Subscribe to RSS
DOI: 10.1055/s-0028-1102944
© Georg Thieme Verlag KG Stuttgart · New York
COX-2 Expression in Highly Aggressive Thyroid Malignancies – Indication for a Possible Therapeutic Option?
Publication History
received 26.09.2008
accepted 16.10.2008
Publication Date:
01 December 2008 (online)
![](https://www.thieme-connect.de/media/hmr/200904/lookinside/thumbnails/10.1055-s-0028-1102944-1.jpg)
Abstract
Both anaplastic thyroid carcinoma (ATC) and angiosarcoma of the thyroid (AST) are highly aggressive malignancies with very limited therapeutic options. Since selective inhibition of COX-2, for example, by celecoxib has been shown to suppress both tumour formation and progression, we investigated COX-2 protein expression in a series of ATC and AST (26 cases each) using immunohistochemistry. COX-2 expression was demonstrated in 13 ATC (50%) and 11 AST (42%); a strong COX-2 expression in more than 50% of vital tumour cells was found in 5 ATC and 5 AST, respectively. Although a recently performed phase II trial applying celecoxib failed overall to halt tumour progression in differentiated thyroid carcinoma, the two cases with partial or complete remission noted in this study were related to tumours with immunohistochemically proven strong COX-2 expression. The strong COX-2 expression observed in approximately 20% of our ATC and AST samples may thus indicate selective patients with a possible therapeutic option for an otherwise fatal disease.
Key words
anaplastic thyroid carcinoma - angiosarcoma of the thyroid - COX-2 - celecoxib - immunohistochemistry
References
-
1 Ordonez N, Baloch Z, Matias-Guiu X, Evans H, Farid NR, Fagin JA, Kitamura Y, Tallini G, Eng C, Haigh PI, Faquin WC, Sugitani I, Giuffrida D, Boerner S. Undifferentiated (anaplastic) carcinoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds.
World Health Organization Classification of Tumours Pathology & Genetics Tumours of Endocrine Organs . Lyon: IARC Press 2004: 77-80 - 2 Shaha AR. Implications of prognostic factors and risk groups in the management of differentiated thyroid cancer. Laryngoscope. 2004; 114 393-402
- 3 Pacheco-Ojeda LA, Martinez AL, Alvarez M. Anaplastic thyroid carcinoma in ecuador: analysis of prognostic factors. Int Surg. 2001; 86 117-121
- 4 Sugitani I, Kasai N, Fujimoto Y, Yanagisawa A. Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg. 2001; 25 617-622
- 5 Miccoli P, Materazzi G, Antonelli A, Panicucci E, Frustaci G, Berti P. New trends in the treatment of undifferentiated carcinomas of the thyroid. Langenbecks Arch Surg. 2007; 392 397-404
- 6 McIver B, Hay ID, Giuffrida DF, Dvorak CE, Grant CS, Thompson GB, Heerden JA van, Goellner JR. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery. 2001; 130 1028-1034
- 7 Lang BH, Lo CY. Surgical options in undifferentiated thyroid carcinoma. World J Surg. 2007; 31 969-977
- 8 Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol. 1999; 50 33-38
- 9 Egloff B. The hemangioendothelioma of the thyroid. Virchows Arch A Pathol Anat Histopathol. 1983; 400 119-142
- 10 Hedinger C. Geographic pathology of thyroid diseases. Pathol Res Pract. 1981; 171 285-292
- 11 Ladurner D, Totsch M, Luze T, Bangerl I, Sandbichler P, Schmid KW. Malignant hemangioendothelioma of the thyroid gland. Pathology, clinical aspects and prognosis. Wien Klin Wochenschr. 1990; 102 256-259
- 12 Pfaltz M, Hedinger C, Saremaslani P, Egloff B. Malignant hemangioendothelioma of the thyroid and factor VIII-related antigen. Virchows Arch A Pathol Anat Histopathol. 1983; 401 177-184
- 13 Thaler W, Riccabona G, Riedler L, Schmid K. Malignant hemangioendothelioma of the thyroid gland. Chirurg. 1986; 57 397-400
- 14 Totsch M, Dobler G, Feichtinger H, Sandbichler P, Ladurner D, Schmid KW. Malignant hemangioendothelioma of the thyroid. Its immunohistochemical discrimination from undifferentiated thyroid carcinoma. Am J Surg Pathol. 1990; 14 69-74
- 15 Eusebi V, Carcangiu ML, Dina R, Rosai J. Keratin-positive epithelioid angiosarcoma of thyroid. A report of four cases. Am J Surg Pathol. 1990; 14 737-747
