Thyroid: Anaplastic (undifferentiated) carcinoma

2012-07-01   Sai-Ching Jim Yeung , Mouhammed Amir Habra 

1.The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment, Emergency Care, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA (SCJY); The University of Texas M. D. Anderson Cancer Center, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 1416, Houston, Texas 77030, USA (MAH)
2.Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy
3.The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment, Emergency Care, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA

Summary

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.
Atlas Image
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

Pubmed IDLast YearTitleAuthors
109583112000Treatment 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 et al
170726492007Down-regulation of an inhibitor of cell growth, transmembrane protein 34 (TMEM34), in anaplastic thyroid cancer.Akaishi J et al
219366742011Prognostic factors and treatment outcomes of 100 cases of anaplastic thyroid carcinoma.Akaishi J et al
18630999200818F-FDG PET in the management of patients with anaplastic thyroid carcinoma.Bogsrud TV et al
186228942008Expression and mutation analysis of the tyrosine kinase c-kit in poorly differentiated and anaplastic thyroid carcinoma.Broecker-Preuss M et al
89195451996Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues.Capella G et al
25787271985Anaplastic thyroid carcinoma. A study of 70 cases.Carcangiu ML et al
191768702009Phosphorylated insulin like growth factor-I receptor expression and its clinico-pathological significance in histologic subtypes of human thyroid cancer.Chakravarty G et al
188388822008Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results 1983-2002.Chen J et al
220447752011Results of combined treatment of anaplastic thyroid carcinoma (ATC).Derbel O et al
84735151993Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland.Donghi R et al
120679832002A 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 et al
223995192012Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2.Esposito F et al
84232161993High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas.Fagin JA et al
168969302007A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.Fury MG et al
112380462001Beta-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 et al
103296061999DNA copy number changes in thyroid carcinoma.Hemmer S et al
105218091999N-cadherin-mediated adhesion and aberrant catenin expression in anaplastic thyroid-carcinoma cell lines.Husmark J et al
24009711990Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma.Jenkins RB et al
106799132000Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q.Kitamura Y et al
33412771988DNA aneuploidy in anaplastic carcinoma of the thyroid gland.Klemi PJ et al
87749201996Treatment of 37 patients with anaplastic carcinoma of the thyroid.Kobayashi T et al
170793542007Epidermal growth factor receptor status in anaplastic thyroid carcinoma.Lee DH et al
187533632008Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma.Lee JJ et al
174658582007Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models.Lee JJ et al
182012692008Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines.Mitomo S et al
192654942009A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome.Mooney CJ et al
192235532009Identification of Polo-like kinase 1 as a potential therapeutic target in anaplastic thyroid carcinoma.Nappi TC et al
194707272009FOXA1 is a potential oncogene in anaplastic thyroid carcinoma.Nucera C et al
17125401991Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases.Ordóñez NG et al
221368422011Prospective application of our novel prognostic index in the treatment of anaplastic thyroid carcinoma.Orita Y et al
179859852008A phase II study of gefitinib in patients with advanced thyroid cancer.Pennell NA et al
20694463201018F-fluorodeoxyglucose positron emission tomography and computed tomography in anaplastic thyroid cancer.Poisson T et al
179891252008Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer.Santarpia L et al
26511411989Detection of the H-RAS oncogene in human thyroid anaplastic carcinomas.Stringer BM et al
176717252007Quantitative measurement of telomerase reverse transcriptase, thyroglobulin and thyroid transcription factor 1 mRNAs in anaplastic thyroid carcinoma tissues and cell lines.Takano T et al
103661501999Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories.Tallini G et al
16951181990Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases.Venkatesh YS et al
171151022007Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment.Wiseman SM et al
124145032002Genome-wide appraisal of thyroid cancer progression.Wreesmann VB et al
169242342007A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.Yu W et al

External Links

Citation

Sai-Ching Jim Yeung ; Mouhammed Amir Habra

Thyroid: Anaplastic (undifferentiated) carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2012-07-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5069/anacarcithyroidid5069

Historical Card

2007-11-01 Thyroid: Anaplastic (undifferentiated) carcinoma by  Sai-Ching Jim Yeung 

The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment, Emergency Care, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA (SCJY); The University of Texas M. D. Anderson Cancer Center, Department of Endocrine Neoplasia, Hormonal Disorders, 1515 Holcombe Boulevard, Unit 1416, Houston, Texas 77030, USA (MAH)

2003-06-01 Thyroid: Anaplastic (undifferentiated) carcinoma by  Oluwole Fadare,Giovanni Tallini 

Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy