Anaplastic thyroid cancer
- R Michael Tuttle, MD
R Michael Tuttle, MD
- Professor of Medicine
- Memorial Sloan Kettering Cancer Center
- Eric J Sherman, MD
Eric J Sherman, MD
- Assistant Attending
- Memorial Sloan-Kettering Cancer Center
- Section Editors
- David S Cooper, MD
David S Cooper, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Thyroid Disease
- Professor of Medicine and International Health
- Johns Hopkins University School of Medicine
- Douglas S Ross, MD
Douglas S Ross, MD
- Section Editor — Thyroid Disease
- Professor of Medicine
- Harvard Medical School
Anaplastic thyroid cancers are undifferentiated tumors of the thyroid follicular epithelium. In marked contrast to differentiated thyroid cancers, anaplastic cancers are extremely aggressive, with a disease-specific mortality approaching 100 percent. Given the very rapid course of disease progression and the poor treatment outcomes, end-of-life issues and plans for comfort care measures are an integral part of initial disease management planning . Early recognition of the disease is essential to allow prompt initiation of therapy.
The major clinical issues related to anaplastic thyroid cancer will be reviewed here. The molecular pathogenesis of this disorder is discussed separately. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer".)
The age-adjusted annual incidence of anaplastic cancer is approximately one to two per million persons [2-4] and accounts for 0.9 to 9.8 percent of all thyroid cancers globally [5,6]. Patients with anaplastic cancer are older than those with differentiated cancer; the mean age at diagnosis is 65 years and fewer than 10 percent are younger than 50 years. Sixty to 70 percent of tumors occur in women [7,8].
ANTECEDENT THYROID DISEASE
Approximately 20 percent of patients with anaplastic thyroid cancer have a history of differentiated thyroid cancer, and 20 to 30 percent have a coexisting differentiated cancer [9-13]; the percentage may be even higher with extensive sectioning of the thyroid gland . The majority of synchronous thyroid tumors are papillary cancers, but coexisting follicular cancers have also been reported. Nearly 10 percent of patients with Hürthle cell cancers have foci of anaplastic cancer within the Hürthle cell cancer . In addition, transformation from differentiated to anaplastic cancer has been described in a patient who was followed with serial biopsies .
These findings lend support to the hypothesis that anaplastic cancer develops from more differentiated tumors as a result of one or more dedifferentiating events . Since activating mutations in BRAF and RAS are seen in both well-differentiated thyroid malignancies and anaplastic thyroid cancer, these are presumed to be early events in the progression pathway . Late events that are seen more commonly in the anaplastic tumor rather than the precursor well-differentiated tumor include mutations in p53 tumor suppressor protein [19-22], 16p , catenin (cadherin-associated protein), beta 1, and PIK3CA .
- Neff RL, Farrar WB, Kloos RT, Burman KD. Anaplastic thyroid cancer. Endocrinol Metab Clin North Am 2008; 37:525.
- Akslen LA, Haldorsen T, Thoresen SO, Glattre E. Incidence of thyroid cancer in Norway 1970-1985. Population review on time trend, sex, age, histological type and tumour stage in 2625 cases. APMIS 1990; 98:549.
- Burke JP, Hay ID, Dignan F, et al. Long-term trends in thyroid carcinoma: a population-based study in Olmsted County, Minnesota, 1935-1999. Mayo Clin Proc 2005; 80:753.
- Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006; 295:2164.
- Smallridge RC, Copland JA. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol) 2010; 22:486.
- SEER Cancer Statistics Review 1975-2009. http://seer.cancer.gov/csr/1975_2009_pops09/results_merged/sect_26_thyroid.pdf (Accessed on February 12, 2013).
- Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005; 103:1330.
- Nagaiah G, Hossain A, Mooney CJ, et al. Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. J Oncol 2011; 2011:542358.
- Nel CJ, van Heerden JA, Goellner JR, et al. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases. Mayo Clin Proc 1985; 60:51.
- Carcangiu ML, Steeper T, Zampi G, Rosai J. Anaplastic thyroid carcinoma. A study of 70 cases. Am J Clin Pathol 1985; 83:135.
- Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 1990; 66:321.
- Tan RK, Finley RK 3rd, Driscoll D, et al. Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 1995; 17:41.
- McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001; 130:1028.
- Aldinger KA, Samaan NA, Ibanez M, Hill CS Jr. Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 1978; 41:2267.
- Chiu AC, Oliveira AA, Schultz PN, et al. Prognostic clinicopathologic features in Hürthle cell neoplasia. Thyroid 1996; 6:S29.