- 16 Vollenweider I, Hedinger C, Saremaslani P, Pfaltz M. Malignant haemangioendothelioma of the thyroid, immunohistochemical evidence of heterogeneity. Pathol Res Pract. 1989; 184 376-381
- 17 Beer TW. Malignant thyroid haemangioendothelioma in a non-endemic goitrous region, with immunohistochemical evidence of a vascular origin. Histopathology. 1992; 20 539-541
- 18 Goh SG, Chuah KL, Goh HK, Chen YY. Two cases of epithelioid angiosarcoma involving the thyroid and a brief review of non-Alpine epithelioid angiosarcoma of the thyroid. Arch Pathol Lab Med. 2003; 127 E70-E73
- 19 Maiorana A, Collina G, Cesinaro AM, Fano RA, Eusebi V. Epithelioid angiosarcoma of the thyroid. Clinicopathological analysis of seven cases from non-Alpine areas. Virchows Arch. 1996; 429 131-137
- 20 Al-Abbadi MA, Almasri NM, Al-Quran S, Wilkinson EJ. Cytokeratin and epithelial membrane antigen expression in angiosarcomas: an immunohistochemical study of 33 cases. Arch Pathol Lab Med. 2007; 131 288-292
- 21 Cutlan RT, Greer JE, Wong FS, Eltorky M. Immunohistochemical characterization of thyroid gland angiomatoid tumors. Exp Mol Pathol. 2000; 69 159-164
- 22 Sniezek JC, Holtel M. Rare tumors of the thyroid gland. Otolaryngol Clin North Am. 2003; 36 107-115
- 23 Rhomberg W, Gruber-Mosenbacher U, Eiter H, Fritzsche H, Breitfellner G. Prognosis and epidemiology of malignant hemangioendotheliomas of the thyroid gland. Schweiz Med Wochenschr. 1993; 123 1640-1644
- 24 Samaan NA, Ordonez NG. Uncommon types of thyroid cancer. Endocrinol Metab Clin North Am. 1990; 19 637-648
- 25 Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol. 2005; 23 254-266
- 26 Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999; 18 7908-7916
- 27 Wang MT, Honn KV, Nie D. Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev. 2007; 26 525-534
- 28 Casey MB, Zhang S, Jin L, Kajita S, Lloyd RV. Expression of cyclooxygenase-2 and thromboxane synthase in non-neoplastic and neoplastic thyroid lesions. Endocr Pathol. 2004; 15 107-116
- 29 Cornetta AJ, Russell JP, Cunnane M, Keane WM, Rothstein JL. Cyclooxygenase-2 expression in human thyroid carcinoma and Hashimoto's thyroiditis. Laryngoscope. 2002; 112 238-242
- 30 Specht MC, Tucker ON, Hocever M, Gonzalez D, Teng L, Fahey III TJ. Cyclooxygenase-2 expression in thyroid nodules. J Clin Endocrinol Metab. 2002; 87 358-363
- 31 Lee KJ, Jung YS, Kim WH, Yoon TI, Joo HJ, Soh EY. Cyclooxygenase-2 expression in human thyroid disease. J Endocrinol Invest. 2008; 31 111-118
- 32 Puxeddu E, Mitsutake N, Knauf JA, Moretti S, Kim HW, Seta KA, Brockman D, Myatt L, Millhorn DE, Fagin JA. Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway. J Biol Chem. 2003; 278 52131-52138
- 33 Siironen P, Ristimaki A, Nordling S, Louhimo J, Haapiainen R, Haglund C. Expression of COX-2 is increased with age in papillary thyroid cancer. Histopathology. 2004; 44 490-497
- 34 Grossman EM, Longo WE, Panesar N, Mazuski JE, Kaminski DL. The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis. 2000; 21 1403-1409
- 35 Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: evidence for growth suppression by inhibiting COX-2 expression. Int J Cancer. 2000; 86 667-671
- 36 Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 1999; 59 4356-4362
- 37 Souza RF, Shewmake K, Beer DG, Cryer B, Spechler SJ. Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells. Cancer Res. 2000; 60 5767-5772
- 38 Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control. 2002; 9 28-35
- 39 Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN. Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res. 2000; 60 6045-6051
- 40 Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001; 1 11-21
- 41 Mrozek E, Kloos RT, Ringel MD, Kresty L, Snider P, Arbogast D, Kies M, Munden R, Busaidy N, Klein MJ, Sherman SI, Shah MH. Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006; 91 2201-2204
-
42 Fletcher CDM, Rydholm A, Singer S, Sundaram M, Coindre JM. Soft tissue tumours: Epidemiology, clinical features, histopathological typing and grading. In: Fletcher CDM, Unni KK, Mertens F, eds.
