1. Chairman, Diabetes Steering Committee, AMG/NHP, Appleton, WI
Neoplastic Thyroid Disease: Thyroid Nodules, Goiter, and Thyroid Cancer
Thomas Repas D.O.
Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI
Chairman, Diabetes Steering Committee, AMG/NHP, Appleton, WI
Tuesday March 15, 2005
Website:

2. Neoplastic Thyroid Disease
Thyroid Nodules
Goiter
Multinodular
Diffuse
Endemic
Thyroid Cancer
Well differentiated and poorly differentiated

3. Thyroid Nodular Disease
Thyroid gland nodules are common in the general population
Palpable nodules occur in approximately 5% of the US population, mainly in women
Most thyroid nodules are benign
Less than 5% are malignant
Only 8% to 10% of patients with thyroid nodules have thyroid cancer
Thyroid Nodular Disease.
Thyroid nodules are the most common endocrine disorder.1,2 Although thyroid nodules commonly occur and their presence raises questions about malignancy, fewer than 5% are found to be malignant3 and only 8%-10% of patients with thyroid nodules have thyroid cancer.2 The prevalence of thyroid nodules is about 4%-7% in iodine-sufficient areas and much higher in iodine-deficient countries.2,4 Thyroid nodular disease is very common in the US, with palpable nodules occurring in approximately 5% of adults, especially women.5 The frequency of thyroid nodular disease increases throughout adult life.2 Nodules can be detected in an otherwise normal gland, but are especially prevalent in iodine-deficient areas in the form of multiple nodules in an enlarged thyroid gland (multinodular goiter).1 Toxic uninodular or multinodular goiter accounts for 10% to 40% of cases of hyperthyroidism and is more common in older patients.2
Thyroid nodules can be divided into 2 types: "hot" or autonomously functioning thyroid nodules (AFTN), and nonfunctioning or "cold" thyroid nodules (CTN).6 AFTN are characterized by nonautoimmune hyperthyroidism and nodular proliferation. CTN are without function and are less differentiated.6 A defect in the expression or structure of the NIS gene is thought to cause impaired iodide trapping in nonfunctioning CTN.1
References
Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:
2. Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1396.
3. Bennedbaek FN, et al. J Clin Endocrinol Metab. 2000;85:
4. Tonacchera M, et al. J Clin Endocrinol Metab. 1999;84:
5. Singer PA. Otolaryngol Clin North Am. 1996; 29:
6. Eszlinger M, et al. J Clin Endocrinol Metab. 2001;86:

4. Multinodular Goiter (MNG)
MNG is an enlarged thyroid gland containing multiple nodules
The thyroid gland becomes more nodular with increasing age
In MNG, nodules typically vary in size
Most MNGs are asymptomatic
MNG may be toxic or nontoxic
Toxic MNG occurs when multiple sites of autonomous nodule hyperfunction develop, resulting in thyrotoxicosis
Toxic MNG is more common in the elderly
Multinodular Goiter (MNG).
The thyroid gland becomes more nodular with age.1 MNG develops in an enlarged thyroid gland and is especially prevalent in populations in iodine-deficient areas.2 Thyroid enlargement may have progressed from a simple nontoxic goiter or have been associated with Hashimoto disease.3 MNG usually results from a low-grade, probably intermittent stimulus to the thyroid gland from iodine deficiency, goitrogens (foods that induce hypothyroidism and goiter in the diet such as cabbage, broccoli, cauliflower, and brussels sprouts),4 decreased thyroid hormone production, or an autoimmune disease, which causes multiplication and growth of small groups of thyroid cells.3 After Graves disease, toxic multinodular goiter (TMG) is the most common cause of hyperthyroidism5 and thyrotoxicosis in the elderly.6 TMG occurs most often in patients aged 50 or older and mainly in women, when the nodules in a nontoxic MNG become autonomous5 and function independent of TSH stimulation.7 It is very prevalent in geographic regions with iodine deficiency and rarely occurs in places where iodine intake is sufficient. Thyroid autonomy is most frequently found in TMGs.7 Patients are often asymptomatic or very mildly toxic, and have a goiter, and lab findings that indicate suppressed TSH with normal FT4 and T3 levels.5
References
1. Hurley DL, et al. Geriatrics. 1995;50:24-26,29-31.
2. Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:
3. Bayliss RIS, Tunbridge WMG. Thyroid Disease: the Facts. 3rd ed. Oxford, UK: Oxford University Press; 1998:121.
4. Stoewsand GS. Food Chem Toxicol. 1995;33:
5. Fisher JN. South Med J. 2002;95:
6. Vitti P, et al. J Endocrinol Invest. 2002;25(10 Suppl):16-18.
7. Krohn K, et al. J Clin Endocrinol Metab. 2001;86:

5. Endemic Goiter No longer a problem in the US and the developed world
Still a serious health concern in parts of the world with iodine deficiency including mountainous areas or areas with high rainfall/flooding
Kaplan, E. et al. Thyroid Disease Manager “Surgery of the Thyroid Gland” Chapter 21, May 99

6. Thyroid Carcinoma Incidence
Thyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid disease
Thyroid cancers account for only 0.74% of cancers among men, and 2.3% of cancers in women in the US
The annual rate has increased nearly 50% since 1973 to approximately cases
Thyroid carcinomas (percentage of all US cases)
Papillary (80%)
Follicular (about 10%)
Medullary thyroid (5%-10%)
Anaplastic carcinoma (1%-2%)
Primary thyroid lymphomas (rare)
Metastatic from other primary sites (rare)
Thyroid Carcinoma.
The annual rate of thyroid cancer in the United States has risen nearly 50% since 1973, striking approximately people.1 Thyroid cancers account for about 90% of newly diagnosed endocrine malignancies and cause about 1200 deaths each year.1,2 Thyroid carcinoma is 3 times more common in women than in men.3 Thyroid cancer mortality rates fell significantly (20%) in the US between 1973 and 1996, most likely because of early diagnosis and effective treatment of the common forms of thyroid cancer.1 The decline in mortality was seen only in women, possibly because they undergo routine medical examinations more frequently than men.1
Thyroid cancers comprise 4 carcinoma and 2 miscellaneous types (percentage of thyroid neoplasms in the US): papillary (80%), follicular (about 10%), medullary (5%-10%), and anaplastic carcinomas (1%- 2%); plus primary thyroid lymphoma and sarcoma (rare).3 Anaplastic thyroid carcinomas are invasive and almost always fatal.2 Papillary and follicular thyroid cancers are referred to as differentiated thyroid cancer (DTC), which is usually curable when discovered at an early stage.1 DTC comprises 90% of thyroid cancers and 70% of thyroid cancer deaths.1 A known cause of thyroid carcinoma is low-dose radiation exposure.4 The risk is increased in women, who have a 40% higher rate of radiation-induced thyroid cancer than men, and if radiation exposure occurs before15 years of age.4 Ninety percent of radiation-induced thyroid cancers are papillary thyroid carcinoma; the remaining 9%-10% are follicular carcinomas. Anaplastic or medullary carcinomas are rare.4
References
1. Mazzaferri E, et al. J Clin Endocrinol Metab. 2001;86:
2. Heaney AT, et al. J Clin Endocrinol Metab. 2001;86:
3. Sharma PK, Johns MM. Thyroid cancer. [eMedicine Specialties Web site]. September 14, Available at Accessed July 2, 2003.
4. Yeung S-CJ. Endocr Rev. 1998;19:

7. Initial Evaluation of a Thyroid Nodule/Mass

8. Risk factors for Malignancy
Solitary thyroid nodules in patients >60 or <30 years of age
Irradiation of the neck or face during infancy or teenage years
Symptoms of pain or pressure (especially a change in voice)
Male sex
Large Nodules (>3 or 4 cm)
Growth of nodule

9. Evaluating Thyroid Nodules
TSH measurement
Ultrasound of the thyroid
Fine needle aspiration
Radioactive iodine imaging
Evaluating Thyroid Nodules.
Evaluation of a thyroid nodule begins with an assessment of the underlying function of the thyroid with a TSH measurement.1 A low TSH level suggests a hyperfunctioning nodule, which is unlikely to be malignant and can be diagnosed readily with RAI scanning.1 If TSH is elevated, levothyroxine sodium (LT4) therapy is used to return the TSH to normal levels before additional evaluation of the nodule.2 In many cases with elevated TSH, the palpable nodule is indicative of Hashimoto’s thyroiditis, and it resolves after several weeks of LT4 therapy.2 Nodules that persist after adequate LT4 replacement therapy for several weeks should be re-evaluated.
Following the functional assessment, a structural assessment of the thyroid should be done by physical examination and thyroid ultrasound.1 The thyroid ultrasound provides valuable information on the location and size of the thyroid nodule.1
After the nodule is localized in the thyroid, fine needle aspiration (FNA) is the most cost-effective method for distinguishing between benign and malignant nodules.1 Because only 5% of all nodules are malignant, most FNA tests will identify benign nodules.3 Approximately 5% of FNA samples will be frankly malignant.2 Approximately 10% of FNAs have an adequate cell sample, but cytological features of the thyroid cells are not sufficient for differentiating between benign and malignant nodules, particularly in follicular lesions in which the cellular architecture of benign follicular cells and FTC are very similar.3 These lesions can only be differentiated on the basis of vascular or capsular invasion and therefore require surgical removal and careful histological evaluation of the nodule. Occasionally, an FNA will not yield an adequate thyroid follicular cell sample for evaluation, and these samples are deemed inadequate to make a definitive diagnosis.3 Usually, the FNA is repeated in order to obtain an adequate number of thyroid cells for evaluation.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Castro MR, et al. Endocr Pract. 2003;9:
Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Castro MR, et al. Endocr Pract. 2003;9:

10. Thyroid Ultrasonography
Evaluating Thyroid Nodules.
Evaluation of a thyroid nodule begins with an assessment of the underlying function of the thyroid with a TSH measurement.1 A low TSH level suggests a hyperfunctioning nodule, which is unlikely to be malignant and can be diagnosed readily with RAI scanning.1 If TSH is elevated, levothyroxine sodium (LT4) therapy is used to return the TSH to normal levels before additional evaluation of the nodule.2 In many cases with elevated TSH, the palpable nodule is indicative of Hashimoto’s thyroiditis, and it resolves after several weeks of LT4 therapy.2 Nodules that persist after adequate LT4 replacement therapy for several weeks should be re-evaluated.
Following the functional assessment, a structural assessment of the thyroid should be done by physical examination and thyroid ultrasound.1 The thyroid ultrasound provides valuable information on the location and size of the thyroid nodule.1
After the nodule is localized in the thyroid, fine needle aspiration (FNA) is the most cost-effective method for distinguishing between benign and malignant nodules.1 Because only 5% of all nodules are malignant, most FNA tests will identify benign nodules.3 Approximately 5% of FNA samples will be frankly malignant.2 Approximately 10% of FNAs have an adequate cell sample, but cytological features of the thyroid cells are not sufficient for differentiating between benign and malignant nodules, particularly in follicular lesions in which the cellular architecture of benign follicular cells and FTC are very similar.3 These lesions can only be differentiated on the basis of vascular or capsular invasion and therefore require surgical removal and careful histological evaluation of the nodule. Occasionally, an FNA will not yield an adequate thyroid follicular cell sample for evaluation, and these samples are deemed inadequate to make a definitive diagnosis.3 Usually, the FNA is repeated in order to obtain an adequate number of thyroid cells for evaluation.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Castro MR, et al. Endocr Pract. 2003;9:

11. Thyroid Ultrasonography
Excellent for characterizing size and other features of nodule
Useful in localizing nodule for FNA
Cannot distinguish between benign vs. malignant
Evaluating Thyroid Nodules.
Evaluation of a thyroid nodule begins with an assessment of the underlying function of the thyroid with a TSH measurement.1 A low TSH level suggests a hyperfunctioning nodule, which is unlikely to be malignant and can be diagnosed readily with RAI scanning.1 If TSH is elevated, levothyroxine sodium (LT4) therapy is used to return the TSH to normal levels before additional evaluation of the nodule.2 In many cases with elevated TSH, the palpable nodule is indicative of Hashimoto’s thyroiditis, and it resolves after several weeks of LT4 therapy.2 Nodules that persist after adequate LT4 replacement therapy for several weeks should be re-evaluated.
Following the functional assessment, a structural assessment of the thyroid should be done by physical examination and thyroid ultrasound.1 The thyroid ultrasound provides valuable information on the location and size of the thyroid nodule.1
After the nodule is localized in the thyroid, fine needle aspiration (FNA) is the most cost-effective method for distinguishing between benign and malignant nodules.1 Because only 5% of all nodules are malignant, most FNA tests will identify benign nodules.3 Approximately 5% of FNA samples will be frankly malignant.2 Approximately 10% of FNAs have an adequate cell sample, but cytological features of the thyroid cells are not sufficient for differentiating between benign and malignant nodules, particularly in follicular lesions in which the cellular architecture of benign follicular cells and FTC are very similar.3 These lesions can only be differentiated on the basis of vascular or capsular invasion and therefore require surgical removal and careful histological evaluation of the nodule. Occasionally, an FNA will not yield an adequate thyroid follicular cell sample for evaluation, and these samples are deemed inadequate to make a definitive diagnosis.3 Usually, the FNA is repeated in order to obtain an adequate number of thyroid cells for evaluation.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Castro MR, et al. Endocr Pract. 2003;9:

12. Thyroid Ultrasonography
Certain features may suggest greater risk of cancer:
Irregular or poorly defined borders of nodule
Lack of a "halo“
Hypo-echogenicity
Evidence of microcalcifications
Increased blood flow
Growth and interval change on serial ultrasounds
Evaluating Thyroid Nodules.
Evaluation of a thyroid nodule begins with an assessment of the underlying function of the thyroid with a TSH measurement.1 A low TSH level suggests a hyperfunctioning nodule, which is unlikely to be malignant and can be diagnosed readily with RAI scanning.1 If TSH is elevated, levothyroxine sodium (LT4) therapy is used to return the TSH to normal levels before additional evaluation of the nodule.2 In many cases with elevated TSH, the palpable nodule is indicative of Hashimoto’s thyroiditis, and it resolves after several weeks of LT4 therapy.2 Nodules that persist after adequate LT4 replacement therapy for several weeks should be re-evaluated.
Following the functional assessment, a structural assessment of the thyroid should be done by physical examination and thyroid ultrasound.1 The thyroid ultrasound provides valuable information on the location and size of the thyroid nodule.1
After the nodule is localized in the thyroid, fine needle aspiration (FNA) is the most cost-effective method for distinguishing between benign and malignant nodules.1 Because only 5% of all nodules are malignant, most FNA tests will identify benign nodules.3 Approximately 5% of FNA samples will be frankly malignant.2 Approximately 10% of FNAs have an adequate cell sample, but cytological features of the thyroid cells are not sufficient for differentiating between benign and malignant nodules, particularly in follicular lesions in which the cellular architecture of benign follicular cells and FTC are very similar.3 These lesions can only be differentiated on the basis of vascular or capsular invasion and therefore require surgical removal and careful histological evaluation of the nodule. Occasionally, an FNA will not yield an adequate thyroid follicular cell sample for evaluation, and these samples are deemed inadequate to make a definitive diagnosis.3 Usually, the FNA is repeated in order to obtain an adequate number of thyroid cells for evaluation.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Castro MR, et al. Endocr Pract. 2003;9:

13. RAI imaging
Formerly had been used extensively in the initial work up of nodular thyroid disease
FNA is now considered the gold standard

14. RAI imaging The problem:
Although “hot” nodules are usually never cancer, only 5% of all nodules are hyperfunctioning
The remaining 90-95% that are warm or cold could be cancer and thus require FNA

15. RAI imaging
Circumstances where RAI imaging may be useful and indicated:
Suppressed TSH (more likely to have a autonomously functioning nodule)
Multiple nodules, none dominant
Other
Evaluating Thyroid Nodules.
Evaluation of a thyroid nodule begins with an assessment of the underlying function of the thyroid with a TSH measurement.1 A low TSH level suggests a hyperfunctioning nodule, which is unlikely to be malignant and can be diagnosed readily with RAI scanning.1 If TSH is elevated, levothyroxine sodium (LT4) therapy is used to return the TSH to normal levels before additional evaluation of the nodule.2 In many cases with elevated TSH, the palpable nodule is indicative of Hashimoto’s thyroiditis, and it resolves after several weeks of LT4 therapy.2 Nodules that persist after adequate LT4 replacement therapy for several weeks should be re-evaluated.
Following the functional assessment, a structural assessment of the thyroid should be done by physical examination and thyroid ultrasound.1 The thyroid ultrasound provides valuable information on the location and size of the thyroid nodule.1
After the nodule is localized in the thyroid, fine needle aspiration (FNA) is the most cost-effective method for distinguishing between benign and malignant nodules.1 Because only 5% of all nodules are malignant, most FNA tests will identify benign nodules.3 Approximately 5% of FNA samples will be frankly malignant.2 Approximately 10% of FNAs have an adequate cell sample, but cytological features of the thyroid cells are not sufficient for differentiating between benign and malignant nodules, particularly in follicular lesions in which the cellular architecture of benign follicular cells and FTC are very similar.3 These lesions can only be differentiated on the basis of vascular or capsular invasion and therefore require surgical removal and careful histological evaluation of the nodule. Occasionally, an FNA will not yield an adequate thyroid follicular cell sample for evaluation, and these samples are deemed inadequate to make a definitive diagnosis.3 Usually, the FNA is repeated in order to obtain an adequate number of thyroid cells for evaluation.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Castro MR, et al. Endocr Pract. 2003;9:

16. Thyroid FNA
Now considered the most cost effective and sensitive/specific diagnostic test of thyroid nodules
The use of US has expanded the role of FNA in evaluating nodules and improved the validity of the results

17. Possible FNA Results Thyroid FNA Benign: 70 -75 % Malignant: Up to 5%
Suspicious: About 10%
Nondiagnostic: About %

18. Thyroid FNA Limitations
False negatives: (< 5% of FNA) more likely in large (>4cm) or small (<1cm) nodules
Suspicious FNA (Follicular and Hurhtle cell neoplasm): cannot distinguish benign vs malignant of hypercellular nodules by FNA alone, ALWAYS require surgical pathology for dx (up to 10 – 30% of these will be CA)
Non-diagnostic results: NEVER consider equivalent to benign, up to 10% of ND FNA will contain CA on resection

19. Management and Follow up

20. Management of Thyroid Nodules
Depends on FNA results (see algorithm)
Benign:
False negatives rare, but be cautious in large (>4cm) or small nodules (<1cm) , repeat US in 6 to 12 months to assess for interval change
Consider surgical resection if change or suspicious
Malignant:
Surgery and RAI ablation

21. Suspicious FNA About 10% of all FNA results
CANNOT distinguish benign vs malignant of hypercellular nodules (follicular/Hurthle cell) by FNA alone
ALWAYS require surgical resection for dx
Up to 10 – 30% of these will be malignant

22. Non-diagnostic FNA About 15% of all FNA results
NEVER consider equivalent to benign FNA
Up to 10% of ND FNA will contain CA on resection
Be very cautious of a pathology report: “consistent with benign colloid nodule”; if limited/no follicular epithelial cells noted, then this is a ND FNA rather than benign

23. Non-diagnostic FNA cont’d
Three options:
Repeat FNA now- may get valid FNA on repeat up to 30 – 50% of the time
Follow-up US in 6 months, repeat FNA or resect then if any interval change
Surgical resection now- usually reserved only for patients with history suggestive of increased risk or patients who are very anxious and do not want to wait

24. LT4 Suppression of Thyroid Nodules

25. LT4 Suppression of Nodules
Although once more commonly used, it has begun to fall out of favor
Some endocrinologists still recommend LT4 suppression for a TSH between 0.1 – 0.5
However, studies demonstrate lack of efficacy or improved outcome
There is significant risks associated with long term iatrogenic hyperthyroidism (loss of bone density, arrhythmias in the elderly, etc.)