- Moore JH Jr, Bacharach B, Choi HY. Anaplastic transformation of metastatic follicular carcinoma of the thyroid. J Surg Oncol 1985; 29:216.
- Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res 2009; 69:4885.
- Quiros RM, Ding HG, Gattuso P, et al. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 2005; 103:2261.
- Nakamura T, Yana I, Kobayashi T, et al. p53 gene mutations associated with anaplastic transformation of human thyroid carcinomas. Jpn J Cancer Res 1992; 83:1293.
- Ito T, Seyama T, Mizuno T, et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 1992; 52:1369.
- Ito T, Seyama T, Mizuno T, et al. Genetic alterations in thyroid tumor progression: association with p53 gene mutations. Jpn J Cancer Res 1993; 84:526.
- Moretti F, Farsetti A, Soddu S, et al. p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells. Oncogene 1997; 14:729.
- Komoike Y, Tamaki Y, Sakita I, et al. Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma. Int J Oncol 1999; 14:1157.
- Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 2009; 16:17.
- Tennvall J, Lundell G, Wahlberg P, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 2002; 86:1848.
- Nishiyama RH, Dunn EL, Thompson NW. Anaplastic spindle-cell and giant-cell tumors of the thyroid gland. Cancer 1972; 30:113.
- Hadar T, Mor C, Har-El G, Sidi J. Anaplastic thyroid carcinoma metastatic to the tonsil. J Laryngol Otol 1987; 101:953.
- Phillips DL, Benner KG, Keeffe EB, Traweek ST. Isolated metastasis to small bowel from anaplastic thyroid carcinoma. With a review of extra-abdominal malignancies that spread to the bowel. J Clin Gastroenterol 1987; 9:563.
- Murabe H, Akamizu T, Kubota A, Kusaka S. Anaplastic thyroid carcinoma with prominent cardiac metastasis, accompanied by a marked leukocytosis with a neutrophilia and high GM-CSF level in serum. Intern Med 1992; 31:1107.
- Hadar T, Mor C, Shvero J, et al. Anaplastic carcinoma of the thyroid. Eur J Surg Oncol 1993; 19:511.
- Lip GY, Jaap AJ, McCruden DC. A presentation of anaplastic carcinoma of the thyroid with symptomatic intra-abdominal metastases. Br J Clin Pract 1992; 46:143.
- Glikson M, Feigin RD, Libson E, Rubinow A. Anaplastic thyroid carcinoma in a retrosternal goiter presenting as fever of unknown origin. Am J Med 1990; 88:81.
- Hanslik T, Gepner P, Franc B, et al. [Anaplastic cancer of the thyroid gland disclosed by prolonged fever or hyperleukocytosis. Two cases]. Ann Med Interne (Paris) 1996; 147:122.
- Chang TC, Liaw KY, Kuo SH, et al. Anaplastic thyroid carcinoma: review of 24 cases, with emphasis on cytodiagnosis and leukocytosis. Taiwan Yi Xue Hui Za Zhi 1989; 88:551.
- Murakami T, Noguchi S, Murakami N, et al. Destructive thyrotoxicosis in a patient with anaplastic thyroid cancer. Endocrinol Jpn 1989; 36:905.
- Oppenheim A, Miller M, Anderson GH Jr, et al. Anaplastic thyroid cancer presenting with hyperthyroidism. Am J Med 1983; 75:702.
- Barr R, Dann F. Anaplastic thyroid carcinoma metastatic to skin. J Cutan Pathol 1974; 1:201.
- Fujita T, Ogasawara Y, Naito M, et al. Anaplastic thyroid carcinoma associated with granulocyte colony-stimulating factor: report of a case. Surg Today 2006; 36:63.
- Sato T, Omura M, Saito J, et al. Neutrophilia associated with anaplastic carcinoma of the thyroid: production of macrophage colony-stimulating factor (M-CSF) and interleukin-6. Thyroid 2000; 10:1113.
- Us-Krasovec M, Golouh R, Auersperg M, et al. Anaplastic thyroid carcinoma in fine needle aspirates. Acta Cytol 1996; 40:953.
- Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012; 22:1104.
- Bogsrud TV, Karantanis D, Nathan MA, et al. 18F-FDG PET in the management of patients with anaplastic thyroid carcinoma. Thyroid 2008; 18:713.
- Poisson T, Deandreis D, Leboulleux S, et al. 18F-fluorodeoxyglucose positron emission tomography and computed tomography in anaplastic thyroid cancer. Eur J Nucl Med Mol Imaging 2010; 37:2277.
- Khan N, Oriuchi N, Higuchi T, Endo K. Review of fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the follow-up of medullary and anaplastic thyroid carcinomas. Cancer Control 2005; 12:254.