World Health Organization Classification of Tumours. Pathology & Genetics. Tumours of Soft Tissue and Bone . Lyon: IARC Press 2002: 12-18 - 43 Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000; 60 1306-1311
- 44 Dickens DS, Kozielski R, Khan J, Forus A, Cripe TP. Cyclooxygenase-2 expression in pediatric sarcomas. Pediatr Dev Pathol. 2002; 5 356-364
- 45 Sutton KM, Wright M, Fondren G, Towle CA, Mankin HJ. Cyclooxygenase-2 expression in chondrosarcoma. Oncology. 2004; 66 275-280
- 46 Endo M, Matsumura T, Yamaguchi T, Yamaguchi U, Morimoto Y, Nakatani F, Kawai A, Chuman H, Beppu Y, Shimoda T, Hasegawa T. Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas. Hum Pathol. 2006; 37 471-476
- 47 Lassus P, Ristimaki A, Huuhtanen R, Tukiainen E, Asko-Seljavaara S, Andersson LC, Miettinen M, Blomqvist C, Haglund C, Böhling T. Cyclooxygenase-2 expression in human soft-tissue sarcomas is related to epithelial differentation. Anticancer Res. 2005; 25 2669-2674
- 48 Heller DA, Clifford CA, Goldschmidt MH, Holt DE, Manfredi MJ, Sorenmo KU. Assessment of cyclooxygenase-2 expression in canine hemangiosarcoma, histiocytic sarcoma, and mast cell tumor. Vet Pathol. 2005; 42 350-353
- 49 Ito Y, Yoshida H, Nakano K, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsuzuka F, Matsuura N, Kuma K, Miyauchi A. Cyclooxygenase-2 expression in thyroid neoplasms. Histopathology. 2003; 42 492-497
- 50 Kim KH, Kim SH, Kim SH, Back JH, Park MJ, Kim JM. Cyclooxygenase-2 and inducible nitric oxide synthase expression in thyroid neoplasms and their clinicopathological correlation. J Korean Med Sci. 2006; 21 1064-1069
- 51 Kim SJ, Lee JH, Yoon JS, Mok JO, Kim YJ, Park HK, Kim CH, Byun DW, Suh KI, Yoo MH. Immunohistochemical expression of COX-2 in thyroid nodules. Korean J Intern Med. 2003; 18 225-229
- 52 Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS. Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res. 2001; 7 1410-1418
- 53 Kulkarni S, Rader JS, Zhang F, Liapis H, Koki AT, Masferrer JL, Subbaramaiah K, Dannenberg AJ. Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin Cancer Res. 2001; 7 429-434
- 54 Frohlich E, Machicao F, Wahl R. Action of thiazolidinediones on differentiation, proliferation and apoptosis of normal and transformed thyrocytes in culture. Endocr Relat Cancer. 2005; 12 291-303
- 55 Klopper JP, Hays WR, Sharma V, Baumbusch MA, Hershman JM, Haugen BR. Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment. Mol Cancer Ther. 2004; 3 1011-1020
- 56 Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG, Lobo M, Cotter P, Duh QY, Clark OH. Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid. 2005; 15 222-231
- 57 Philips JC, Petite C, Willi JP, Buchegger F, Meier CA. Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers. Nucl Med Commun. 2004; 25 1183-1186
- 58 Hayashi N, Nakamori S, Hiraoka N, Tsujie M, Xundi X, Takano T, Amino N, Sakon M, Monden M. Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma. Int J Oncol. 2004; 24 89-95
- 59 Schonthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA. Cele-coxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs. Expert Opin Investig Drugs. 2008; 17 197-208
1 Member of the West German Cancer Centre Essen (WTZE).
Correspondence
K. W. SchmidMD, MRCPath
Institute of Pathology and Neuropathology
University Hospital of Essen
University of Duisburg-Essen
Hufelandstr. 55
45122 Essen
Germany
Phone: +49/201/723 28 90
Fax: +49/201/723 59 26
Email: kw.schmid@uk-essen.de