26. LT4 Suppression of Goiter
Patients with a MNG especially could later develop an autonomously functioning nodule with subsequent thyrotoxicosis if not followed closely
Is useful for goiter suppression in patients with subclinical or overt hypothyroidism
May also have a role in goiter patients with TSHs in the upper limits of normal (>3.0) who also have + thyroid autoantibodies (controversial)

27. Thyroid Carcinoma

28. Typical Presentation of Thyroid Cancer
Painless lump
Normal thyroid function tests
Found on routine examination or by the patient
Slow growth or no growth over several months
Typical Presentation of Thyroid Cancer.
Most thyroid cancers present in clinically euthyroid patients who have normal thyroid function tests. These tests, including those measuring thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3), are measurements of the functional status of the thyroid and provide no information on the presence or absence of structural disease of the thyroid (eg, nodules).1
A mass in the thyroid may be found during a routine examination by a health care provider or may be noted by the patient.1 Often thyroid cancer is present in a nodule for months or years with only minimal growth.2 Thus, lack of consistent nodule size over long periods of time does not rule out the presence of thyroid cancer.3
References
1. Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
2. Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
3. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33.
Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:

29. Newly Diagnosed Cancer in the United States
Thyroid Cancer
new cases
1400 deaths
Newly Diagnosed Cancer in the United States.
Although the incidence of thyroid cancer is not as high as that of lung, breast, or prostate cancer, the number of thyroid cases diagnosed annually is comparable to the number of cases of multiple myeloma, kidney cancer, and leukemia diagnosed each year.1
In 2003, an estimated new cases of thyroid cancer will be diagnosed and an estimated 1400 patients will die of thyroid cancer.1
Reference
1. Cancer facts and figures. American Cancer Society Web site. Available at: Accessed December 10, 2003.
Cancer facts and figures. American Cancer Society Web site. Available at: Accessed December 10, 2003.
New Cases, Thousands

30. Types of Thyroid Cancer
Papillary (80%-85%): develops from thyroid follicle cells in 1 or both lobes; grows slowly but can spread
Follicular (5%-10%): common in countries with insufficient iodine consumption; lymph node metastases are uncommon
Medullary: develops from C-cells, can spread quickly; sporadic and familial types
Anaplastic: develops from existing papillary or follicular cancers; aggressive, usually fatal
Lymphoma: develops from lymphocytes; uncommon
Types of Thyroid Cancer.
Thyroid cancer is more common in women than in men, and occurs most frequently in individuals between 35 and 45 years of age. There are several types of thyroid cancer.1 Papillary thyroid cancer (PTC) is the most common form, comprising 80% to 85% of thyroid cancers. Papillary thyroid cancer and follicular thyroid cancer (FTC) arise from thyroid follicle cells. Papillary thyroid cancer is frequently a multifocal and bilateral disease while follicular thyroid cancer tends to present as a single focus within the thyroid gland.2 Papillary cancers grow slowly, but often spread to regional cervical lymph nodes.
Follicular thyroid cancer accounts for approximately 5% to 10% of thyroid cancers.1 It is more common in countries where the population does not have sufficient iodine intake.1 Follicular cancer infrequently spreads to regional cervical nodes, but can spread to the lungs and bones.1
Medullary thyroid cancer (MTC) develops from the C-cells and can spread quickly to the lymph nodes, lungs, or liver before a thyroid nodule is detected.1 Medullary cancer can either be sporadic or can arise as a part of a number of genetic syndromes associated with endocrine abnormalities, including hyperparathyroidism and pheochromocytoma (such as multiple endocrine neoplasia [MEN] 2 syndrome).1
Anaplastic thyroid cancer (ATC) is uncommon, and is believed to develop from existing papillary or follicular carcinomas.1 Anaplastic thyroid cancer is one of the most aggressive and lethal of all solid malignancies. In most series, 3-year survival rates were less than 10%.3
Thyroid lymphoma is a rare disease that usually arises in the setting of pre-existing chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis).2
References
1. Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.
Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.

31. Papillary Thyroid Cancer
Most common type
Makes up about 80% of all thyroid carcinomas in the United States
Females outnumber males 3:1
Highest incidence in women in midlife
Papillary Thyroid Cancer.
Papillary thyroid cancer is the most common type of thyroid cancer and accounts for approximately 80% to 85% of all diagnosed thyroid cancers in the United States.1
Papillary thyroid cancer has a 3-fold higher incidence in women than in men, and has a peak incidence in the third and fourth decades of life.2
Approximately two thirds of PTC is found to have follicular elements and is often classified histologically as a follicular variant of papillary thyroid carcinoma.2
References
1. Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.
2. Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.
Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.

32. Papillary Thyroid Cancer Characteristics
Unencapsulated tumor nodule with ill-defined margins
Tumor typically firm and solid
May present as nodal enlargement
Commonly metastasizes to neck and mediastinal lymph nodes
40% to 60% in adults and 90% in children
<5% of patients have distant metastases at time of diagnosis
Lung is most common site
Papillary Thyroid Cancer. Characteristics.
Approximately 80% to 90% of PTC cases are comprised of unencapsulated or partially encapsulated tumor nodules with poorly defined margins.1
Papillary thyroid tumors are typically firm and solid. They may be associated with a loss of differentiation that suggests an aggressive neoplasm in middle-aged or elderly patients.1
The tall cell variant is a more aggressive form of PTC compared with the standard PTC variety.1,2 It comprises approximately 10% of total cases2 and some of the tumors are composed of cells with oncocytic cytoplasm.1
Papillary thyroid cancer may present as a nodal enlargement and usually metastasizes in the neck and mediastinal lymph nodes.2 Fewer than 5% of patients have distant metastases at the time of diagnosis, and metastases most often appear in the lungs.2
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000
Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.

33. Follicular Thyroid Cancer
Second most common type of thyroid cancer
Solid invasive tumors, usually solitary and encapsulated
Usually stays in the thyroid gland, but can spread to the bones, lungs, and central nervous system
Usually does not spread to the lymph nodes
Follicular Thyroid Cancer.
Follicular thyroid cancer is the second most common type of thyroid cancer, accounting for approximately 15% of all thyroid cancers.1 Its peak incidence is in the fifth decade of life in patients living in the United States and it occurs more frequently in women.1
Follicular thyroid cancer usually presents as a fleshy, solid, encapsulated mass that is sometimes focally fibrotic and calcified.2 These tend to be slow-growing tumors and are usually recognized prior to metastasis as a nodule in the thyroid gland.2
Follicular thyroid cancers with only minimal capsular invasion (minimally invasive FTCs) rarely spread to distant sites and are often cured with surgical resection. However, follicular cancers with widespread capsular invasion and/or vascular invasion are more likely to spread to the skeleton, lungs, brain, and other tissues.2 These neoplasms rarely spread to cervical lymph nodes.3
References
1. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.
Follicular Thyroid Cancer
Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.

34. Follicular Thyroid Cancer Diagnosis and Prognosis
Most FTCs present as an asymptomatic neck mass
If caught early, this type of thyroid cancer is often curable
Tumors >3 cm have a much higher mortality rate
Follicular Thyroid Cancer. Diagnosis and Prognosis.
Most FTCs present as an asymptomatic neck mass.1 Treatment requires surgically removing as much of the thyroid gland as possible and destroying any remaining thyroid tissue, including the metastases, with radioactive iodine (RAI).2 Follicular thyroid cancer is usually curable, but is less so than papillary cancer, and patients with tumors larger than 3 cm have a higher mortality rate as compared with patients who have smaller tumors.3,4 Of the patients who die from FTC, three fourths do so because of distant metastases while only one fourth die from locally invasive disease.3
References
1. Hebra A, et al. Solitary thyroid nodule. eMedicine Web site. Available at: Accessed December 10, 2003.
2. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
3. DeGroot LJ, et al. J Clin Endocrinol Metab. 1990;71:
4. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY:Marcel Dekker, Inc.; 2001:
Hebra A, et al. Solitary thyroid nodule. eMedicine Web site. Available at: Accessed December 10, 2003.
Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
DeGroot LJ, et al. J Clin Endocrinol Metab. 1990;71:
Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY:Marcel Dekker, Inc.: 2001;

35. High power magnification
Hürthle Cell Cancer
A variant of follicular cancer that tends to be aggressive
Represents about 3% to 5% of all types of thyroid cancer
Hürthle Cell Tumor
Hürthle Cell Cancer.
Hürthle cell cancer is a rare type of thyroid cancer that accounts for 3% to 10% of all thyroid cancers.1 It is an aggressive cancer that tends to poorly concentrate RAI.1,2
Scattered benign Hürthle cells are frequently seen in chronic lymphocytic thyroiditis, multinodular goiter, and subacute thyroiditis.1 However, Hürthle cell neoplasms are hypercellular nodules, with a predominance of Hürthle cells (greater than 75%), few or no lymphocytes, and scanty or absent colloid.1 The presence of an invasion of blood vessels or of the tumor capsule differentiates a malignant Hürthle carcinoma from a benign Hürthle cell adenoma.1
References
1. Aytug S, et al. Hürthle cell carcinoma. eMedicine Web site. Available at: Accessed December 10, 2003.
2. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY:Marcel Dekker, Inc.; 2001:
High power magnification
Aytug S, et al. Hürthle cell carcinoma. eMedicine Web site. Available at: Accessed December 10, 2003.
Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY: Marcel Dekker, Inc.: 2001:

36. Hürthle Cell Cancer Prognosis
May be benign or malignant, based on demonstration of vascular or capsular invasion
Malignancies tend to have a worse prognosis than other follicular tumors and rarely respond to 131I therapy
Tend to be locally invasive
Hürthle Cell Cancer. Prognosis.
Hürthle cell carcinomas can metastasize to regional lymph nodes as well as spread hematogenously.1 In addition, they are invasive and the capsule and blood vessels should be assessed for invasion.1,2
Patients with malignant Hürthle cell carcinomas have a decreased survival prognosis compared with patients who have other follicular tumors.2 Hürthle cell carcinomas rarely respond to RAI therapy, so the discovery of a Hürthle cell cytology should lead to surgical resection of the lesion; however, there is a strong likelihood of recurrence following surgery.1,2
Caplan et al3 found that 4.4% of Hürthle cell cancers were hot on scan and 8.9% were warm.
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Mazzaferri EL. Thyroid carcinoma: papillary and follicular. In: Mazzaferri, EL, Samaan N, eds. Endocrine Tumors. Cambridge, MA: Blackwell; 1993:
3. Caplan RH, et al. Thyroid. 1994;4:
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Mazzaferri EL. Thyroid carcinoma: papillary and follicular. In: Mazzaferri, EL, Samaan N, eds. Endocrine Tumors. Cambridge, MA: Blackwell; 1993:

37. Anaplastic Thyroid Cancer
Extremely aggressive and exceptionally virulent
Composed wholly or in part of undifferentiated cells
Anaplastic Thyroid Cancer.
Fewer than 10% of thyroid carcinomas are classified as anaplastic.1 These tumors are commonly of the spindle cell and giant cell types.1 They are aggressive neoplasms that usually occur in the elderly and in women.1 They are composed wholly or in part of undifferentiated cells and demonstrate a high incidence of remnants of well-differentiated FTC or PTC.1,2
Anaplastic thyroid cancer does not concentrate RAI and is often treated primarily with external beam irradiation and chemotherapy.2,3 Despite an initial response to external beam irradiation, local recurrence is expected in most patients.2,3 This local recurrence usually results in the death of the patient in less than 1 year from the time of diagnosis.3
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Sherman SI. Lancet. 2003;361:
3. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Sherman SI. Lancet. 2003;361:
Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.

38. Anaplastic Thyroid Cancer (Continued)
Tumor is typically hard, poorly circumscribed, and fixed to surrounding structures
Often occurs in the elderly population (mean age: 65 years)
3-fold greater risk in iodine-deficient areas
Anaplastic Thyroid Cancer (continued).
Anaplastic thyroid tumors are hard, poorly circumscribed, pale, and fixed to surrounding structures.1 They most often occur in elderly patients and are most common in regions of the world where iodine is deficient, which causes a 3-fold greater risk of occurrence in those populations.1
Reference
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

39. Medullary Thyroid Cancer
Tumor arising from the calcitonin-secreting C-cells of the thyroid gland
Mortality rate of 10% to 20% at 10 years
Medullary (C-cell) Carcinoma
Medullary Thyroid Cancer.
Medullary thyroid cancer is associated with C-cell proliferation, causing tumors that appear from the calcitonin-secreting C-cells of the thyroid gland.1,2 Medullary thyroid cancer constitutes approximately 5% of thyroid cancers and has a mortality rate of 10% to 20% at 10 years.1-3
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Sherman SI. Lancet. 2003;361:
3. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Sherman SI. Lancet. 2003;361:
Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.

40. Medullary Thyroid Cancer Types
70% to 80% of cases are sporadic disease (median age=51 years)
20% to 30% are part of 3 familial autosomal dominant syndromes (MEN-2A, MEN-2B, or familial non-MEN medullary thyroid cancer [median age=21 years])
Medullary Thyroid Cancer. Types.
Sporadic cases of MTC involve only 1 lobe of the thyroid and are not associated with other endocrine lesions.1 Fortunately, 70% to 80% of MTC cases are sporadic and not associated with other endocrine diseases.1,2 The second type is called familial MTC and occurs in approximately 20% to 30% of MTC cases.1,2
The combination of familial MTC and tumors of certain other organs is called type 2 MEN,2 which has 2 subtypes: MEN-2A and MEN-2B.2 In MEN-2A, MTC is associated with bilateral pheochromocytomas and parathyroid hyperplasia.2 In MEN-2B, MTC is associated with pheochromocytoma but not with parathyroid gland disease.1,2 The classic appearance of MEN-2B patients includes mucosal and cutaneous neuromas and skeletal abnormalities.1
In these familial forms of MTC, the cancer may develop during childhood or early adulthood and can spread to the lymph nodes, lungs, or liver.1,2
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: Accessed December 10, 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: Accessed December 10, 2003.

41. Medullary Thyroid Cancer Metastases
Cervical lymph node metastases occur early
Tumors >1.5 cm are likely to metastasize, often to bone, lungs, liver, and the central nervous system
Metastases usually contain calcitonin and stain for amyloid
Medullary Thyroid Cancer. Metastases.
In MTC, cervical lymph node metastases occur early and tumors larger than 1.5 cm are likely to metastasize and spread.1,2 Medullary thyroid cancer can also spread to the skeleton, lungs, liver, and the central nervous system.1
The metastases that occur with MTC usually contain calcitonin, which is found in the C-cell, or carcinoembryonic antigen (CEA).3 Both calcitonin and CEA are released into the blood and can be detected with a blood test.3
References
1. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.
2. Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
3. Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: Accessed December 10, 2003.
Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.
Thyroid gland disorders. Beers MH, Fletcher AJ, Jones TV, et al, eds. Merck Manual of Medical Information – Home Edition. 2nd ed. Whitehouse Station, NJ: Merck & Co., Inc.; 2003.
Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: Accessed December 10, 2003.

