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. Elizabeths Hospital, Appleton, WI Chairman, Diabetes Steering Committee, AMG/NHP, Appleton, WI

Tuesday March 15, 2005

Website: www.endocrinology-online.com

Neoplastic Thyroid Disease

Thyroid Nodules Goiter
Multinodular Diffuse Endemic

Thyroid Cancer
Well differentiated and poorly differentiated

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

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

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

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 18 000 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)

Initial Evaluation of a Thyroid Nodule/Mass

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

Evaluating Thyroid Nodules

TSH measurement Ultrasound of the thyroid

Fine needle aspiration

Radioactive iodine imaging

Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33. Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Castro MR, et al. Endocr Pract. 2003;9:128-136.

Thyroid Ultrasonography

Thyroid Ultrasonography

Excellent for characterizing size and other features of nodule

Useful in localizing nodule for FNA

Cannot distinguish between benign vs. malignant

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

RAI imaging

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

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

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

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

Thyroid FNA

Possible FNA Results

Benign: 70 -75 %

Malignant: Up to 5%
Suspicious: About 10% Nondiagnostic: About 10 - 20%

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

Management and Follow up

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

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

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

Non-diagnostic FNA contd

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

LT4 Suppression of Thyroid Nodules

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.)

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)

Thyroid Carcinoma

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

Kim N, et al. Otolaryngol Clin North Am. 2003;36:17-33. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463.

Newly Diagnosed Cancer in the United States

Hodgkin Multiple Myeloma Thyroid Kidney Leukemia Lymphoma Colon Lung Prostate Breast

Thyroid Cancer 22 000 new cases 1400 deaths

50

100

150

200

250

New Cases, Thousands

Cancer facts and figures. American Cancer Society Web site. Available at: http://www.cancer.org/downloads/ STT/CAFF2003PWSecured.pdf. Accessed December 10, 2003.

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
Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=43. Accessed December 10, 2003.

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

Detailed guide: thyroid cancer. American Cancer Society Web site. Available at: http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=43. Accessed December 10, 2003. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

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

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000 Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

Lung is most common site

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

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 & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003.

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 Hebra A, et al. Solitary thyroid nodule. eMedicine Web site. Available at: mortality http://www.emedicine.com/ped/topic2120.htm. rate 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;71:414-424. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY:Marcel Dekker, Inc.: 2001;239-241.

Hrthle Cell Cancer

A variant of follicular cancer that tends to be aggressive
Represents about 3% to 5% of all types of thyroid cancer

Hrthle Cell Tumor

High power magnification

Aytug S, et al. Hrthle cell carcinoma. eMedicine Web site. Available at: http://www.emedicine.com/med/topic1045.htm. Accessed December 10, 2003. Kloos RT, Mazzaferri E. Thyroid carcinoma. In: Cooper DS, ed. Medical Management of Thyroid Disease. Monticello, NY: Marcel Dekker, Inc.: 2001:239-241.

Hrthle 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 Braverman Tend to be locally invasive LE, Utiger RD, eds. Werner & Ingbars 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; 1993:278-333.

Anaplastic Thyroid Cancer

Extremely aggressive and exceptionally virulent

Composed wholly or in part of undifferentiated cells

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Sherman SI. Lancet. 2003;361:501-511. 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.

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

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

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

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Sherman SI. Lancet. 2003;361:501-511. Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: http://www.vmmc.org/dbCancer/sec180604.htm. Accessed December 10, 2003.

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 Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. age=21 years]) Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Thyroid Cancer Detailed Guide. American Cancer Society Web site. Available at: http://documents.cancer.org/196.00/196.00.pdf. Accessed December 10, 2003.

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
Types of thyroid cancer. Virginia Masen Medical Center Web site. Available at: http://www.vmmc.org/dbCancer/sec180604.htm. 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: http://documents.cancer.org/196.00/196.00.pdf. Accessed December 10, 2003.

Primary Thyroid Lymphoma

A rare type of thyroid cancer

Affects fewer than 1 in 2 million people

Large Cell Lymphoma of the Thyroid

Constitutes 5% of thyroid malignancies

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Cabanillas F. Thyroid lymphoma. eMedicine Web site. Available at: http://www.emedicine.com/med/topic2271.htm. Accessed December 10, 2003.

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

Thyroid Disease Manager Web site. Available at: http://www.thyroidmanager.org. Accessed December 10, 2003. Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Ansell SM, et al. Semin Oncol. 1999;26:316-323.

