Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

TNM Definitions AJCC Stage Groupings Papillary and Follicular Thyroid Cancer Medullary Thyroid Cancer Anaplastic Thyroid Cancer

Stage I and II Papillary and Follicular Thyroid Cancer

Current Clinical Trials

Stage III Papillary and Follicular Thyroid Cancer

Current Clinical Trials

Stage IV Papillary and Follicular Thyroid Cancer

Current Clinical Trials

Medullary Thyroid Cancer

Current Clinical Trials

Anaplastic Thyroid Cancer

Current Clinical Trials

Recurrent Thyroid Cancer

Current Clinical Trials

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Changes to This Summary (06/04/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of thyroid cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: A separate PDQ summary on Genetics of Medullary Thyroid Cancer ⁵ is also available and information on thyroid cancer in children is available in the PDQ summary on Unusual Cancers of Childhood ⁶.

Note: Estimated new cases and deaths from thyroid cancer in the United States in 2008:[1]

• New cases: 37,340.
• Deaths: 1,590.

Carcinoma of the thyroid gland is an uncommon cancer but is the most common malignancy of the endocrine system.[2] Differentiated tumors (papillary or follicular) are highly treatable and usually curable. Poorly differentiated tumors (medullary or anaplastic) are much less common, are aggressive, metastasize early, and have a much poorer prognosis. Thyroid cancer affects women more often than men and usually occurs in people between the ages of 25 and 65 years. The incidence of this malignancy has been increasing over the last decade. Thyroid cancer commonly presents as a cold nodule. The overall incidence of cancer in a cold nodule is 12% to 15%, but it is higher in people younger than 40 years and in people with calcifications present on preoperative ultrasonography.[3,4]

Risk factors

Patients with a history of radiation administered in infancy and childhood for benign conditions of the head and neck, such as enlarged thymus, acne, or tonsillar or adenoidal enlargement, have an increased risk of cancer as well as other abnormalities of the thyroid gland. In this group of patients, malignancies of the thyroid gland first appear beginning as early as 5 years following radiation and may appear 20 or more years later.[5] Radiation exposure as a consequence of nuclear fallout has also been associated with a high risk of thyroid cancer, especially in children.[6-8] Other risk factors for the development of thyroid cancer include a history of goiter, family history of thyroid disease, female gender, and Asian race.[9]

Prognostic factors

The prognosis for differentiated carcinoma is better for patients younger than 40 years without extracapsular extension or vascular invasion.[10-14] Age appears to be the single most important prognostic factor.[12] The prognostic significance of lymph node status is controversial. One retrospective surgical series of 931 previously untreated patients with differentiated thyroid cancer found that female gender, multifocality, and regional node involvement are favorable prognostic factors.[15] Adverse factors included age older than 45 years, follicular histology, primary tumor larger than 4 cm (T2–T3), extrathyroid extension (T4), and distant metastases.[15,16] Other studies, however, have shown that regional lymph node involvement had no effect [17,18] or even an adverse effect on survival.[13,14,19] Diffuse, intense immunostaining for vascular endothelial growth factor in patients with papillary cancer has been associated with a high rate of local recurrence and distant metastases.[20] An elevated serum thyroglobulin level correlates strongly with recurrent tumor when found in patients with differentiated thyroid cancer during postoperative evaluations.[21,22] Serum thyroglobulin levels are most sensitive when patients are hypothyroid and have elevated serum thyroid-stimulating hormone levels.[23] Expression of the tumor suppressor gene p53 has also been associated with an adverse prognosis for patients with thyroid cancer.[24]

Patients considered to be low risk by the age, metastases, extent, and size (AMES) risk criteria include women younger than 50 years and men younger than 40 years without evidence of distant metastases. Also included in the low-risk group are older patients with primary tumors smaller than 5 cm and papillary cancer without evidence of gross extrathyroid invasion or follicular cancer without either major capsular invasion or blood vessel invasion.[11] Using these criteria, a retrospective study of 1,019 patients showed that the 20-year survival rate is 98% for low-risk patients and 50% for high-risk patients.[11] The 10-year overall relative survival rates for patients in the United States are 93% for papillary cancer, 85% for follicular cancer, 75% for medullary cancer, and 14% for undifferentiated/anaplastic cancer.[2]

The thyroid gland may occasionally be the site of other primary tumors, including sarcomas, lymphomas, epidermoid carcinomas, and teratomas and may be the site of metastasis from other cancers, particularly of the lung, breast, and kidney.

