eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Thyroid, Anaplastic Carcinoma

Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic, Billings, Montana

Updated: Dec 16, 2009

Introduction

Background

Anaplastic carcinoma of the thyroid (ATC) is the most aggressive thyroid gland malignancy. Although ATC accounts for less than 2% of all thyroid cancers, it causes up to 40% of deaths from thyroid cancer.

The aggressive nature of ATC makes treatment studies difficult to perform.

Pathophysiology

Anaplastic carcinoma of the thyroid (ATC) generally occurs in people in iodine-deficient areas and in a setting of previous thyroid pathology (eg, preexisting goiter, follicular thyroid cancer, papillary thyroid cancer). Local invasion of adjacent structures (eg, trachea, esophagus) commonly occurs.

ATC has a rapid course and early dissemination. The most common sites of distant spread include, in descending order, the lung, bone, and brain. Metastases, particularly in the lung, are likely to be present at diagnosis more than 50% of the time.

Frequency

United States

Anaplastic carcinoma of the thyroid (ATC) constitutes less than 2% of all thyroid malignancies. Fortunately, the incidence appears to be declining.

International

Worldwide frequency likely approximates that in the United States.

Mortality/Morbidity

Anaplastic carcinoma of the thyroid (ATC) typically has a rapidly progressive course. The overall 5-year survival rate is reportedly less than 10%, and most patients do not live longer than a few months after diagnosis.^{[1 ]}

Sex

The female-to-male ratio is approximately 3:1.

Age

Peak incidence occurs during the sixth to seventh decades of life. The age range of affected patients reportedly is 15-90 years.

Clinical

History

Patients with anaplastic thyroid carcinoma (ATC) typically present with a rapidly growing neck mass. Patients with metastases may also note bone pain, weakness, and cough. Neurologic deficits may be observed with brain metastases. The rapidly growing neck mass may produce the following symptoms:

• Dysphagia
• Cough
• Neck pain
• Dyspnea

Physical

Physical examination typically reveals a dominant neck mass. More than 40% of affected patients have lymph node enlargement, indicating local metastases. Pleural effusions may lead to decreased breath sounds on auscultation. With metastases, the physician may note bone pain and neurologic deficits.

Causes

Anaplastic carcinoma of the thyroid (ATC) is believed to occur from a terminal dedifferentiation of previously undetected long-standing thyroid carcinoma (eg, papillary, follicular). ATC has a genetic association with oncogenes C-myc, H-ras, and Nm23. Mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes have been found in ATC, and chromosomal abnormalities are common.^{[2 ]}

Differential Diagnoses

Other Problems to Be Considered

Thyroid, adenoma

Workup

Laboratory Studies

• Anaplastic thyroid carcinoma (ATC) cannot be definitively diagnosed with laboratory examinations of the blood or urine.
• Obtain serum calcium levels to rule out medullary thyroid carcinoma or parathyroid neoplasms.

Imaging Studies

• Chest radiography may be used to determine the presence of lung metastases.
• Preoperative cervical ultrasonography can detect lymph node metastases.
• Cervical CT scanning can be used to define the local spread of disease. Detection of distant metastases to the mediastinum, liver, lung, bone, and brain is also possible via CT scanning or MRI.
• Bone scanning can be used to determine the presence of bone metastases.
• Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) can visualize primary tumors, lymph node metastases, lung metastases, and other distant metastases.^{[3 ]}

Procedures

• Fine-needle aspiration often yields enough cytologic information to allow diagnosis; however, if the fine-needle aspiration does not provide definitive results, the patient may require an open surgical biopsy.

Histologic Findings

Grossly, anaplastic carcinoma of the thyroid (ATC) is a large, fleshy, off-white tumor. Infiltration of adjacent structures can be observed grossly and microscopically. Histologically, the tumor may contain regions of spontaneous necrosis and hemorrhage. Typically, angioinvasion is detectable.

The main histologic variants include spindle cell, giant cell (osteoclastlike), squamoid, and paucicellular. The giant cell subtype typically exhibits local calcification with significant osteoid formation. The paucicellular subtype demonstrates rapid growth, intense fibrosis, focal infarction, diffuse calcification, and encroachment of adjacent vascular tissue by atypical spindle cells.

Thyroid lymphoma is the only curable condition that may be confused with ATC. Rule out lymphoma in the presence of a poorly differentiated large cell thyroid tumor. This investigation involves lymphoid tissue markers (eg, cytoplasmic immunoglobulin, immunoglobulin receptors, gene rearrangement studies).

Treatment

Medical Care

• Treatment is mostly palliative.
• Consider patients with unresectable tumors who are in good general condition for phase I studies.
  • Phase I trials represent the only opportunity to identify drugs with some activity against this unusual disease.
  • These studies are available in any major cancer center, are generally financed by the industry, and may help individual patients.

