Thyroid: Anaplastic (undifferentiated) carcinoma

Identity

ICD-Topo	C739 THYROID GLAND
ICD-Morpho	8020/3 Carcinoma, undifferentiated type, NOS
Atlas_Id	5069
Phylum	Neuro-Endocrine/Endocrine system: Thyroid::Anaplastic (undifferentiated) carcinoma
Note	Anaplastic (undifferentiated) carcinoma of the thyroid gland is a highly malignant tumor composed in part or wholly by undifferentiated malignant cells.

Clinics and Pathology

Epidemiology	Anaplastic (undifferentiated) carcinoma of the thyroid gland is uncommon, accounting for less than 5% of all cases of thyroid carcinoma. The average age at diagnosis was 66.5 years, with a female to male ratio of 3.1:1 in one study of 70 cases.
Clinics	Most patients are euthyroid with a history of a rapidly enlarging neck mass. Sometimes, the tumor presents as a new-onset thyroid enlargement in a patient with longstanding thyroid nodule(s) or as the recurrence of a well-differentiated thyroid carcinoma. Tumor infiltration of surrounding structures results in secondary symptoms (dyspnea, dysphonia, and dysphagia).
Pathology	Tumors are poorly defined, fleshy masses with areas of necrosis and hemorrhage. Microscopically they are composed of anaplastic cells with marked cytologic atypia and high mitotic activity. Tumor necrosis and vascular invasion are common. About one-third of cases of anaplastic thyroid carcinoma (ATC) have coexisting areas of well-differentiated thyroid carcinoma, supporting the hypothesis that ATC arises from well-differentiated thyroid carcinoma. Histologic patterns include spindle, giant and squamoid cell types. Other patterns (e.g. angiomatoid, carcinosarcoma, lymphoepithelioma-like, adenosquamous) have been described. Undifferentiated (anaplastic) carcinoma of the thyroid must be differentiated from other high grade tumors with similar microscopic appearance originating from adjacent structures in the neck (e.g. larynx). Sometimes this distinction is only possible on clinical/anatomical grounds. Immunohistochemically, undifferentiated thyroid carcinoma is generally negative for thyroglobulin and calcitonin. Pan-keratin and epithelial membrane antigen (EMA) are positive in about one-half and one-third of cases respectively. Vimentin is positive in about 90%, and epithelial membrane antigen is positive in about 30% of cases. Thyroid transcription factor-1 (TTF-1) staining is present in 0-50% of cases. Although immunostaining is negative for muscle-specific actin, Factor VIII-related antigen, and desmin, these markers can differentiate ATC from some soft tissue sarcomas with which they can be confused.
	Anaplastic (undifferentiated) thyroid carcinoma is a highly malignant tumor composed by undifferentiated malignant cells. The inset in the left lower corner shows a magnified view of a cell in metaphase of mitosis.
Treatment	No effective treatment modalities are currently available. A few patients with resectable disease have been reported to have long-term survival with aggressive multimodal therapy that included surgery, radiation, and chemotherapy. Current clinical practice emphasizes the use of multimodal therapy to achieve local disease control and stabilization of airway patency. Radiotherapy may be hyperfractionated and in combination with chemotherapy. Chemotherapy is usually doxorubicin-based or taxane-based combinations. Preclinical studies using human ATC cell lines show promise that new effective combinations including novel drugs will be found in the future. ATC has high 18 F-fluorodeoxyglucose (FDG) uptake. FDG-PET imaging can complement traditional imaging modalities and detect metastatic foci not readily visible otherwise (Bogsrud et al., 2008).
Prognosis	Anaplastic (undifferentiated) carcinomas are highly aggressive neoplasms that are usually widely invasive at presentation. Regional and distant metastases are common, and about 75% of patients have distant metastasis in the course of their disease. Most patients die within 1 year of the diagnosis with a median survival of 1 month in one study to 6 months. Factors associated with worse prognosis include distant metastases and large primary tumor size (> 7cm) (Chen et al., 2008). The 5-year survival rate is around 5%, and the surviving cases are typically small tumors confined to the thyroid amenable to local resection.