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁷ Last accessed October 1, 2008. 
   
   
2. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998.  [PUBMED Abstract]
   
   
3. Tennvall J, Biörklund A, Möller T, et al.: Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer 57 (7): 1405-14, 1986.  [PUBMED Abstract]
   
   
4. Khoo ML, Asa SL, Witterick IJ, et al.: Thyroid calcification and its association with thyroid carcinoma. Head Neck 24 (7): 651-5, 2002.  [PUBMED Abstract]
   
   
5. Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1502-19. 
   
   
6. Pacini F, Vorontsova T, Molinaro E, et al.: Prevalence of thyroid autoantibodies in children and adolescents from Belarus exposed to the Chernobyl radioactive fallout. Lancet 352 (9130): 763-6, 1998.  [PUBMED Abstract]
   
   
7. Cardis E, Kesminiene A, Ivanov V, et al.: Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97 (10): 724-32, 2005.  [PUBMED Abstract]
   
   
8. Tronko MD, Howe GR, Bogdanova TI, et al.: A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: thyroid cancer in Ukraine detected during first screening. J Natl Cancer Inst 98 (13): 897-903, 2006.  [PUBMED Abstract]
   
   
9. Iribarren C, Haselkorn T, Tekawa IS, et al.: Cohort study of thyroid cancer in a San Francisco Bay area population. Int J Cancer 93 (5): 745-50, 2001.  [PUBMED Abstract]
   
   
10. Grant CS, Hay ID, Gough IR, et al.: Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 104 (6): 954-62, 1988.  [PUBMED Abstract]
    
    
11. Sanders LE, Cady B: Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 133 (4): 419-25, 1998.  [PUBMED Abstract]
    
    
12. Mazzaferri EL: Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 66 (1): 105-11, 1991.  [PUBMED Abstract]
    
    
13. Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994.  [PUBMED Abstract]
    
    
14. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994.  [PUBMED Abstract]
    
    
15. Shah JP, Loree TR, Dharker D, et al.: Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 164 (6): 658-61, 1992.  [PUBMED Abstract]
    
    
16. Andersen PE, Kinsella J, Loree TR, et al.: Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg 170 (5): 467-70, 1995.  [PUBMED Abstract]
    
    
17. Coburn MC, Wanebo HJ: Prognostic factors and management considerations in patients with cervical metastases of thyroid cancer. Am J Surg 164 (6): 671-6, 1992.  [PUBMED Abstract]
    
    
18. Voutilainen PE, Multanen MM, Leppäniemi AK, et al.: Prognosis after lymph node recurrence in papillary thyroid carcinoma depends on age. Thyroid 11 (10): 953-7, 2001.  [PUBMED Abstract]
    
    
19. Sellers M, Beenken S, Blankenship A, et al.: Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg 164 (6): 578-81, 1992.  [PUBMED Abstract]
    
    
20. Lennard CM, Patel A, Wilson J, et al.: Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 129 (5): 552-8, 2001.  [PUBMED Abstract]
    
    
21. van Herle AJ, van Herle KA: Thyroglobulin in benign and malignant thyroid disease. In: Falk SA: Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Philadelphia, Pa: Lippincott-Raven, 1997, pp 601-618. 
    
    
22. Ruiz-Garcia J, Ruiz de Almodóvar JM, Olea N, et al.: Thyroglobulin level as a predictive factor of tumoral recurrence in differentiated thyroid cancer. J Nucl Med 32 (3): 395-8, 1991.  [PUBMED Abstract]
    
    
23. Duren M, Siperstein AE, Shen W, et al.: Value of stimulated serum thyroglobulin levels for detecting persistent or recurrent differentiated thyroid cancer in high- and low-risk patients. Surgery 126 (1): 13-9, 1999.  [PUBMED Abstract]
    
    
24. Godballe C, Asschenfeldt P, Jørgensen KE, et al.: Prognostic factors in papillary and follicular thyroid carcinomas: p53 expression is a significant indicator of prognosis. Laryngoscope 108 (2): 243-9, 1998.  [PUBMED Abstract]
    
    

Cellular Classification

Cell type is an important determinant of prognosis in thyroid cancer. There are four main varieties of thyroid cancer (although, for clinical management of the patient, thyroid cancer is generally divided into two categories: well differentiated or poorly differentiated):[1]

• Papillary carcinoma.
  • Papillary/follicular carcinoma.
• Follicular carcinoma.
  • Hürthle cell carcinoma.
• Medullary carcinoma.
• Anaplastic carcinoma.
  • Small cell carcinoma.
  • Giant cell carcinoma.
• Others.
  • Lymphoma.
  • Sarcoma.
  • Carcinosarcoma.