Surgical Care

• Use surgery to obtain a definitive diagnosis when fine-needle aspiration is unsuccessful.
• Perform surgery in conjunction with radiation and chemotherapy.
• Protect the airway when performing surgery; thus, an early prophylactic tracheostomy may be required.
• Despite the typically large size of these tumors, the extent of resection is limited when the diagnosis is made.
• Rather than performing complete thyroidectomy, resect as much thyroid tissue as possible without attempting resection of all adjacent structures because of the high incidence of postoperative morbidity (eg, vocal cord paralysis, esophageal fistula). Although a greater extent of resection may be associated with slightly longer survival, this hypothesis is not confirmed.

Consultations

Involve a surgeon with experience in thyroid operations in the operative care of affected patients.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antineoplastics

Chemotherapeutic agents that may be used in advanced disease include doxorubicin and cisplatin.

Doxorubicin (Adriamycin, Rubex)

This is an antineoplastic agent of the anthracycline antibiotic class. Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can in turn inhibit the growth of neoplastic cells. In metastatic thyroid carcinoma, doxorubicin is probably the most effective antineoplastic agent.

Dosing

Adult

Recommended dose can vary from 60-75 mg/m² typically as a single rapid IV infusion; dose may be repeated after 21 d

Pediatric

Administer as in adults

Interactions

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity of doxorubicin; cyclophosphamide increases cardiac toxicity of doxorubicin

Contraindications

Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; preexisting myelosuppression

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Myelosuppression is a major dose-limiting toxicity; leukopenia usually reaches a nadir by week 2 of therapy and recovers by week 4; stomatitis, alopecia, and gastrointestinal upset are common but usually reversible adverse effects; erythematous streaking near the site of infusion; facial flushing; conjunctivitis; lacrimation; local toxicity may occur in irradiated tissues (eg, skin, heart, lung, esophagus, gastrointestinal mucosa)
Cardiomyopathy is a well known adverse effect of anthracycline antibiotics; acute and chronic heart failure may occur; mortality rate may exceed 50%; a dose as small as 250 mg/m² can cause myocardial toxicity; cardiac irradiation or other concomitant anthracycline administration may increase risk of cardiotoxicity; late-onset cardiac toxicity, manifesting as congestive heart failure years after treatment, may occur in both children and adults

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.

Dosing

Adult

Average dose: 20 mg/m² IV qd for 5 d or 100 mg/m² as single dose q4wk

Pediatric

Administer as in adults

Interactions

Increases toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur; ototoxicity can be unilateral or bilateral and may be more severe in children; marked nausea and vomiting occurs in almost all patients; at high doses or after several treatment cycles, cisplatin causes peripheral neuropathy; mild-to-moderate myelosuppression may occur transiently; electrolyte disturbances, particularly hypomagnesemia secondary to renal wasting, may occur

Follow-up

Further Inpatient Care

• Role of adjuvant therapy
  • Radiotherapy: Despite the fact that anaplastic thyroid carcinoma (ATC) is largely radioresistant, use external-beam radiotherapy for local control. Some evidence shows that hyperfractionation may lead to better success at local control by permitting delivery of higher doses of total radiation with less toxicity.
    • Bhatia et al reported on the use of conformal 3-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT) in 53 consecutive patients with anaplastic thyroid cancer. Median radiation dose was 55 Gray (Gy; range, 4-70 Gy); IMRT was given to a median 60 Gy (range, 39.9-69.0 Gy). Superior survival was noted in patients without distant metastases who received >50 Gy.^{[4 ]}
  • Chemotherapy: Currently, no available chemotherapeutic agent or combination of chemotherapeutic agents shows sufficient antineoplastic activity to prevent death; yet, in rare instances, chemotherapy may prolong life by a few weeks or perhaps months. Doxorubicin and cisplatin are the 2 most common agents used; however, resistance from cellular extrusion of the drugs occurs. Valproic acid has been introduced into treatment regimens because it induces apoptosis, modulates differentiation gene expression of thyroid tumors, and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin.^{[5 ]}
  • A study from the Netherlands reported significantly improved local control and improved median survival with a protocol consisting of locoregional radiotherapy in 46 fractions of 1.1 Gy, given twice daily, followed by prophylactic irradiation of the lungs in 5 daily fractions of 1.5 Gy. Low-dose doxorubicin (15 mg/m²) is administered weekly during radiotherapy, followed by adjuvant doxorubicin (50 mg/m²) 3 times a week up to a cumulative dose of 550 mg/m².^{[6 ]}
• Since ATC is a relatively uncommon disease, large phase III clinical trials of systemic therapies are not possible to perform. For that reason, the value of newer therapies, such as taxanes, gemcitabine, and irinotecan, and targeted therapies, such as receptor tyrosine kinase inhibitors, is unknown.
• Immunohistochemical evaluation of molecular markers in ATC showed frequent and strong overexpression of beta-catenin, aurora A, cyclin E, cyclin D1, and epidermal growth factor receptor. These findings support the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors.^{[7 ]}

Complications

• Risk of local complications from thyroid surgery (eg, permanent hypoparathyroidism, recurrent laryngeal nerve palsy) may be increased with anaplastic thyroid carcinoma (ATC) if aggressive resection is attempted.
• With limited thyroid resection, incidence of these local complications should not be significantly greater.
• ATC may cause airway obstruction. Patients with impending airway obstruction who are not candidates for local resection or chemoradiation should undergo tracheostomy; interventional bronchoscopy, including Nd-YAG laser and airway stenting, is an alternative to surgery in inoperable cases.^{[8 ]}

