Langenbeck's Archives of Surgery

, Volume 392, Issue 4, pp 397–404 | Cite as

New trends in the treatment of undifferentiated carcinomas of the thyroid

  • Paolo Miccoli
  • Gabriele MaterazziEmail author
  • Alessandro Antonelli
  • Erica Panicucci
  • Gianluca Frustaci
  • Piero Berti
Current Concepts in Endocrine Surgery



Malignant tumours of the thyroid are generally classified as either well-differentiated thyroid carcinoma, which is composed of papillary and follicular carcinoma, or undifferentiated/anaplastic thyroid carcinoma (ATC). ATC is not only the most lethal disease in the field of endocrine surgery but also one of the most aggressive tumours characterized by an almost invariable fatal outcome, which only very rarely exceeds a 1-year course.


The impact of surgical resection in association with external beam radiation on ATC outcome has been extensively investigated also in studies based on multicentric database, and there is a general agreement on the significance of a complete resection of the tumour. It has been difficult up to now to collect data regarding chemotherapy adjuvant treatment. In spite of the lack of an extensive review about the results of this kind of treatment by itself or as part of a multimodal approach, it seems that among the several chemotherapy agents experienced, none proved to influence significantly ATC prognosis. Neither doxorubicin (the most commonly used) nor other drugs, such as cisplatin, bleomycin, fluorouracil or cyclophosphamide, showed any real efficacy in controlling the disease.


The most recent development in this field seems to be represented by the possibility offered by PPARg agonists; even more promising might be the use of adenovirus-mediated p53 tumour suppressor gene therapy or BMP-7. All these new therapies need further confirmation coming from ongoing clinical trials such as those involving the use of vascular and growth factor-targeted agents.