A definition for each major type can be found under stage information.

References

1. LiVolsi VA: Pathology of thyroid disease. In: Falk SA: Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Philadelphia, Pa: Lippincott-Raven, 1997, pp 127-175. 
   
   

Stage Information

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

Primary tumor (T)

 [Note: All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor (the largest determines the classification).]

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• T1: Tumor 2 cm or less in greatest dimension, limited to the thyroid
• T2: Tumor larger than 2 cm but 4 cm or smaller in greatest dimension, limited to the thyroid
• T3: Tumor larger than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
• T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
• T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

All anaplastic carcinomas are considered T4 tumors.

• T4a: Intrathyroidal anaplastic carcinoma—surgically resectable
• T4b: Extrathyroidal anaplastic carcinoma—surgically unresectable

Regional lymph nodes (N)

Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Regional lymph node metastasis
  • N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
  • N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes

Distant metastases (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic (undifferentiated) carcinoma.

Papillary or follicular thyroid cancer

Younger than 45 years

• Stage I
  • Any T, any N, M0
• Stage II
  • Any T, any N, M1

Age 45 years and older

• Stage I
  • T1, N0, M0
• Stage II
  • T2, N0, M0
• Stage III
  • T3, N0, M0
  • T1, N1a, M0
  • T2, N1a, M0
  • T3, N1a, M0
• Stage IVA
  • T4a, N0, M0
  • T4a, N1a, M0
  • T1, N1b, M0
  • T2, N1b, M0
  • T3, N1b, M0
  • T4a, N1b, M0
• Stage IVB
  • T4b, any N, M0
• Stage IVC
  • Any T, any N, M1

Medullary thyroid cancer

• Stage I
  • T1, N0, M0
• Stage II
  • T2, N0, M0
• Stage III
  • T3, N0, M0
  • T1, N1a, M0
  • T2, N1a, M0
  • T3, N1a, M0
• Stage IVA
  • T4a, N0, M0
  • T4a, N1a, M0
  • T1, N1b, M0
  • T2, N1b, M0
  • T3, N1b, M0
  • T4a, N1b, M0
• Stage IVB
  • T4b, any N, M0
• Stage IVC
  • Any T, any N, M1

Anaplastic thyroid cancer

All anaplastic carcinomas are considered stage IV.

• Stage IVA
  • T4a, any N, M0

• Stage IVB
  • T4b, any N, M0

• Stage IVC
  • Any T, any N, M1

Stage I papillary thyroid cancer

Stage I papillary carcinoma is localized to the thyroid gland. In as many as 50% of cases, there are multifocal sites of papillary adenocarcinomas throughout the gland. Most papillary cancers have some follicular elements, and these may sometimes be more numerous than the papillary formations, but this does not change the prognosis. The 10-year survival rate is slightly better for patients younger than 40 years than for patients older than 40 years.

Stage II papillary thyroid cancer

Stage II papillary carcinoma is defined as either (1) tumor that has spread distantly in patients younger than 45 years or (2) tumor that is larger than 2 cm but 4 cm or smaller and is limited to the thyroid gland in patients older than 45 years. In as many as 50% to 80% of cases there are multifocal sites of papillary adenocarcinomas throughout the gland. Most papillary cancers have some follicular elements, and these may sometimes be more numerous than the papillary formations, but this does not appear to change the prognosis.

Stage III papillary thyroid cancer

Stage III is papillary carcinoma in patients older than 45 years that is larger than 4 cm and is limited to the thyroid or with minimal extrathyroid extension, or positive lymph nodes limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes. Papillary carcinoma that has invaded adjacent cervical tissue has a worse prognosis than tumors confined to the thyroid.

Stage IV papillary thyroid cancer

Stage IV is papillary carcinoma in patients older than 45 years with extension beyond the thyroid capsule to the soft tissues of the neck, cervical lymph node metastases, or distant metastases. The lungs and bone are the most frequent distant sites of spread, though such distant spread is rare in this type of thyroid cancer. Papillary carcinoma more frequently metastasizes to regional lymph nodes than to distant sites. The prognosis for patients with distant metastases is poor.