Cytogenetics

Cytogenetics Morphological

Anaplastic (undifferentiated) carcinoma represents not only morphologically but also in terms of somatic genetic alterations the extreme malignant form of thyroid cancer and as such it is characterized by complex chromosomal alterations. Aneuploidy is present in over 65% of the tumors.

Cytogenetics Molecular

LOH: Allelic loss has been identified at 1q (40%), 9p (58%), 11p (33%), 11q (33%), 17p (44%), 17q (43%), 19p (36%), 22q (38%). CGH: DNA imbalance can be demonstrated at a variety of chromosomal loci in 80% of undifferentiated carcinomas with a median number of chromosomal losses or gains of 10 per case with abnormal CGH profile. Gains were more common than DNA losses. Loss of chromosomal DNA was identified at 1p, 2q, 4q, 5q, 6q, 8p, 13q, 22q. Specific chromosomal DNA alterations (i.e. 3p13-14+, 5q11-31-, 11q13+) may be associated with the transition from more differentiated phenotypes to ATC. Comparative genome hybridization (CGH) shows frequent gain of 20q, including the UBCH10 gene in 20q13.12, which may also be associated with progression of differentiated thyroid cancers to ATC (Lee et al., 2007). Using microarray-based CGH with further fluorescence in situ hybridization (FISH) analysis, the MAP kinase phosphatase-8 (DUSP26) gene, which codes for a phosphatase that inhibits p38-mediated apoptosis, is shown to be amplified in ATC (Yu et al., 2007). Human telomerase reverse transcriptase (hTERT) protein expression is increased in ATC samples and cell lines (Takano et al., 2007). In ATC cell lines, miR-138 was significantly down regulated in comparison to papillary thyroid cancer cell lines. miR-138 was inversely correlated with the human telomerase reverse transcriptase (hTERT) protein expression (Mitomo et al., 2008).

Genes involved and Proteins

Note

The genetic mechanisms involved with the development of anaplastic thyroid cancer are complex. Mutational inactivation of p53 has been identified in 70-80% of anaplastic carcinomas while H-Ras, K-Ras, or N-Ras activating mutations are present in less than 50% of the cases. BRAF V600E mutation is found in 20% to 25% of cases. PTEN mutations are present in 6%. PIK3CA kinase domain mutations are found in 14%. PIK3CA gene copy amplification is present in 39%. Aberrant Wnt/beta-Catenin signaling appears to be a distinctive feature of ATC since stabilizing mutations and/or aberrant beta-Catenin nuclear localization are present in 80% of ATC. beta-Catenin nuclear localization is accompanied by its cellular redistribution with marked decrease of the beta-Catenin membrane bound fraction. ATC are characterized by increased cell replication and high Ki67/Mib1 proliferation index, loss of the apoptotic protein bcl-2 and of Fas and its ligand (usually highly expressed in well differentiated thyroid tumors), by an increase in the proapoptotic protein Bax, by Cyclin D1 over-expression and conversely by a fall in the CDK inhibitor p27. Transmembrane protein 34 (TMEM34) is down-regulated in ATC. It is not clear whether these changes represent the cause or (more likely) the effect of dysregulated cell differentiation and growth in ATC. Immunohistochemical staining of a tissue microarray of 12 cases of ATC showed the following: beta-catenin (positive in 41% of the cases), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). Thyroglobulin, Bcl-2, E-cadherin, vascular endothelial growth factor and beta-catenin are more expressed in differentiated thyroid cancer while topoisomerase II-alpha, MIB-1, and p53 are more expressed in ATC and these changes are expected to occur during progression from differentiated thyroid cancer to ATC (Wiseman et al., 2007).

Bibliography

Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group.

Ain KB, Egorin MJ, DeSimone PA.

Thyroid. 2000 Jul;10(7):587-94.

PMID 10958311

Down-regulation of an inhibitor of cell growth, transmembrane protein 34 (TMEM34), in anaplastic thyroid cancer.

Akaishi J, Onda M, Okamoto J, Miyamoto S, Nagahama M, Ito K, Yoshida A, Shimizu K.

J Cancer Res Clin Oncol. 2007 Apr;133(4):213-8. Epub 2006 Oct 28.