42. Primary Thyroid Lymphoma
A rare type of thyroid cancer
Affects fewer than 1 in 2 million people
Constitutes 5% of thyroid malignancies
Large Cell Lymphoma of the Thyroid
Primary Thyroid Lymphoma.
Primary thyroid lymphoma (PTL) is a rare form of thyroid cancer that usually arises in the setting of chronic lymphocytic thyroiditis. The tumors usually appear as rapidly enlarging masses that develop over a period of time ranging from several days to a few weeks.1
Primary thyroid lymphoma affects fewer than 1 in 2 million people, constitutes approximately 5% of thyroid cancers, and is 2 to 3 times more common in women than in men.2
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Cabanillas F. Thyroid lymphoma. eMedicine Web site. Available at: Accessed December 10, 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Cabanillas F. Thyroid lymphoma. eMedicine Web site. Available at: Accessed December 10, 2003.

43. Primary Thyroid Lymphoma Characteristics and Diagnosis
Develops in the setting of pre-existing lymphocytic thyroiditis
Often diagnosed because of airway obstruction symptoms
Tumors are firm, fleshy, and usually pale
Primary Thyroid Lymphoma. Characteristics and Diagnosis.
Patients may have a history of diffuse goiter (probably the result of an autoimmune thyroiditis) that suddenly increases in size,1 and PTL is often diagnosed because of symptoms of airway obstruction.1
Examination reveals PTL tumors to be firm, fleshy tissues that are usually pale,2 and many patients who have PTL present with pain, hoarseness, dysphagia, dyspnea, or stridor. In rare cases, patients have superior vena cava syndrome.1
The mainstay of treatment for PTL is chemotherapy.3 Thyroidectomy is rarely indicated for thyroid lymphoma.3
References
1. Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
2. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
3. Ansell SM, et al. Semin Oncol. 1999;26:
Thyroid Disease Manager Web site. Available at: Accessed December 10, 2003.
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Ansell SM, et al. Semin Oncol. 1999;26:

44. Newly Detected and Fatal Cases of Thyroid Cancer
Thyroid Cancer Cases
Diagnosed in 2000
(N= )
Deaths by 2010
(N=1426)
Anaplastic 11%
Hürthle 4%
Anaplastic 1%
Papillary
50%
Hürthle
12%
Follicular
14%
Newly Detected and Fatal Cases of Thyroid Cancer.
These graphs show the percentage of new cases and deaths caused by carcinomas arising from thyroid follicular cells (ie, excluding lymphoma and medullary carcinomas).1 Hürthle cell cancer is a subtype of follicular cancer.2
Because anaplastic thyroid cancer has a high mortality rate, many clinicians assume that most deaths from thyroid cancer are caused by these aggressive variants of thyroid cancer.3 However, because more new cases of PTC and FTC are diagnosed each year than other types of thyroid cancer, the majority of thyroid cancer deaths occur in patients initially diagnosed with these cancers.4 This is true despite the fact that PTC and FTC have 10-year disease-specific mortality rates of less than 10%.5
Long-term follow-up is required in all patients with thyroid cancer in order to detect the disease at an early stage and minimize the risk of death.2
References
1. Robbins R, et al. Adv Intern Med. 2001;46:
2. Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: Accessed December 10, 2003.
3. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: Accessed December 10, 2003.
4. Incidence and prevalence. Thyroid Community Web site. Available at: Accessed December 10, 2003.
5. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2003;86:
Follicular
27%
Papillary
80%
Robbins R, et al. Adv Intern Med. 2001;46:

45. Recurrence and Death After Diagnosis of Thyroid Cancer
In a study conducted by Mazzaferri et al in patients with papillary and follicular thyroid cancer, the 30-year disease-specific mortality rate was slightly less than 10%.1 However, recurrences occur in 20% to 30% of patients and may not become clinically apparent until 20 to 30 years after diagnosis.1 Therefore, lifelong follow-up for detection and treatment of recurrent thyroid cancer is mandatory for all patients with thyroid cancer.1
Reference
1. Mazzaferri EL, et al. Am J Med. 1994;97:
N=1355
Mazzaferri EL, et al. Am J Med. 1994;97:

46. Etiology of Thyroid Cancers
Usually unknown
Radiation exposure
Medical uses during childhood in the 1950s
Current medical uses in cancer therapy
Nuclear accidents
Etiology of Thyroid Cancer.
The cause of thyroid cancer is unknown in the majority of patients who develop thyroid cancer. One well-known risk factor for the development of thyroid cancer is exposure to ionizing radiation during childhood.
External beam radiation was widely used for the treatment of many benign and malignant conditions of the head and neck during the 1950s and 1960s.1 By the 1970s, it was recognized that external beam radiation treatment in children was associated with a dramatic rise in thyroid cancer 10 to 20 years after exposure.1 Currently, external beam irradiation is used in the treatment of head and neck cancers, and patients who receive this form of therapy are at risk for developing hypothyroidism, benign thyroid nodules, and thyroid cancer for several years after treatment.1
In addition, a dramatic increase in thyroid cancer has been noted in areas of Belarus, Ukraine, and in other geographic areas that were exposed to nuclear fallout from the 1986 Chernobyl nuclear power plant accident.2
References
1. Ron E, et al. Radiat Res. 1995;141:
2. Tuttle RM, et al. Semin Nucl Med. 2000;30:
Ron E, et al. Radiat Res. 1995;141:
Tuttle RM, et al. Semin Nucl Med. 2000;30:

47. Genetic Basis of Thyroid Cancer
Papillary and follicular thyroid cancer
Usually sporadic
Approximately 5% of patients have other family members with thyroid cancer
Rare genetic syndromes in which thyroid cancer is associated with other benign and malignant neoplasms
Genetic Basis of Thyroid Cancer.
Most patients with PTC and FTC are unaware of a family history of thyroid cancer. Although recent reports suggest that up to 5% of patients diagnosed with PTC have a relative with thyroid cancer, the pattern of inheritance has not been determined.1
Autosomal dominant disorders, including gastrointestinal polyposis, Gardner syndrome (large and small bowel tumors, desmoid tumors, lipomas, and epidermoid cysts), and Cowden syndrome (multiple hamartomas, breast cancer, colon cancer, and nodular goiter) have been associated with an increased risk of thyroid cancer.1
Reference
1. Alsanea O, et al. Curr Opin Oncol. 2001;13:44-51.
Alsanea O, et al. Curr Opin Oncol. 2001;13:44-51.