Stage I follicular thyroid cancer

Stage I follicular carcinoma is localized to the thyroid gland. Follicular thyroid carcinoma must be distinguished from follicular adenomas, which are characterized by their lack of invasion through the capsule into the surrounding thyroid tissue. While follicular cancer has a good prognosis, it is less favorable than that of papillary carcinoma. The 10-year survival is better for patients with follicular carcinoma without vascular invasion than it is for patients with vascular invasion.

Stage II follicular thyroid cancer

Stage II follicular carcinoma is defined as either tumor that has spread distantly in patients younger than 45 years, or tumor that is larger than 2 cm but 4 cm or smaller and is limited to the thyroid gland in patients older than 45 years. The presence of lymph node metastases does not worsen the prognosis among patients younger than 45 years. Follicular thyroid carcinoma must be distinguished from follicular adenomas, which are characterized by their lack of invasion through the capsule into the surrounding thyroid tissue. While follicular cancer has a good prognosis, it is less favorable than that of papillary carcinoma; the 10-year survival is better for patients with follicular carcinoma without vascular invasion than for patients with vascular invasion.

Stage III follicular thyroid cancer

Stage III is follicular carcinoma in patients older than 45 years, larger than 4 cm and limited to the thyroid or with minimal extrathyroid extension, or positive lymph nodes limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes. Follicular carcinoma invading cervical tissue has a worse prognosis than tumors confined to the thyroid gland. The presence of vascular invasion is an additional poor prognostic factor. Metastases to lymph nodes do not worsen the prognosis in patients younger than 45 years.

Stage IV follicular thyroid cancer

Stage IV is follicular carcinoma in patients older than 45 years with extension beyond the thyroid capsule to the soft tissues of the neck, cervical lymph node metastases, or distant metastases. The lungs and bone are the most frequent sites of spread. Follicular carcinomas more commonly have blood vessel invasion and tend to metastasize hematogenously to the lungs and to the bone rather than through the lymphatic system. The prognosis for patients with distant metastases is poor.

Hürthle cell carcinoma

Hürthle cell carcinoma is a variant of follicular carcinoma with a similar prognosis and should be treated in the same way as equivalent stage non-Hürthle cell follicular carcinoma.[2]

Several staging systems have been employed to correlate extent of disease with long-term survival in medullary thyroid cancer. The clinical staging system of the AJCC correlates survival to size of the primary tumor, presence or absence of lymph node metastases, and presence or absence of distance metastasis. Patients with the best prognosis are those who are diagnosed by provocative screening, prior to the appearance of palpable disease.[3]

Stage 0 medullary thyroid cancer

Clinically occult disease detected by provocative biochemical screening.

Stage I medullary thyroid cancer

Tumor smaller than 2 cm.

Stage II medullary thyroid cancer

Tumor larger than 2 cm but 4 cm or smaller.

Stage III medullary thyroid cancer

Tumor larger than 4 cm with minimal extrathyroid extension or any primary tumor smaller than 4 cm with metastases limited to the pretracheal, paratracheal, or prelaryngeal/Delphian lymph nodes.

Stage IV medullary thyroid cancer

Stage IV medullary thyroid cancer is divided into:

• Stage IVA (potentially resectable with or without lymph node metastases [for T4a] but without distant metastases).



• Stage IVB (locally unresectable with or without lymph node metastases but no distant metastases).



• Stage IVC (distant metastases).

Medullary carcinoma usually presents as a hard mass and is often accompanied by blood vessel invasion. Medullary thyroid cancer occurs in two forms, sporadic and familial. In the sporadic form, the tumor is usually unilateral. In the familial form, the tumor is almost always bilateral. In addition, the familial form may be associated with benign or malignant tumors of other endocrine organs, commonly referred to as the multiple endocrine neoplasia syndromes (MEN 2A or MEN 2B).

In these syndromes, there is an association with pheochromocytoma of the adrenal gland and parathyroid hyperplasia. Medullary carcinoma usually secretes calcitonin, a hormonal marker for the tumor, and may be detectable in blood even when the tumor is clinically occult. Metastases to regional lymph nodes are found in about 50% of cases. Prognosis depends on extent of disease at presentation, presence or absence of regional lymph node metastases, and completeness of the surgical resection.[4]

Family members should be screened for calcitonin elevation to identify individuals who are at risk of developing familial medullary thyroid cancer. MEN 2A gene carrier status can be more accurately determined by analysis of mutations in the RET gene. Whereas modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the RET mutation is the optimal approach in evaluating MEN 2A. All patients with medullary carcinoma of the thyroid (whether familial or sporadic) should be tested for RET mutations, and, if they are positive, family members should also be tested. Family members who are gene carriers should undergo prophylactic thyroidectomy at an early age.[5-7]

No generally accepted staging system is available for anaplastic thyroid cancer. All patients are considered to have stage IV disease.