PMID 17072649

Prognostic factors and treatment outcomes of 100 cases of anaplastic thyroid carcinoma.

Akaishi J, Sugino K, Kitagawa W, Nagahama M, Kameyama K, Shimizu K, Ito K, Ito K.

Thyroid. 2011 Nov;21(11):1183-9. Epub 2011 Sep 21.

PMID 21936674

18F-FDG PET in the management of patients with anaplastic thyroid carcinoma.

Bogsrud TV, Karantanis D, Nathan MA, Mullan BP, Wiseman GA, Kasperbauer JL, Reading CC, Hay ID, Lowe VJ.

Thyroid. 2008 Jul;18(7):713-9.

PMID 18630999

Expression and mutation analysis of the tyrosine kinase c-kit in poorly differentiated and anaplastic thyroid carcinoma.

Broecker-Preuss M, Sheu SY, Worm K, Feldkamp J, Witte J, Scherbaum WA, Mann K, Schmid KW, Schott M.

Horm Metab Res. 2008 Oct;40(10):685-91. Epub 2008 Jul 11.

PMID 18622894

Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues.

Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J.

Diagn Mol Pathol. 1996 Mar;5(1):45-52.

PMID 8919545

Anaplastic thyroid carcinoma. A study of 70 cases.

Carcangiu ML, Steeper T, Zampi G, Rosai J.

Am J Clin Pathol. 1985 Feb;83(2):135-58.

PMID 2578727

Phosphorylated insulin like growth factor-I receptor expression and its clinico-pathological significance in histologic subtypes of human thyroid cancer.

Chakravarty G, Santillan AA, Galer C, Adams HP, El-Naggar AK, Jasser SA, Mohsin S, Mondal D, Clayman GL, Myers JN.

Exp Biol Med (Maywood). 2009 Apr;234(4):372-86. Epub 2009 Jan 28.

PMID 19176870

Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results 1983-2002.

Chen J, Tward JD, Shrieve DC, Hitchcock YJ.

Am J Clin Oncol. 2008 Oct;31(5):460-4.

PMID 18838882

Phase II study of combretastatin A4 phosphate (CA4P) in patients with advanced anaplastic thyroid carcinoma (ATC).

Cooney MM, Savvides P, Agarwala S, Wang D, Flick S, Bergant S, Bhakta S, Lavertu P, Ortiz J, Remick S.

Journal of Clinical Oncology 2006; 24: 300S.

Results of combined treatment of anaplastic thyroid carcinoma (ATC).

Derbel O, Limem S, Segura-Ferlay C, Lifante JC, Carrie C, Peix JL, Borson-Chazot F, Bournaud C, Droz JP, de la Fouchardiere C.

BMC Cancer. 2011 Nov 1;11:469.

PMID 22044775

Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland.

Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA.

J Clin Invest. 1993 Apr;91(4):1753-60.

PMID 8473515

A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer.

Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, Rafie N, Overmoyer B, Makkar V, Stambler B, Taylor A, Waas J, Lewin JS, McCrae KR, Remick SC.

Cancer Res. 2002 Jun 15;62(12):3408-16.

PMID 12067983

Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2.

Esposito F, Tornincasa M, Pallante P, Federico A, Borbone E, Pierantoni GM, Fusco A.

J Clin Endocrinol Metab. 2012 May;97(5):E710-8. Epub 2012 Mar 7.

PMID 22399519

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas.

Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP.

J Clin Invest. 1993 Jan;91(1):179-84.

PMID 8423216

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.

Fury MG, Solit DB, Su YB, Rosen N, Sirotnak FM, Smith RP, Azzoli CG, Gomez JE, Miller VA, Kris MG, Pizzo BA, Henry R, Pfister DG, Rizvi NA.

Cancer Chemother Pharmacol. 2007 Mar;59(4):467-75. Epub 2006 Aug 1.

PMID 16896930

Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis.

Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G.

Am J Pathol. 2001 Mar;158(3):987-96.

PMID 11238046

DNA copy number changes in thyroid carcinoma.

Hemmer S, Wasenius VM, Knuutila S, Franssila K, Joensuu H.

Am J Pathol. 1999 May;154(5):1539-47.