Anaplastic carcinoma Undifferentiated Thyroidectomy Chemotherapy Radiotherapy 


  1. 1.
    Shaha R (2004) Implications of prognostic factors and risk groups in the management of differentiated thyroid cancer. Laryngoscope 114:393–402PubMedCrossRefGoogle Scholar
  2. 2.
    Sakamoto A, Kasai N, Sugano H (1983) Poorly differentiated carcinoma of the thyroid. A clinicopathologic entity for a high-risk group of papillary and follicular carcinomas. Cancer 52:1849–1855PubMedCrossRefGoogle Scholar
  3. 3.
    Carcangiu ML, Zampi G, Rosai J et al (1984) Poorly differentiated (“insular”) thyroid carcinoma: a reinterpretation of Langhans’ “wuchernde Struma.” Am J Surg Pathol 8:655–668PubMedCrossRefGoogle Scholar
  4. 4.
    Nishida T, Katayama S, Tsujimoto M et al (1999) Clinicopathological significance of poorly differentiated thyroid carcinoma. Am J Surg Pathol 23:205–211PubMedCrossRefGoogle Scholar
  5. 5.
    Sobrinho-Simoes M, Sambade C, Fonseca E et al (2002) Poorly differentiated carcinomas of the thyroid gland: a review of the clinicopathologic features of a series of 28 cases of a heterogeneous, clinically aggressive group of thyroid tumors. Int J Surg Pathol 10:123–131PubMedGoogle Scholar
  6. 6.
    Pellegriti G, Giuffrida D, Scollo C et al (2002) Long-term outcome of patients with insular carcinoma of the thyroid: the insular histotype is an independent predictor of poor prognosis. Cancer 95:2076–2085PubMedCrossRefGoogle Scholar
  7. 7.
    Sasaki A, Daa T, Kashima K, Yokoyama S, Nakayama I, Noguchi S (1996) Insular component as a risk factor of thyroid carcinoma. Pathol Int 46:939–946PubMedCrossRefGoogle Scholar
  8. 8.
    Gilliland FD, Hunt WC, Morris DM, Key CR (1997) Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973–1991. Cancer 79:564–573PubMedCrossRefGoogle Scholar
  9. 9.
    Hundahl SA, Fleming ID, Fremgen AM, Manck HR (1998) A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer 2638–2648Google Scholar
  10. 10.
    Kitamura Y, Shimizu K, Nagahama M et al (1999) Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 84:4043–4049PubMedCrossRefGoogle Scholar
  11. 11.
    Nel CJ, van Heerden JA, Goellner JR et al (1985) Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 60:51–58PubMedGoogle Scholar
  12. 12.
    Tan RK, Finley RK III, Driscoll D et al (1995) Anaplastic of the thyroid: a 24-year experience. Head Neck 17:41–48PubMedCrossRefGoogle Scholar
  13. 13.
    Kebebew E, Greenspan FS, Clark OH, Woeber KA, Mc Millan A (2005) Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103:1330–1335PubMedCrossRefGoogle Scholar
  14. 14.
    Ain KB (1998) Anaplastic thyroid carcinoma: behaviour, biology and therapeutic approaches. Thyroid 8:715–726PubMedGoogle Scholar
  15. 15.
    Holting T, Moller P, Tschahargane C, Meybier H, Buhr H, Herfarth C (1990) Immunohistochemical reclassification of anaplastic carcinoma reveals small and giant cell lymphoma. World J Surg 14:291–295PubMedCrossRefGoogle Scholar
  16. 16.
    Carty SE (2001) Anaplastic thyroid cancer. In: Doherty G, Skogeid B (eds) Surgical Endocrinology. Lippincott Williams & Wilkins, Philadelphia, pp 127–134Google Scholar
  17. 17.
    Tan RK, Finley RK III, Driscoll D, Bakamjian V, Hicks WL Jr, Shedd DP (1995) Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 17:41–48PubMedCrossRefGoogle Scholar
  18. 18.
    Giuffrida D, Gharib D (2000) Anaplastic thyroid carcinoma: current diagnosis and treatment. Ann Oncol 127–134Google Scholar
  19. 19.
    Sugitani I, Kasai N, Fujimoto Y, Yanagisawa A (2001) Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg 25:617–622PubMedCrossRefGoogle Scholar
  20. 20.
    Pacheco-Ojeda LA, Marinez AL, Alvarez M (2001) Anaplastic thyroid carcinoma in Ecuador: analysis of prognostic factors. Int Surg 86:117–121PubMedGoogle Scholar
  21. 21.
    Busnardo B, Daniele O, Pellizzo MR et al (2000) A multimodality therapeutic approach in anaplastic thyroid carcinoma: a study on 39 patients. J Endocrinol Investig 23:755–761Google Scholar
  22. 22.
    Pierie JP, Muzikansky A, Gaz RD, Faquin WC, Ott MJ (2002) The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma. Ann Surg Oncol 9:57–64PubMedCrossRefGoogle Scholar
  23. 23.