Undifferentiated (anaplastic) carcinomas are highly malignant cancers of the thyroid. They may be subclassified as small cell or large cell carcinomas. Both grow rapidly and extend to structures beyond the thyroid. Both small cell and large cell carcinomas present as hard, ill-defined masses, often with extension into the structures surrounding the thyroid. Small cell anaplastic thyroid carcinoma must be carefully distinguished from lymphoma. This tumor usually occurs in an older age group and is characterized by extensive local invasion and rapid progression. Five-year survival with this tumor is poor. Death is usually from uncontrolled local cancer in the neck, usually within months of diagnosis.

References

1. Thyroid. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 77-87. 
   
   
2. Haigh PI, Urbach DR: The treatment and prognosis of Hürthle cell follicular thyroid carcinoma compared with its non-Hürthle cell counterpart. Surgery 138 (6): 1152-7; discussion 1157-8, 2005.  [PUBMED Abstract]
   
   
3. Colson YL, Carty SE: Medullary thyroid carcinoma. Am J Otolaryngol 14 (2): 73-81, 1993 Mar-Apr.  [PUBMED Abstract]
   
   
4. Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1502-19. 
   
   
5. Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994.  [PUBMED Abstract]
   
   
6. Decker RA, Peacock ML, Borst MJ, et al.: Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete? Surgery 118 (2): 257-63; discussion 263-4, 1995.  [PUBMED Abstract]
   
   
7. Skinner MA, Moley JA, Dilley WG, et al.: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353 (11): 1105-13, 2005.  [PUBMED Abstract]
   
   

Stage I and II Papillary and Follicular Thyroid Cancer

Surgery is the therapy of choice for all primary lesions. Surgical options include total thyroidectomy or lobectomy. The choice of procedure is influenced mainly by the age of the patient and the size of the nodule. Survival results may be similar; the difference between them lies in the rates of surgical complications and local recurrences.[1-7]

Standard treatment options:

1. Total thyroidectomy: This procedure is advocated because of the high incidence of multicentric involvement of both lobes of the gland and the possibility of dedifferentiation of any residual tumor to the anaplastic cell type. The procedure is associated with a higher incidence of hypoparathyroidism, but this complication may be reduced when a small amount of tissue remains on the contralateral side. This approach facilitates follow-up thyroid scanning.

   I¹³¹: Studies have shown that a postoperative course of therapeutic (ablative) doses of I¹³¹ results in a decreased recurrence rate among high-risk patients with papillary and follicular carcinomas.[4] It may be given in addition to exogenous thyroid hormone but is not considered routine.[8] Patients presenting with papillary thyroid microcarcinomas (tumors <10 mm) have an excellent prognosis when treated surgically, and additional therapy with I¹³¹ would not be expected to improve the prognosis.[9]




2. Lobectomy: This procedure is associated with a lower incidence of complications, but approximately 5% to 10% of patients will have a recurrence in the thyroid following lobectomy.[10] Patients younger than 45 years will have the longest follow-up period and the greatest opportunity for recurrence. Follicular thyroid cancer commonly metastasizes to lungs and bone; with a remnant lobe in place, use of I¹³¹ as ablative therapy is compromised. Abnormal regional lymph nodes should be biopsied at the time of surgery. Recognized nodal involvement should be removed at initial surgery, but selective node removal can be performed, and radical neck dissection is usually not required. This results in a decreased recurrence rate, but has not been shown to improve survival.

   Following the surgical procedure, patients should receive postoperative treatment with exogenous thyroid hormone in doses sufficient to suppress thyroid-stimulating hormone (TSH); studies have shown a decreased incidence of recurrence when TSH is suppressed.

   I¹³¹: Studies have shown that a postoperative course of therapeutic (ablative) doses of I¹³¹ results in a decreased recurrence rate among high-risk patients with papillary and follicular carcinomas.[4] It may be given in addition to exogenous thyroid hormone but is not considered routine.[8] Patients presenting with papillary thyroid microcarcinomas (tumors <10 mm) have an excellent prognosis when treated surgically, and additional therapy with I¹³¹ would not be expected to improve the prognosis.[9]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I papillary thyroid cancer ⁸, stage I follicular thyroid cancer ⁹, stage II papillary thyroid cancer ¹⁰ and stage II follicular thyroid cancer ¹¹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1502-19. 
   