Newly Detected and Fatal Cases of Thyroid Cancer

Thyroid Cancer Cases Diagnosed in 2000 (N=18 000 ) Deaths by 2010 (N=1426) Anaplastic 11% Hrthle 12% Papillary 50%

Hrthle 4% Follicular 14%

Anaplastic 1%

Follicular 27% Papillary 80%

Robbins R, et al. Adv Intern Med. 2001;46:277-294.

Recurrence and Death After Diagnosis of Thyroid Cancer

Recurrence Death

40

Cumulative, %

30 20 10 0 0 10 20 30 40 50 Years After Diagnosis

Mazzaferri EL, et al. Am J Med. 1994;97:418-428.

N=1355

Etiology of Thyroid Cancers

Usually unknown Radiation exposure

Medical uses during childhood in the 1950s Current medical uses in cancer therapy Nuclear accidents
Ron E, et al. Radiat Res. 1995;141:259-277. Tuttle RM, et al. Semin Nucl Med. 2000;30:133-140.

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
Alsanea O, et al. Curr Opin Oncol. 2001;13:44-51.

Management and Follow up of Thyroid Carcinoma

Thyroid Cancer Risk Stratification

Low Risk Age Gender Size Extent Grade Distant Metastases Treated, % Death Rate, % <45 years Female <2 cm Intraglandular Low Absent 39 <1 39 13 Intermediate Risk High Risk >45 years Male >4 cm

Mixture of Features

Extraglandular High Present 22 53

Shaha AR, et al. Acta Otolaryngol. 2002;122:343-347. Shaha AR. Cancer Control. 2000;7:240-245.

Thyroid Cancer Initial Treatment Strategy

Diagnosis of Thyroid Cancer

Low Risk

Surgery

Intermediate and High Risk

Total Thyroidectomy
Shaha AR. Cancer Control. 2000;7:240-245. Kinder BK. Curr Opin Oncol. 2003;15:71-77.

Lobectomy Isthmusectomy

Thyroid Cancer Initial Treatment Strategy

Diagnosis of Thyroid Cancer

Low Risk Lobectomy Isthmusectomy Physical Exam Ultrasound

Surgery

Intermediate and High Risk

Total Thyroidectomy RAI Ablation

Kinder BK. Curr Opin Oncol. 2003;15):71-77. Sherman SI. Lancet. 2003;361:501-511. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463.

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

Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463. Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:129-157.

Standard Treatment of Thyroid Cancer

Total Thyroidectomy

RAI Ablation
Suppression Therapy
Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:129-157. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2003;88:1433-1441. Sherman SI. Lancet. 2003;361:501-511. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463. Mazzaferri EL, et al. Endocr Relat Cancer. 2002;9(4):227-247.

1 Year

Whole Body Scan Tg Assay

Standard Treatment of Thyroid Cancer Phases of Follow-Up

Phase 1 Determine extent of disease Treat detectable disease Phase 2 No detectable disease At risk for recurrence Initial surgery RAI ablation

Whole body scan Stimulated Tg 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;86:1447-1463. Cohen EG, et al. Otolaryngol Clin North Am. 2003;36:129-157.

Thyroid Stimulating Hormone Suppression in Patients With Thyroid Cancer

Normal Pituitary TSH Thyroid Cancer Patients Pituitary TSH -

+ Thyroid T4

Minimum LT4 to suppress TSH without thyrotoxicosis

Thyroid T4

Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463. Sherman SI. Lancet. 2003;361:501-511.

Target TSH Suppression in Patients With Thyroid Cancer

Optimal TSH Low to Undetectable TSH, mIU/L <0.1 Suppressed but Detectable 0.1 to 0.4

Low Normal
0.5 to 1 Very lowrisk patients Long-term survivors

Most patients Persistent or with no Patients recurrent disease evidence of High-risk patients disease

Mazzaferri EL, et al. J Clin Endocrinol Metab. 2001;86:1447-1463. Sherman SI. Lancet. 2003;361:501-511. Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

Treatment of Thyroid Cancer Summary

Papillary and follicular thyroid cancer

Generally excellent prognosis Risk for recurrence for as long as 30 years

Initial management

Follow-up

Surgery and radioactive iodine LT4 suppressive therapy Physical examination Radioactive iodine scans Serum Tg TSH and T