Prognosis

• Anaplastic thyroid carcinoma (ATC) typically has a rapidly progressive course. The overall 5-year survival rate is reportedly less than 10%, and most patients do not live longer than a few months after diagnosis.
• One study has shown that patients younger than 60 years who have intrathyroidal ATC have a better prognosis than patients who are older and have distant metastases.^{[9 ]}
• A retrospective study from Korea found that age less than 60 years, tumor size less than 7 cm, and lesser extent of disease were independent predictors of lower disease-specific mortality.^{[10 ]}
• While some studies have suggested that postoperative radiotherapy may be of benefit in terms of survival, definitive prospective trials are lacking.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose anaplastic thyroid carcinoma (ATC) at an early stage before it spreads both locally and distantly, which underscores the importance of meticulous history and physical examination in the assessment
• Failure to perform fine-needle aspiration for any suspicious thyroid mass; if results are equivocal or indeterminate, the mass should be re-aspirated or surgically excised
• Failure to seriously consider intervention (eg, intubation and/or tracheostomy) if the cancer is producing local airway compromise

Special Concerns

• Because ATC tends to occur in areas of previous thyroid pathology, consider the diagnosis in patients with a medical history of thyroid disease who present with a recently enlarging neck mass.
• If metastases are found, aggressive surgical therapy is not warranted.
• While recent trials of immunotherapy and gene therapy have been postulated, no definitive evidence suggests any benefit from these modalities; they should be considered experimental at best.

References

1. Neff RL, Farrar WB, Kloos RT, Burman KD. Anaplastic thyroid cancer. Endocrinol Metab Clin North Am. Jun 2008;37(2):525-38, xi. [Medline].

2. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. Mar 2009;16(1):17-44. [Medline].

3. Bogsrud TV, Karantanis D, Nathan MA, Mullan BP, Wiseman GA, Kasperbauer JL, et al. 18F-FDG PET in the management of patients with anaplastic thyroid carcinoma. Thyroid. Jul 2008;18(7):713-9. [Medline].

4. Bhatia A, Rao A, Ang KK, Garden AS, Morrison WH, Rosenthal DI, et al. Anaplastic thyroid cancer: Clinical outcomes with conformal radiotherapy. Head Neck. Nov 2 2009;[Medline].

5. Noguchi H, Yamashita H, Murakami T, Hirai K, Noguchi Y, Maruta J, et al. Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery. Endocr J. Apr 2009;56(2):245-9. [Medline].

6. Swaak-Kragten AT, de Wilt JH, Schmitz PI, Bontenbal M, Levendag PC. Multimodality treatment for anaplastic thyroid carcinoma--treatment outcome in 75 patients. Radiother Oncol. Jul 2009;92(1):100-4. [Medline].

7. Wiseman SM, Masoudi H, Niblock P, Turbin D, Rajput A, Hay J, et al. Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment. Ann Surg Oncol. Feb 2007;14(2):719-29. [Medline].

8. Chiacchio S, Lorenzoni A, Boni G, Rubello D, Elisei R, Mariani G. Anaplastic thyroid cancer: prevalence, diagnosis and treatment. Minerva Endocrinol. Dec 2008;33(4):341-57. [Medline].

9. Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer. Apr 1 2005;103(7):1330-5. [Medline].

10. Kim TY, Kim KW, Jung TS, Kim JM, Kim SW, Chung KW, et al. Prognostic factors for Korean patients with anaplastic thyroid carcinoma. Head Neck. Aug 2007;29(8):765-72. [Medline].

11. Ain KB. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin Surg Oncol. 1999;16:64-69. [Medline].

12. Austin JR, el-Naggar AK, Goepfert H. Thyroid cancers. II. Medullary, anaplastic, lymphoma, sarcoma, squamous cell. Otolaryngol Clin North Am. 1996;29:611-27. [Medline].

13. Goutsouliak V, Hay JH. Anaplastic thyroid cancer in British Columbia 1985-1999: a population-based study. Clin Oncol (R Coll Radiol). Apr 2005;17(2):75-8. [Medline].

14. Kapp DS, LiVolsi VA, Sanders MM. Anaplastic carcinoma following well-differentiated thyroid cancer: etiological considerations. Yale J Biol Med. 1982;55:521-8.

15. Schott M, Scherbaum WA. Immunotherapy and gene therapy of thyroid cancer. Minerva Endocrinol. Dec 2004;29(4):175-87. [Medline].

16. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg. 1996;20:88-93. [Medline].

17. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. Jun 2005;12(2):245-62. [Medline].

Keywords

undifferentiated thyroid carcinoma, anaplastic carcinoma of the thyroid, anaplastic thyroid carcinoma, ATC, thyroid gland malignancy, anaplastic thyroid carcinoma, thyroid cancer, thyroid tumor, metastases, thyroid malignancy

Contributor Information and Disclosures

Author

Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic, Billings, Montana
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

Debra J Graham, MD, is gratefully acknowledged for the contributions made to this topic.

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