   
2. Grant CS, Hay ID, Gough IR, et al.: Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery 104 (6): 954-62, 1988.  [PUBMED Abstract]
   
   
3. Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104 (6): 947-53, 1988.  [PUBMED Abstract]
   
   
4. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994.  [PUBMED Abstract]
   
   
5. Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994.  [PUBMED Abstract]
   
   
6. Tollefsen HR, Shah JP, Huvos AG: Follicular carcinoma of the thyroid. Am J Surg 126 (4): 523-8, 1973.  [PUBMED Abstract]
   
   
7. Edis AJ: Surgical treatment for thyroid cancer. Surg Clin North Am 57 (3): 533-42, 1977.  [PUBMED Abstract]
   
   
8. Beierwaltes WH, Rabbani R, Dmuchowski C, et al.: An analysis of "ablation of thyroid remnants" with I-131 in 511 patients from 1947-1984: experience at University of Michigan. J Nucl Med 25 (12): 1287-93, 1984.  [PUBMED Abstract]
   
   
9. Hay ID, Grant CS, van Heerden JA, et al.: Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 112 (6): 1139-46; discussion 1146-7, 1992.  [PUBMED Abstract]
   
   
10. Hay ID, Grant CS, Bergstralh EJ, et al.: Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 124 (6): 958-64; discussion 964-6, 1998.  [PUBMED Abstract]
    
    

Stage III Papillary and Follicular Thyroid Cancer

Standard treatment options:

1. Total thyroidectomy plus removal of involved lymph nodes or other sites of extrathyroid disease.
2. I¹³¹ ablation following total thyroidectomy if the tumor demonstrates uptake of this isotope.[1]
3. External-beam radiation therapy if I¹³¹ uptake is minimal.[2]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III papillary thyroid cancer ¹³ and stage III follicular thyroid cancer ¹⁴. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Beierwaltes WH, Rabbani R, Dmuchowski C, et al.: An analysis of "ablation of thyroid remnants" with I-131 in 511 patients from 1947-1984: experience at University of Michigan. J Nucl Med 25 (12): 1287-93, 1984.  [PUBMED Abstract]
   
   
2. Simpson WJ, Carruthers JS: The role of external radiation in the management of papillary and follicular thyroid cancer. Am J Surg 136 (4): 457-60, 1978.  [PUBMED Abstract]
   
   

Stage IV Papillary and Follicular Thyroid Cancer

The most common sites of metastases are lymph nodes, lung, and bone. Treatment of lymph node metastases alone is often curative. Treatment of distant metastases is usually not curative but may produce significant palliation.

Standard treatment options:

1. I¹³¹: Metastases that demonstrate uptake of this isotope may be ablated by therapeutic doses of I¹³¹.



2. External-beam radiation therapy for patients with localized lesions that are unresponsive to I¹³¹.[1]



3. Resection of limited metastases, especially symptomatic metastases, should be considered when the tumor has no uptake of I¹³¹.



4. Thyroid-stimulating hormone suppression with thyroxine is also effective in many lesions not sensitive to I¹³¹.

Patients unresponsive to I¹³¹ should also be considered candidates for clinical trials testing new approaches to this disease.

Treatment options under clinical evaluation:

• Clinical trials evaluating new treatment approaches to this disease should also be considered for these patients. Chemotherapy has been reported to produce occasional complete responses of long duration.[2-4]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV papillary thyroid cancer ¹⁵ and stage IV follicular thyroid cancer ¹⁶. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Simpson WJ, Carruthers JS: The role of external radiation in the management of papillary and follicular thyroid cancer. Am J Surg 136 (4): 457-60, 1978.  [PUBMED Abstract]
   
   
2. Gottlieb JA, Hill CS Jr, Ibanez ML, et al.: Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients. Cancer 30 (3): 848-53, 1972.  [PUBMED Abstract]
   
   
3. Harada T, Nishikawa Y, Suzuki T, et al.: Bleomycin treatment for cancer of the thyroid. Am J Surg 122 (1): 53-7, 1971.  [PUBMED Abstract]
   
   
4. Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985.  [PUBMED Abstract]
   
   

Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. These tumors usually present as a mass in the neck or thyroid, often associated with lymphadenopathy,[1] or they may be diagnosed through screening family members. MTC can also be diagnosed by fine-needle aspiration biopsy. Cytology typically reveals hypercellular tumors with spindle-shaped cells and poor adhesion.[2]