48. Management and Follow up of Thyroid Carcinoma

49. Thyroid Cancer Risk Stratification
Low Risk
Intermediate Risk
High Risk
Age
<45 years
>45 years
Gender
Female
Male
Size
<2 cm
>4 cm
Mixture of
Features
Extent
Intraglandular
Extraglandular
Grade
Low
High
Thyroid Cancer Risk Stratification.
Characteristics of the patient and the thyroid cancer can be used to estimate risk of recurrence and risk of disease-specific death.1 In patients younger than 45 years of age, thyroid tumors that are 1 to 2 cm in size, confined to the thyroid gland, and completely excised are generally considered low-risk tumors that are unlikely to affect the survival of the patient.1 However, some of these patients will have clinically evident recurrences that are easily treated with additional surgery or RAI.1
Patients with tumors larger than 4 cm, with extraglandular extension, high-grade histologies, and distant metastases have a poor prognosis with a very high recurrence rate and a high disease-specific mortality rate.1 In addition, many patients have a mixture of high-risk and low-risk signs and are considered at intermediate risk of recurrence and death.1 This initial risk stratification is used to guide treatment recommendations regarding the extent of initial surgery, the need for RAI ablation, and the type and intensity of testing needed to detect recurrent or persistent disease.1
At Memorial Sloan-Kettering Cancer Center, low-risk patients account for 39% of the patients treated, but have a less than 1% disease-specific mortality rate over 20 years.2 High-risk patients have a 53% disease-specific mortality rate but represent only 22% of patients.2 Thirty-nine percent of patients have intermediate-risk factors with a 13% risk of dying from thyroid cancer.2
References
1. Shaha AR, et al. Acta Otolaryngol. 2002;122:
2. Shaha AR. Cancer Control. 2000;7:
Distant
Metastases
Absent
Present
Treated, % 39 39 22
Death Rate, %
<1 13 53
Shaha AR, et al. Acta Otolaryngol. 2002;122:
Shaha AR. Cancer Control. 2000;7:

50. Thyroid Cancer Initial Treatment Strategy
Diagnosis of Thyroid Cancer
Surgery
Intermediate
and High Risk
Low Risk
Thyroid Cancer. Initial Treatment Strategy.
The initial management of thyroid cancer entails surgical removal of the thyroid nodule and the surrounding thyroid lobe.1 While many experts recommend a total thyroidectomy for nearly all patients with papillary thyroid cancer,2 many low-risk patients can be managed by the removal of the ipsilateral lobe and isthmus of the thyroid.1
There is controversy regarding how much of the thyroid should be removed in patients with tumor sizes ranging from 1.5 to 3 cm. Most physicians agree that lobectomy is sufficient for solitary PTCs that are confined to the thyroid gland and are less than 1 cm in maximum dimension.1
Patients at high risk for local or distant recurrence, such as primary size of the tumor more than 3 to 4 cm, extrathyroidal extension, cervical metastases, and high-grade histologies, can benefit from a total thyroidectomy to ensure removal of all evidence of thyroid cancer.2 Follow-up involves RAI scanning and serum thyroglobulin (Tg) assays.2
References
1. Shaha AR. Cancer Control. 2000;7:
2. Kinder BK. Curr Opin Oncol. 2003;15:71-77.
Lobectomy
Isthmusectomy
Total
Thyroidectomy
Shaha AR. Cancer Control. 2000;7:
Kinder BK. Curr Opin Oncol. 2003;15:71-77.

51. Thyroid Cancer Initial Treatment Strategy
Diagnosis of Thyroid Cancer
Surgery
Intermediate
and High Risk
Low Risk
Lobectomy
Isthmusectomy
Total
Thyroidectomy
Thyroid Cancer. Initial Treatment Strategy.
Low-risk patients can receive a lobectomy and isthmusectomy to remove the cancerous thyroid nodule and surrounding normal tissue.1 They are at a low risk for recurrence in the opposite lobe and in cervical lymph nodes, so long-term follow-up involves a physical examination every 6 to 12 months and annual ultrasound evaluations of the neck. Depending on the preference of the patient and the operating surgeon, some patients have a total thyroidectomy as the primary therapy even though they are classified as low risk.1
Intermediate-risk and high-risk patients benefit from total thyroidectomy to remove all traces of thyroid cancer.2 Radioactive iodine is then used to destroy any remaining normal or malignant thyroid cells.2 Radioactive iodine ablation has been shown to decrease recurrence and disease-specific mortality in intermediate-risk and high-risk patients.2 Because the thyroid cells selectively concentrate RAI, this targeted therapy can be given with minimal side effects.2,3 Most patients experience no side effects, but occasionally patients will develop altered taste, mild dry mouth, and/or sialadenitis from RAI being concentrated by the normal salivary glands.3 Most patients require only a single dose of RAI.
References
1. Kinder BK. Curr Opin Oncol. 2003;15):71-77.
2. Sherman SI. Lancet. 2003;361:
3. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Physical Exam
Ultrasound
RAI Ablation
Kinder BK. Curr Opin Oncol. 2003;15):71-77.
Sherman SI. Lancet. 2003;361:
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:

52. Treatment of Thyroid Cancer With Radioactive Iodine
Destroys remnants of normal thyroid tissue
Destroys thyroid cancer cells
Identifies distant metastases
Maximizes sensitivity and specificity of serum thyroglobulin
Treatment of Thyroid Cancer With Radioactive Iodine.
Radioactive iodine has been used to treat thyroid cancer since the 1950s. The use of RAI to destroy any residual thyroid cancer cells remaining after surgery results in lower recurrence rates and a decrease in death from thyroid cancer.1
Another important reason to destroy remaining thyroid tissue (normal and malignant) is so that serum Tg can be used as a sensitive and specific tumor marker.1 Thyroglobulin is only produced by, and secreted from, the thyroid gland. Therefore, a total thyroidectomy followed by RAI ablation should result in undetectable serum Tg levels.2
The presence of serum Tg following these initial interventions indicates the presence of persistent thyroid tissue (benign or malignant), which warrants additional investigation and treatment.2 Because serum Tg is the most sensitive and specific marker for detection of recurrent disease, it should be measured annually in all patients who have a history of thyroid cancer.2 Since anti-Tg antibodies can interfere with Tg measurement, it is imperative that serum Tg and serum anti-Tg antibody levels are measured together.1
References
1. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
2. Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:

53. Standard Treatment of Thyroid Cancer
Total
Thyroidectomy
RAI
Ablation
Suppression
Therapy
Standard Treatment of Thyroid Cancer.
Following the initial surgery and RAI ablation, the patient is placed on the appropriate suppressive dose of LT4 and followed every 4 to 6 months for 2 to 3 years.1 At each follow-up visit, a neck examination is conducted to detect clinically evident recurrent disease. Serum TSH and T4 levels are measured to monitor the degree of TSH suppression. Serum Tg and anti-Tg antibodies are measured as an indicator of persistent or recurrent thyroid cancer.2
The patient usually undergoes RAI scanning approximately 1 year after initial ablation to ensure that all thyroid tissue has been destroyed with the initial surgery and ablation.3 Serum Tg is also measured during the time of TSH stimulation for the RAI scan.4 The stimulated serum Tg assay is more sensitive for the detection of persistent or recurrent thyroid cancer than is the baseline serum Tg assay that is measured while the patient is receiving LT4.4
A recent consensus conference has suggested that RAI scanning is not required for all patients 1 year after initial ablation.5 In low risk patients with an undetectable Tg level who are on LT4 suppression 6 to 12 months after initial ablation, a rhTSH-stimulated Tg without RAI scanning appears to be adequate for detecting residual disease.5 This approach seems reasonable in low-risk patients. However, RAI scanning should still be done routinely 1 year after RAI ablation in moderate- to high-risk patients, and in all patients on LT4 medication who have a detectable Tg level 6 to 12 months after initial therapy.1
If the RAI scan shows no RAI-avid disease and the serum Tg level is less than 2 ng/dL with TSH suppression, the patient continues to be followed at 12-month intervals for the next 2 to 3 years.2 Additional testing may include a neck ultrasound, a computed tomography (CT) scan, neck magnetic resonance imaging (MRI), or an 18 fluoro-deoxy-glucose (FDG) positron emission tomography (PET) scan depending on the clinical course of the disease, the risk stratification of the patient, and the likelihood of having non-RAI–avid thyroid cancer.3
References
1. Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:
2. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2003;88:
3. Sherman SI. Lancet. 2003;361:
4. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
5. Mazzaferri EL, et al. Endocr Relat Cancer. 2002;9(4):
1 Year
Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2003;88:
Sherman SI. Lancet. 2003;361:
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Mazzaferri EL, et al. Endocr Relat Cancer. 2002;9(4):
Whole Body Scan
Tg Assay

54. Standard Treatment of Thyroid Cancer Phases of Follow-Up
Determine extent of disease
Treat detectable disease
Initial surgery
RAI ablation
Phase 2
No detectable disease
At risk for recurrence
Whole body scan
Stimulated Tg
Standard Treatment of Thyroid Cancer. Phases of Follow-Up.
The long-term follow-up of patients with thyroid cancer can be divided into 3 phases. Phase 1 includes all of the initial treatments, including surgery and RAI ablation.1 Once the patient is disease free (usually after a negative RAI scan 1 year later), the patient enters phase 2.2
Patients in phase 2 are at risk for recurrence and need to be followed closely for several years. Low-risk patients may stay in phase 2 for 2 to 3 years, while high-risk patients may be monitored in phase 2 for as long as 10 years. Fortunately, most thyroid cancer patients are long-term survivors who receive lifelong follow-up in phase 3. Usual follow-up procedures in phase 3 are a suppressed Tg assay, TSH assay, T4 assay, and neck examination performed annually for at least 20 to 30 years.
References
1. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
2. Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:
Suppressed Tg assay
TSH assay
T4 assay
Neck examination
Phase 3
Long-term disease-free survivor
Low risk for recurrence
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:

55. Thyroid Stimulating Hormone Suppression in Patients With Thyroid Cancer
Pituitary
TSH
Thyroid T4 - +
Normal
Thyroid Cancer Patients
Minimum LT4 to
suppress TSH
without thyrotoxicosis
Thyroid Stimulating Hormone Suppression in Patients With Thyroid Cancer.
Removal of cancerous and normal thyroid tissue in patients with thyroid cancer disrupts the normal negative feedback mechanism between the pituitary and the thyroid.1 Removal of thyroid tissue results in a loss of T4 production and a loss of inhibition of pituitary TSH secretion.1 Treatment with LT4 can suppress TSH and re-establish normal levels of the hormone.2
Several retrospective clinical studies have demonstrated decreased recurrence rates and decreased disease-specific mortality rates in thyroid cancer patients on long-term suppressive doses of LT4.1 The standard therapy aims to use the minimal LT4 dose necessary to suppress TSH without causing thyrotoxic symptoms.1
In clinical practice, this has been translated into a goal of achieving an undetectable TSH level in most patients with thyroid cancer.3 However, data over the last 10 years showing an increased risk of cardiac arrhythmias (atrial fibrillation) and an increase in bone loss in patients with long-term TSH suppression has caused physicians to re-evaluate the degree of suppression necessary in patients with thyroid cancer.3
References
1. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
2. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
3. Sherman SI. Lancet. 2003;361:
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Sherman SI. Lancet. 2003;361:

56. Target TSH Suppression in Patients With Thyroid Cancer
Optimal TSH
Low to
Undetectable
Suppressed but
Detectable
Low Normal
TSH,
mIU/L
<0.1
0.1 to 0.4
0.5 to 1
Target TSH Suppression in Patients With Thyroid Cancer.
A review of published studies suggested that most patients with thyroid cancer with no evidence of persistent disease can be well managed when TSH levels are maintained in the suppressed but detectable range.1 This range of TSH level suppression also minimizes the risk of cardiac arrhythmias and bone loss.2 Patients with persistent disease or with a high-risk of recurrence may benefit from more aggressive TSH level suppression, generally with a TSH level maintained at undetectable levels.2 The TSH level can be maintained at the low-normal range in very low-risk patients and long-term survivors.2 An elevated TSH level should be avoided in all patients, as this may increase the risk of developing clinically evident recurrent disease.3
Patients with thyroid cancer have a more narrow therapeutic window than hypothyroid patients treated with replacement doses of LT4. Very small changes in an LT4 dose can result in symptomatic thyrotoxicosis if the patient receives more LT4 than expected, or can result in an increased risk of recurrence if TSH is undersuppressed.3 Careful monitoring of LT4 dosing and TSH levels is mandatory in the long-term follow-up of patients with thyroid cancer.
References
1. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
2. Sherman SI. Lancet. 2003;361:
3. Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Persistent or recurrent disease
High-risk patients
Most patients with no evidence of disease
Very low-risk patients
Long-term survivors
Patients
Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:
Sherman SI. Lancet. 2003;361:
Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

57. Treatment of Thyroid Cancer Summary
Papillary and follicular thyroid cancer
Generally excellent prognosis
Risk for recurrence for as long as 30 years
Initial management
Surgery and radioactive iodine
LT4 suppressive therapy
Follow-up
Physical examination
Radioactive iodine scans
Serum Tg
TSH and T4
Treatment of Thyroid Cancer. Summary.
In summary, PTC and FTC generally have a good prognosis with 20-year disease-specific mortality rates of less than 2% to 3%, even if cervical lymph node metastases are present at the initial diagnosis. Despite this low mortality rate, clinically significant recurrences can develop 30 years after initial therapy, making lifelong surveillance for recurrent disease mandatory.
Initial management usually begins with surgical removal of the thyroid gland and RAI ablation in all but the most low-risk thyroid cancer patients. Patients are then placed on LT4 therapy, which is carefully titrated to achieve a TSH level that is detectable but below the normal reference range.
Long-term follow-up requires an annual physical examination to detect recurrent thyroid cancer in the neck, measurement of the serum Tg level to detect recurrent thyroid cancer anywhere in the body, and TSH and thyroid hormone level measurements to adjust LT4 suppressive therapy.
Depending on the individual estimate of the risk of recurrence or persistent disease, RAI scanning and stimulated serum Tg level measurements may also be a necessary part of long-term follow-up.