    Haigh PI, Ituarte PH, Wu HS et al (2001) Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 91:2335–2342PubMedCrossRefGoogle Scholar
  24. 24.
    Besic N, Auersperg M, Us-Krasovec M, Golouh R, Frkovic-Grazio S, Vodnik A (2001) Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur J Surg Oncol 27:260–264PubMedCrossRefGoogle Scholar
  25. 25.
    De Crevoisier R, Baudin E, Bachelot A, Leboulleux S, Travagli JP, Caillou B, Schlumberger M (2004) Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys 60(4):1137–1143, Nov 15PubMedCrossRefGoogle Scholar
  26. 26.
    Haddad R, Mahadevan A, Posner MR, Sullivan C (2005) Long-term survival with adjuvant carboplatin, paclitaxel and radiation therapy in anaplastic cancer. Am J Clin Oncol 28(1):104, FebPubMedCrossRefGoogle Scholar
  27. 27.
    Mc Iver B, Hay ID, Giuffrida DF et al (2001) Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 130:1028–1034CrossRefGoogle Scholar
  28. 28.
    Junor EJ, Paul J, Reed NS, et al (1992) Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 18:83–88PubMedGoogle Scholar
  29. 29.
    Kihara M, Miyauchi A, Yamauchi A, Yokomise H (2004) Prognostic factors of anaplastic thyroid carcinoma. Surg Today 34:394–398PubMedCrossRefGoogle Scholar
  30. 30.
    Cobin RH, Gharib H, Berman DAL (2001) AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid cancer. Endocr Pract 7:203–220Google Scholar
  31. 31.
    Hotling T, Maybier H, Buhr H (1990) Status of tracheotomy in treatment of the respiratory emergency in anaplastic thyroid cancer. Wien Klin Wochenschr 102:264–266Google Scholar
  32. 32.
    Kobayashi T, Asakawa H, Umeshita K et al (1996) Treatment of 37 patients with anaplastic carcinoma of the thyroid. Head Neck 18:36–41PubMedCrossRefGoogle Scholar
  33. 33.
    Heron DE, Karimpour S, Grigsby PW (2002) Anaplastic thyroid carcinoma: comparison of conventional radiotherapy and hyperfractionation chemoradiotherapy in two groups. Am J Clin Oncol 25:442–446PubMedCrossRefGoogle Scholar
  34. 34.
    Lo CY, Lam KY, Wan KY (1999) Anaplastic carcinoma of the thyroid. Am J Surg 77:337–339CrossRefGoogle Scholar
  35. 35.
    Tennvall J, Lundell G, Wahlberg P et al (2002) Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 86:1848–1853PubMedCrossRefGoogle Scholar
  36. 36.
    Nilsson O, Lindeberg J, Zedenius J et al (1998) Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period. World J Surg 22:725–730PubMedCrossRefGoogle Scholar
  37. 37.
    Simpson WJ (1980) Anaplastic thyroid carcinoma: a new approach. Can J Surg 23:25–27PubMedGoogle Scholar
  38. 38.
    Wong CS, Van Dyk J, Simpson WJ (1991) Myelopathy following hyperfractionated accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 20:3–9PubMedCrossRefGoogle Scholar
  39. 39.
    Levendag PC, De Porre PM, van Putten WL (1993) Anaplastic carcinoma of the thyroid gland treated by radiation therapy. Int J Radiat Oncol Biol Phys 26:125–128PubMedGoogle Scholar
  40. 40.
    Mitchell G, Huddart R, Harmer C (1999) Phase II evaluation of high-dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol 50:33–38PubMedCrossRefGoogle Scholar
  41. 41.
    Kim JH, Leeper RD (1983) Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination adriamycin and radiation therapy. A new approach. Cancer 52:954–957PubMedCrossRefGoogle Scholar
  42. 42.
    Kim JH, Leeper RD (1987) Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 60:2372–2375PubMedCrossRefGoogle Scholar
  43. 43.
    Asakawa H, Kobayashi T, Komoike Y et al (1997) Chemosensitivity of anaplastic thyroid carcinoma and poorly differentiated thyroid carcinoma. Anticancer Res 17:2757–2762PubMedGoogle Scholar
  44. 44.
    Pacini F, Vitti P, Martino E et al (1984) Treatment of refractory thyroid cancer with adriamycin. Drugs Exp Clin Res 10:911–915Google Scholar
  45. 45.
    Shimaoka K, Schoenfeld DA, DeWys WD et al (1985) A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155–2160PubMedCrossRefGoogle Scholar
  46. 46.
    Chemotherapy Committee, the Japanese Society of Thyroid Surgery (1995) Intensive chemotherapy for anaplastic thyroid carcinoma: combination of cisplatin, doxorubicin, etoposide and peplomycin with granulocyte colony-stimulating factor support. Jpn J Clin Oncol 25:203–207Google Scholar
  47. 47.