The overall survival of patients with MTC is 86% at 5 years and 65% at 10 years. Poor prognostic factors include advanced age, advanced stage, prior neck surgery, and associated multiple endocrine neoplasia (MEN) 2B.[2-4]

Approximately 25% of reported cases of MTC are familial. Familial MTC syndromes include MEN 2A, which is the most common; MEN 2B; and familial non-MEN syndromes. (Refer to the PDQ summary on Genetics of Medullary Thyroid Cancer ⁵ for more information.) Any patient with a familial variant should be screened for other associated endocrine tumors, particularly parathyroid hyperplasia and pheochromocytoma. MTC can secrete calcitonin and other peptide substances. Determining the level of calcitonin is useful for diagnostic purposes and for following the results of treatment.

Family members should be screened for calcitonin elevation and/or for the RET proto-oncogene mutation to identify other individuals at risk for developing familial MTC. All patients with MTC (whether familial or sporadic) should be tested for RET mutations, and if they are positive, family members should also be tested. Whereas modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the RET mutation is the optimal approach. Family members who are gene carriers should undergo prophylactic thyroidectomy at an early age.[5,6]

Treatment options:

1. Thyroidectomy: Patients with medullary thyroid cancer should be treated with a total thyroidectomy, unless there is evidence of distant metastasis. In patients with clinically palpable medullary carcinoma of the thyroid, the incidence of microscopically positive nodes is more than 75%; routine central and bilateral modified neck dissections have been recommended.[7] When cancer is confined to the thyroid gland, the prognosis is excellent.



2. External radiation therapy: External radiation therapy has been used for palliation of locally recurrent tumors, without evidence that it provides any survival advantage.[8] Radioactive iodine has no place in the treatment of patients with MTC.



3. Palliative chemotherapy: Palliative chemotherapy has been reported to produce occasional responses in patients with metastatic disease.[9-12] No single drug regimen can be considered standard. Some patients with distant metastases will experience prolonged survival and can be managed expectantly until they become symptomatic.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with thyroid gland medullary carcinoma ¹⁷. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Soh EY, Clark OH: Surgical considerations and approach to thyroid cancer. Endocrinol Metab Clin North Am 25 (1): 115-39, 1996.  [PUBMED Abstract]
   
   
2. Giuffrida D, Gharib H: Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol 9 (7): 695-701, 1998.  [PUBMED Abstract]
   
   
3. Saad MF, Ordonez NG, Rashid RK, et al.: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 63 (6): 319-42, 1984.  [PUBMED Abstract]
   
   
4. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997.  [PUBMED Abstract]
   
   
5. Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994.  [PUBMED Abstract]
   
   
6. Decker RA, Peacock ML, Borst MJ, et al.: Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete? Surgery 118 (2): 257-63; discussion 263-4, 1995.  [PUBMED Abstract]
   
   
7. Moley JF, DeBenedetti MK: Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg 229 (6): 880-7; discussion 887-8, 1999.  [PUBMED Abstract]
   
   
8. Brierley JD, Tsang RW: External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 25 (1): 141-57, 1996.  [PUBMED Abstract]
   
   
9. Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985.  [PUBMED Abstract]
   
   
10. De Besi P, Busnardo B, Toso S, et al.: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest 14 (6): 475-80, 1991.  [PUBMED Abstract]
    
    
11. Wu LT, Averbuch SD, Ball DW, et al.: Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73 (2): 432-6, 1994.  [PUBMED Abstract]
    
    
12. Orlandi F, Caraci P, Berruti A, et al.: Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 5 (8): 763-5, 1994.  [PUBMED Abstract]
    
    

Anaplastic Thyroid Cancer

Standard treatment options:

1. Surgery: Tracheostomy is frequently necessary. If the disease is confined to the local area, which is rare, total thyroidectomy is warranted to reduce symptoms caused by the tumor mass.[1,2]



2. Radiation therapy: External-beam radiation therapy may be used in patients who are not surgical candidates or whose tumor cannot be surgically excised.