PMID 10329606

N-cadherin-mediated adhesion and aberrant catenin expression in anaplastic thyroid-carcinoma cell lines.

Husmark J, Heldin NE, Nilsson M.

Int J Cancer. 1999 Nov 26;83(5):692-9.

PMID 10521809

Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma.

Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW.

Cancer. 1990 Sep 15;66(6):1213-20.

PMID 2400971

Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q.

Kitamura Y, Shimizu K, Tanaka S, Ito K, Emi M.

Genes Chromosomes Cancer. 2000 Mar;27(3):244-51.

PMID 10679913

DNA aneuploidy in anaplastic carcinoma of the thyroid gland.

Klemi PJ, Joensuu H, Eerola E.

Am J Clin Pathol. 1988 Feb;89(2):154-9.

PMID 3341277

Treatment of 37 patients with anaplastic carcinoma of the thyroid.

Kobayashi T, Asakawa H, Umeshita K, Takeda T, Maruyama H, Matsuzuka F, Monden M.

Head Neck. 1996 Jan-Feb;18(1):36-41.

PMID 8774920

Epidermal growth factor receptor status in anaplastic thyroid carcinoma.

Lee DH, Lee GK, Kong SY, Kook MC, Yang SK, Park SY, Park SH, Keam B, Park do J, Cho BY, Kim SW, Chung KW, Lee ES, Kim SW.

J Clin Pathol. 2007 Aug;60(8):881-4. Epub 2006 Nov 1.

PMID 17079354

Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma.

Lee JJ, Au AY, Foukakis T, Barbaro M, Kiss N, Clifton-Bligh R, Staaf J, Borg A, Delbridge L, Robinson BG, Wallin G, Hoog A, Larsson C.

Endocr Relat Cancer. 2008 Sep;15(3):801-15.

PMID 18753363

Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models.

Lee JJ, Foukakis T, Hashemi J, Grimelius L, Heldin NE, Wallin G, Rudduck C, Lui WO, Hoog A, Larsson C.

Thyroid. 2007 Apr;17(4):289-301.

PMID 17465858

Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines.

Mitomo S, Maesawa C, Ogasawara S, Iwaya T, Shibazaki M, Yashima-Abo A, Kotani K, Oikawa H, Sakurai E, Izutsu N, Kato K, Komatsu H, Ikeda K, Wakabayashi G, Masuda T.

Cancer Sci. 2008 Feb;99(2):280-6. Epub 2008 Jan 14.

PMID 18201269

A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome.

Mooney CJ, Nagaiah G, Fu P, Wasman JK, Cooney MM, Savvides PS, Bokar JA, Dowlati A, Wang D, Agarwala SS, Flick SM, Hartman PH, Ortiz JD, Lavertu PN, Remick SC.

Thyroid. 2009 Mar;19(3):233-40.

PMID 19265494

Identification of Polo-like kinase 1 as a potential therapeutic target in anaplastic thyroid carcinoma.

Nappi TC, Salerno P, Zitzelsberger H, Carlomagno F, Salvatore G, Santoro M.

Cancer Res. 2009 Mar 1;69(5):1916-23. Epub 2009 Feb 17.

PMID 19223553

FOXA1 is a potential oncogene in anaplastic thyroid carcinoma.

Nucera C, Eeckhoute J, Finn S, Carroll JS, Ligon AH, Priolo C, Fadda G, Toner M, Sheils O, Attard M, Pontecorvi A, Nose V, Loda M, Brown M.

Clin Cancer Res. 2009 Jun 1;15(11):3680-9. Epub 2009 May 26.

PMID 19470727

Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases.

Ordonez NG, El-Naggar AK, Hickey RC, Samaan NA.

Am J Clin Pathol. 1991 Jul;96(1):15-24.

PMID 1712540

Prospective application of our novel prognostic index in the treatment of anaplastic thyroid carcinoma.

Orita Y, Sugitani I, Amemiya T, Fujimoto Y.

Surgery. 2011 Dec;150(6):1212-9.

PMID 22136842

A phase II study of gefitinib in patients with advanced thyroid cancer.