    Auersperg M, Us-Krasovec M, Petric G, Pogacnik A, Besic N (1990) Results of combined modality treatment in poorly differentiated and anaplastic thyroid carcinoma. Wien Klin Wochenschr 102:267–270PubMedGoogle Scholar
  48. 48.
    Schlumberger M, Parmentier C, Delisle MJ, Couette JE, Droz JP, Sarrazin D (1991) Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 67:564–566PubMedCrossRefGoogle Scholar
  49. 49.
    Ain KB, Egorin MJ, DeSimone PA (2001) Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 10:587–594CrossRefGoogle Scholar
  50. 50.
    Grommes C et al (2004) Antineoplastic effects of peroxisome proliferator-activated receptor-gamma agonists. Lancet Oncol 5:419–429PubMedCrossRefGoogle Scholar
  51. 51.
    Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, Serio M, Ferrannini E (2006) Interferon-{gamma}-inducible {alpha}-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator-activated receptor-{gamma} agonists. J Clin Endocrinol Metab 91(2):614–620PubMedCrossRefGoogle Scholar
  52. 52.
    Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T (2001) Ligands for peroxisome proliferator-activated receptor gamma inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells. J Clin Endocrinol Metab 86(5):2170–2177PubMedCrossRefGoogle Scholar
  53. 53.
    Klopper JP, Hays WR, Sharma V, Baumbusch MA, Hershman JM, Haugen BR (2004) Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment. Mol Cancer Ther 3(8):1011–1020PubMedGoogle Scholar
  54. 54.
    Philips JC, Petite C, Willi JP, Buchegger F, Meier CA (2004) Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers. Nucl Med Commun 25(12):1183–1186PubMedCrossRefGoogle Scholar
  55. 55.
    Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG, Lobo M, Cotter P, Duh QY, Clark OH (2005) Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid 15(3):222–231PubMedCrossRefGoogle Scholar
  56. 56.
    Frohlich E, Machicao F, Wahl R (2005) Action of thiazolidinediones on differentiation, proliferation and apoptosis of normal and transformed thyrocytes in culture. Endocr Relat Cancer 12(2):291–303PubMedCrossRefGoogle Scholar
  57. 57.
    Hayashi N, Nakamori S, Hiraoka N, Tsujie M, Xundi X, Takano T, Amino N, Sakon M, Monden M (2004) Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma. Int J Oncol 24 (1):89–95PubMedGoogle Scholar
  58. 58.
    Chung SH, Onoda N, Ishikawa T, Ogisawa K, Takenaka C, Yano Y, Hato F, Hirakawa K (2002) Peroxisome proliferator-activated receptor gamma activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer cells. Jpn J Cancer Res 93:1358–1365PubMedGoogle Scholar
  59. 59.
    Davies GF, Roesler WJ, Juurlink BH, Harkness TA (2005) Troglitazone overcomes doxorubicin-resistance in resistant K562 leukemia cells. Leuk Lymphoma 46(8):1199–1206PubMedCrossRefGoogle Scholar
  60. 60.
    Kanbe E, Abe A, Towatari M, Kawabe T, Saito H, Emi N (2003) DR1-like element in human topoisomerase II alpha gene involved in enhancement of etoposide-induced apoptosis by PPARgamma ligand. Exp Hematol 31(4):300–308PubMedCrossRefGoogle Scholar
  61. 61.
    Blagosklonny MV, Giannakakou P, Wojtowicz M, Romanova LY, Ain KB, Bates SE, Fojo T (1998) Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 83:2516–2522PubMedCrossRefGoogle Scholar
  62. 62.
    Nagayama Y, Yokoi H, Takeda K, Hasegawa M, Nishihara E, Namba H, Yamashita S, Niwa M (2000) Adenovirus-mediated tumor suppressor p53 gene therapy for anaplastic thyroid carcinoma in vitro and in vivo. J Clin Endocrinol Metab 85:4081–4086PubMedCrossRefGoogle Scholar
  63. 63.
    Franzen A, Heldin NE (2001) BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21(CIP1) and p27(KIP1). Biochem Biophys Res Commun 285:773–781PubMedCrossRefGoogle Scholar
  64. 64.
    Kotchetkov R, Cinatl J, Krivtchik AA, Vogel JU, Matousek J, Pouckova P, Kornhuber B, Schwabe D, Cinatl J Jr (2001) Selective activity of BS-RNase against anaplastic thyroid cancer. Anticancer Res 21:1035–1042PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Paolo Miccoli
    • 1
  • Gabriele Materazzi
    • 1
    Email author
  • Alessandro Antonelli
    • 2
  • Erica Panicucci
    • 1
  • Gianluca Frustaci
    • 1
  • Piero Berti
    • 1
  1. 1.Department of SurgeryUniversity of PisaPisaItaly
  2. 2.Department of Internal MedicineUniversity of PisaPisaItaly

Personalised recommendations