- Nguyen BD, Ram PC. PET/CT staging and posttherapeutic monitoring of anaplastic thyroid carcinoma. Clin Nucl Med 2007; 32:145.
- Takashima S, Morimoto S, Ikezoe J, et al. CT evaluation of anaplastic thyroid carcinoma. AJR Am J Roentgenol 1990; 154:1079.
- Miyakoshi A, Dalley RW, Anzai Y. Magnetic resonance imaging of thyroid cancer. Top Magn Reson Imaging 2007; 18:293.
- Chiacchio S, Lorenzoni A, Boni G, et al. Anaplastic thyroid cancer: prevalence, diagnosis and treatment. Minerva Endocrinol 2008; 33:341.
- Tuttle RM, Morris LF, Haughen BR, et al. Thyroid - Differentiated and Anaplastic Carcinoma. In: AJCC Cancer Staging Manual, 8th, Amin MB (Ed), Springer, New York 2017. p.873.
- National Comprehensive Cancer Network. NCCN Guidelines Version 2.2014. Thyroid Carcinoma - Anaplastic Carcinoma http://www.nccn.org/professionals/physician_gls/f_guidelines_nojava.asp#site (Accessed on September 17, 2014).
- Haigh PI, Ituarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001; 91:2335.
- De Crevoisier R, Baudin E, Bachelot A, et al. Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys 2004; 60:1137.
- Ito K, Hanamura T, Murayama K, et al. Multimodality therapeutic outcomes in anaplastic thyroid carcinoma: improved survival in subgroups of patients with localized primary tumors. Head Neck 2012; 34:230.
- Tallroth E, Wallin G, Lundell G, et al. Multimodality treatment in anaplastic giant cell thyroid carcinoma. Cancer 1987; 60:1428.
- Sherman SI. Thyroid carcinoma. Lancet 2003; 361:501.
- Swaak-Kragten AT, de Wilt JH, Schmitz PI, et al. Multimodality treatment for anaplastic thyroid carcinoma--treatment outcome in 75 patients. Radiother Oncol 2009; 92:100.
- Chen J, Tward JD, Shrieve DC, Hitchcock YJ. Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results 1983-2002. Am J Clin Oncol 2008; 31:460.
- Pierie JP, Muzikansky A, Gaz RD, et al. The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma. Ann Surg Oncol 2002; 9:57.
- Junor EJ, Paul J, Reed NS. Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 1992; 18:83.
- Wang Y, Tsang R, Asa S, et al. Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twice-daily fractionation regimens. Cancer 2006; 107:1786.
- Kim JH, Leeper RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987; 60:2372.
- Sherman EJ, Lim SH, Ho AL, et al. Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: a critical re-evaluation including uniform pathologic review. Radiother Oncol 2011; 101:425.
- Prasongsook N, Foote RL, Molina JR, et al. Impact of aggressive combined-modality primary therapy in anaplastic thyroid carcinoma (ATC): An updated single-institution experience. J Clin Oncol 2014; 32:e17042.
- Shimaoka K, Schoenfeld DA, DeWys WD, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985; 56:2155.
- Ain KB, Egorin MJ, DeSimone PA. 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 2000; 10:587.
- Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 2015; 373:726.
- Wagle N, Grabiner BC, Van Allen EM, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014; 371:1426.
- Troch M, Koperek O, Scheuba C, et al. High efficacy of concomitant treatment of undifferentiated (anaplastic) thyroid cancer with radiation and docetaxel. J Clin Endocrinol Metab 2010; 95:E54.
- Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid 2011; 21:25.
- Spires JR, Schwartz MR, Miller RH. Anaplastic thyroid carcinoma. Association with differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg 1988; 114:40.
- Sherman SI, Brierley J, Sperling M, Maxon III HR. Initial analysis of staging and outcomes from a prospective multicenter study of treatment of thyroid carcinoma. Thyroid 1996; 6:S39.
- Akslen LA, Haldorsen T, Thoresen SO, Glattre E. Survival and causes of death in thyroid cancer: a population-based study of 2479 cases from Norway. Cancer Res 1991; 51:1234.
- ANTECEDENT THYROID DISEASE
- CLINICAL FEATURES
- Disease presentation
- Clinical manifestations
- DIFFERENTIAL DIAGNOSIS
- Laboratory evaluation
- Metastatic disease
- Our approach
- - Tumor localized to the thyroid or locally advanced operable disease
- - Locally advanced inoperable disease
- - Metastatic disease
- - End-of-life care
- Radiation therapy
- Combined modality therapy
- Radioactive iodine scanning and therapy
- SUMMARY AND RECOMMENDATIONS