Pennell NA, Daniels GH, Haddad RI, Ross DS, Evans T, Wirth LJ, Fidias PH, Temel JS, Gurubhagavatula S, Heist RS, Clark JR, Lynch TJ.

Thyroid. 2008 Mar;18(3):317-23.

PMID 17985985

18F-fluorodeoxyglucose positron emission tomography and computed tomography in anaplastic thyroid cancer.

Poisson T, Deandreis D, Leboulleux S, Bidault F, Bonniaud G, Baillot S, Auperin A, Al Ghuzlan A, Travagli JP, Lumbroso J, Baudin E, Schlumberger M.

Eur J Nucl Med Mol Imaging. 2010 Dec;37(12):2277-85. Epub 2010 Aug 6.

PMID 20694463

Tumors of the thyroid gland.

Rosai J, Carcangiu ML, DeLellis RA.

Atlas of tumor Pathology 1992, 3rd series, fascicle 5.

Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer.

Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI.

J Clin Endocrinol Metab. 2008 Jan;93(1):278-84. Epub 2007 Nov 7.

PMID 17989125

Detection of the H-RAS oncogene in human thyroid anaplastic carcinomas.

Stringer BM, Rowson JM, Parkar MH, Seid JM, Hearn PR, Wynford-Thomas D, Ingemansson S, Woodhouse N, Goyns MH.

Experientia. 1989 Apr 15;45(4):372-6.

PMID 2651141

Quantitative measurement of telomerase reverse transcriptase, thyroglobulin and thyroid transcription factor 1 mRNAs in anaplastic thyroid carcinoma tissues and cell lines.

Takano T, Ito Y, Matsuzuka F, Miya A, Kobayashi K, Yoshida H, Miyauchi A.

Oncol Rep. 2007 Sep;18(3):715-20.

PMID 17671725

Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories.

Tallini G, Garcia-Rostan G, Herrero A, Zelterman D, Viale G, Bosari S, Carcangiu ML.

Am J Surg Pathol. 1999 Jun;23(6):678-85.

PMID 10366150

Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases.

Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H, Samaan NA.

Cancer. 1990 Jul 15;66(2):321-30.

PMID 1695118

Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment.

Wiseman SM, Masoudi H, Niblock P, Turbin D, Rajput A, Hay J, Bugis S, Filipenko D, Huntsman D, Gilks B.

Ann Surg Oncol. 2007 Feb;14(2):719-29. Epub 2006 Nov 10.

PMID 17115102

Genome-wide appraisal of thyroid cancer progression.

Wreesmann VB, Ghossein RA, Patel SG, Harris CP, Schnaser EA, Shaha AR, Tuttle RM, Shah JP, Rao PH, Singh B.

Am J Pathol. 2002 Nov;161(5):1549-56.

PMID 12414503

A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.

Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J.

Oncogene. 2007 Feb 22;26(8):1178-87. Epub 2006 Aug 21.

PMID 16924234

Citation

This paper should be referenced as such :

Yeung, SCJ ; Habra, MA

Thyroid: Anaplastic (undifferentiated) carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):935-939.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/AnaCarciThyroidID5069.html

History of this paper:

Fadare, O ; Tallini, G. Thyroid: Anaplastic (undifferentiated) carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2003;7(3):190-192.

http://documents.irevues.inist.fr/bitstream/handle/2042/37995/06-2003-AnaCarciThyroidID5069.pdf

Yeung, SCJ. Thyroid: Anaplastic (undifferentiated) carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):477-480.

http://documents.irevues.inist.fr/bitstream/handle/2042/38616/11-2007-AnaCarciThyroidID5069.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 28 ]

Genes	AKT1	AURKB	BAG3	ADGRE5	CRYAB	DUSP26	ENPP2	FGFR1	FOXA1	FUT8
	HLTF	ID1	ILK	PCLAF	MCM5	MIR122	MIR141	MIR200C	NNMT	PTK2
		S100A2		STMN1	THRB	TP53INP1	TSHR	UBE2C

External links

arrayMap	Topo ( C73) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other database	ICGC Data Portal - [THCA-SA] Thyroid Cancer - SA
Disease database	Thyroid: Anaplastic (undifferentiated) carcinoma

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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