L, Ciampo- lillo A. Insulin-like growth factor 1 (IGF-1) in multinodular goiters: a possible pathogenetic factor. Pathol Res Pract 1994;190:1012-6. [CrossRef]
14. Völzke H, Friedrich N, Schipf S, Haring R, Lüdemann J, Nauck M, et al. Association between serum insulin-like growth factor-I levels and thyroid disorders in a population-based study. J Clin Endocrinol Metab 2007;92:4039-45. [CrossRef]
15. Gullu BE, Celik O, Gazioglu N, Kadioglu P. Thyroid cancer is the most common cancer associated with acromegaly. Pituitary 2010;13:242-8. [CrossRef]
16. Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, et al. Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 1993;85:200-6. [CrossRef]
17. Kimura T, Dumont JE, Fusco A, Golstein J. Insulin and TSH pro- mote growth in size of PC Cl3 rat thyroid cells, possibly via a pathway different from DNA synthesis: comparison with FRTL-5 cells. Eur J Endocrinol 1999;140:94-103. [CrossRef]
18. Clement S, Refetoff S, Robaye B, Dumont JE, Schurmans S. Low TSH requirement and goiter in transgenic mice overexpressing IGF-I and IGF-Ir receptor in the thyroid gland. Endocrinology 2001;142:131-9. [CrossRef]
19. Minuto F, Barreca A, Del Monte P, Cariola G, Torre GC, Giordano G. Immunoreactive insulin-like growth factor I (IGF-I) and IGF-I- binding protein content in human thyroid tissue. J Clin Endocri- nol Metab 1989;68:621-6. [CrossRef]
20. Maiorano E, Ciampolillo A, Viale G, Maisonneuve P, Ambrosi A, Triggiani V, et al. Insulin-like growth factor 1 expression thyroid tumors. Appl Immunohistochem Mol Morphol 2000;8:110-9. [CrossRef]
21. Maciel RM, Kimura ET, Takahaski MH, Lopes MH, Mesquita MI, Moses AC, et al. Insulin-like growth factor I in human thyroid tis- sue: specific localization by immunohistochemistry and in situ hy- bridization. Endocr Pathol 1995;6:207-15. [CrossRef]
22. Vannelli GB, Barni T, Modigliani U. Insulin-like growth factor-I receptors in nonfunctioning thyroid nodules. J Clin Endocrinol Metab 1990;71:1175-82. [CrossRef]
23. Cannavo S, Squadrito S, Finocchiaro MD, Curtò L, Almoto B, Vi- eni A, et al. Goiter and impairment of thyroid function in acrome- galic patients: basal evaluation and follow-up. Horm Metab Res 2000;32:190-5. [CrossRef]
24. Yu H, Rohan T. Role of insulin like growth factors family in cancer development and progression. J Natl Cancer Inst 2000;92:1472-89. [CrossRef]
25. Pavelic´ K, Spaventi Š, Gluncic´ V, Pavicić D, Karapandza N, Kusić Z, et al. The expression and role of insulin like growth factor II in malignant hemangiopericytomas. J Mol Med 1999;77:865-9. [CrossRef]
26. Eszlinger M, Krohn K, Kratzsch J, Voigt C, Paschke R. Growth factor expression in cold and hot thyroid nodules. Thyroid 2001;11:125-35.
27. Maiorano E, Perlino E, Triggiani V, Nacchiero M, Giove E, Ciam- polillo A. Insulin-like growth factor-1 and insulin-like growth fac- tor receptor in thyroid tissues of patients with Graves’ disease Int J Mol Med 1998;2:483-6.