3. Chemotherapy: Anaplastic thyroid cancer is not responsive to I¹³¹ therapy; treatment with individual anticancer drugs has been reported to produce partial remissions in some patients. Approximately 30% of patients achieve a partial remission with doxorubicin.[3] The combination of doxorubicin plus cisplatin appears to be more active than doxorubicin alone and has been reported to produce more complete responses.[4]

Treatment options under clinical evaluation:

• The combination of chemotherapy plus radiation therapy in patients following complete resection may provide prolonged survival but has not been compared to any one modality alone.[5,6]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with anaplastic thyroid cancer ¹⁸. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Goldman JM, Goren EN, Cohen MH, et al.: Anaplastic thyroid carcinoma: long-term survival after radical surgery. J Surg Oncol 14 (4): 389-94, 1980.  [PUBMED Abstract]
   
   
2. Aldinger KA, Samaan NA, Ibanez M, et al.: Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 41 (6): 2267-75, 1978.  [PUBMED Abstract]
   
   
3. Carling T, Udelsman R: Thyroid tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1502-19. 
   
   
4. Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985.  [PUBMED Abstract]
   
   
5. 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 91 (12): 2335-42, 2001.  [PUBMED Abstract]
   
   
6. 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 60 (4): 1137-43, 2004.  [PUBMED Abstract]
   
   

Recurrent Thyroid Cancer

Patients treated for differentiated thyroid cancer should be followed carefully with physical examinations, serum quantitative thyroglobulin levels, and radiologic studies based on individual risk for recurrent disease.[1] Approximately 10% to 30% of patients thought to be disease-free after initial treatment will develop recurrence and/or metastases. Of these patients, approximately 80% develop recurrence with disease in the neck alone, and 20% develop recurrence with distant metastases. The most common site of distant metastasis is the lung. In a single series of 289 patients who developed recurrences after initial surgery, 16% died of cancer at a median time of 5 years following recurrence.[2]

The prognosis for patients with clinically detectable recurrences is generally poor, regardless of cell type.[3] Those patients who recur with local or regional tumor detected only by I¹³¹ scan, however, have a better prognosis.[4] The selection of further treatment depends on many factors, including cell type, uptake of I¹³¹, prior treatment, site of recurrence, and individual patient considerations. Surgery with or without I¹³¹ ablation can be useful in controlling local recurrences, regional node metastases, or, occasionally, metastases at other localized sites.[5] Approximately 50% of the patients operated on for recurrent tumors can be rendered free of disease with a second operation.[3] Local and regional recurrences detected by I¹³¹ scan and not clinically apparent can be treated with I¹³¹ ablation and have an excellent prognosis.[6]

Up to 25% of recurrences and metastases from well-differentiated thyroid cancer may not show I¹³¹ uptake. For these patients, other imaging techniques shown to be of value include imaging with thallium-201, magnetic resonance imaging, and pentavalent dimercaptosuccinic acid.[7] When recurrent disease does not concentrate I¹³¹, external-beam or intraoperative radiation therapy can be useful in controlling symptoms related to local tumor recurrences.[8] Systemic chemotherapy can be considered. Chemotherapy has been reported to produce occasional objective responses, usually of short duration.[4,9]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent thyroid cancer ¹⁹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹².

References

1. Ross DS: Long-term management of differentiated thyroid cancer. Endocrinol Metab Clin North Am 19 (3): 719-39, 1990.  [PUBMED Abstract]
   
   
2. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994.  [PUBMED Abstract]
   
   
3. Goretzki PE, Simon D, Frilling A, et al.: Surgical reintervention for differentiated thyroid cancer. Br J Surg 80 (8): 1009-12, 1993.  [PUBMED Abstract]
   
   
4. De Besi P, Busnardo B, Toso S, et al.: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest 14 (6): 475-80, 1991.  [PUBMED Abstract]
   
   
5. Pak H, Gourgiotis L, Chang WI, et al.: Role of metastasectomy in the management of thyroid carcinoma: the NIH experience. J Surg Oncol 82 (1): 10-8, 2003.  [PUBMED Abstract]
   
   
6. Coburn M, Teates D, Wanebo HJ: Recurrent thyroid cancer. Role of surgery versus radioactive iodine (I131) Ann Surg 219 (6): 587-93; discussion 593-5, 1994.  [PUBMED Abstract]
   
   
7. Mallin WH, Elgazzar AH, Maxon HR 3rd: Imaging modalities in the follow-up of non-iodine avid thyroid carcinoma. Am J Otolaryngol 15 (6): 417-22, 1994 Nov-Dec.  [PUBMED Abstract]
   
   
8. Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985.  [PUBMED Abstract]
   
   
9. Shimaoka K, Schoenfeld DA, DeWys WD, et al.: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 (9): 2155-60, 1985.  [PUBMED Abstract]
   
   

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