Thyroid Disease

Author Credentials 

Russell B. Smith, MD, 
Baptist MD Anderson Cancer Center
Baptist Health
Jacksonville, FL

Module Summary

Thyroid diseases are common and fortunately the vast majority of these conditions are benign. The evaluation of a patient with suspected thyroid disease involves laboratory assessment as well as imaging, with a neck ultrasound being the most appropriate initial study in the vast majority of patients. Functional diseases of the thyroid may be treated by a variety of approaches including medication, radioactive iodine therapy, as well as surgery.  Nodular disease of the thyroid is common and the combination of fine-needle aspiration biopsy and ultrasound are required as part of the evaluation.  In some scenarios, molecular testing can also be a valuable part of the evaluations.  Surgery is indicated for the vast majority of patients with thyroid malignancies, but frequently even patients with benign nodular disease of the thyroid may also benefit from surgery.  Adjuvant therapies may be required as part of the initial therapy for patients with thyroid cancers.  While the vast majority of patients with thyroid cancer do well from there disease, long-term surveillance is necessary. 

Module Learning Objectives 
  1. Review the prevalence of the different types of thyroid disease and neoplasms.
  2. Describe the clinical presentation of the different types of thyroid disease and neoplasms.
  3. Appropriately utilize radiographic imaging studies in the evaluation of thyroid disease and neoplasms.
  4. Explain the role of fine needle aspiration (FNA) biopsy and molecular testing in the evaluation of a thyroid nodule.
  5. Describe the role of surgery, medical therapy, radioactive iodine therapy, and other therapies in the management of thyroid disease and neoplasms.

Embryology

Learning Objectives 
  1. Know that the thyroid gland develops from endodermal cells of the primitive pharynx (follicular component) and the neural crest (parafollicular component)
  2. Understand that the thyroid gland initially develops in the pharynx from the area that becomes the foramen cecum in the base of the tongue.
  3. As the gland descends into the neck, it passes anterior to the hyoid bone precursors before reaching its final location in front of the laryngotracheal complex.
  4. Thyroglossal duct cysts and the pyramidal lobe are results of the embryologic descent of the thyroid gland into the neck.
References 
  1. Foley DS, Fallat ME. Thyroglossal duct and other congenital midline cervical anomalies.  Seminars in Pediatric Surgery. 2006;15(2):70-5. 
  2. Chou J, Walters A, Hage R, Zurada A, Michalak M, Tubbs RS, Loukas M. Thyroglossal duct cysts: anatomy, embryology and treatment. Surg Radiol Anat. 2013 Dec;35(10):875-81. 

Anatomy

Learning Objectives 
  1. Describe the appearance, size, and shape of thyroid gland.
  2. Know the possible locations of the external branch of the superior laryngeal nerve as it courses toward the superior pedicle of thyroid gland to innervate the cricothyroid muscle.
  3. Know course of the recurrent laryngeal nerve on the right and left relative to the vascular structures and that the recurrent laryngeal nerve innervates all of the intrinsic muscles of the larynx except for the cricothyroid muscle. 
  4. Know the standard and ectopic locations of the parathyroid glands 
  5. Know that the Tubercle of Zuckerkandl is a protuberance on the posterolateral edge of the thyroid and the superior parathyroid and the RLN are intimately associated with it.
  6. Know that a non-recurrent LN is present on the right side (0.5%)
    • Non-recurrent right laryngeal nerve is associated with aberrant, retroesophageal right subclavian artery
    • If a non-recurrent laryngeal nerve is present on the left side, it is in association with situs inversus
  7. Describe the levels of the neck that are at risk for nodal metastases with thyroid cancer.
References 
  1. Whitfield P, Morton RP, Al-Ali S. Surgical anatomy of the external branch of the superior laryngeal nerve. ANZ J Surg. 2010 Nov;80(11):813-6.
  2. Fancy T, Gallagher D, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngol Clin North Am. 2010;43:221-7.
  3. Stack BC Jr, Ferris RL, Goldenberg D, Haymart M, Shaha A, Sheth S, Sosa JA, Tufano RP. American Thyroid Association Surgical Affairs Committee. American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. Thyroid. 2012 May;22:501-8.
     

Pathogenesis

Learning Objectives 
  1. Know that many thyroid diseases are autoimmune mediated.
  2. Know that most patients with thyroid nodules do not have a defined etiology for their disease.
  3. Know that exposure to ionizing radiation is a risk factor for developing thyroid nodules and thyroid cancer.
  4. Know that there are genetic syndromes that can predispose patients to developing thyroid cancers.
  5. Ongoing research is exploring other potential environmental exposures as risk factors for thyroid cancer.
References 
  1. Shukla SK, Singh G, Ahmad S, Pant P. Infections, genetic and environmental factors in pathogenesis of autoimmune thyroid diseases. Microb Pathog. 2018;116:279-288. 
  2. Petr EJ, Else T. Genetic predisposition to endocrine tumors: Diagnosis, surveillance and challenges in care. Semin Oncol. 2016 Oct;43(5):582-590. 

Basic Science

Learning Objectives 

Describe the production of thyroid hormone and the role it plays in metabolism.

Incidence

Learning Objectives 
  1. Know that 4.3% of United States (US) population has subclinical hypothyroidism
  2. Know that 0.7% of US population has subclinical hyperthyroidism
  3. Understand that 5-10% of the US population will have a palpable abnormality of the thyroid gland
  4. Understand that 25-40% of the population will have a radiographic abnormality of the thyroid gland
  5. Understand that there will be 54,000 cases of thyroid cancer in the United States in 2018
  6. Know that it is the seventh most common cancer in women
  7. Know that the malignancy risk of a nodule is approximately 5%
  8. Realize that radiation exposure is associated with a 2% risk of developing a thyroid nodule annually:
    • The risk peaks 15–20 years after the radiation exposure
References 
  1. Davies L, Welch, HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-7.

Genetics

Learning Objectives 
  1. Understand the genetics of well-differentiated thyroid cancer.
    • Implications of molecular profiling of nodules and tumors
  2. Understand the well-differentiated thyroid cancer occurs in patients with Gardner’s Syndrome and Cowden’s Disease.
  3. Understand the genetics of medullary thyroid cancer (MTC). 
    • Somatic mutation in RET occur in MTC
    • In familial MTC and MEN syndromes, genetic testing for germline mutations in the RET proto-oncogene has allowed precise identification of affected RET carriers and provided the opportunity for prophylactic or 'preclinical' surgery to prevent and treat medullary thyroid cancer.
       
References 
  1. Baloch ZW, LiVolsi VA. Pathologic diagnosis of papillary thyroid carcinoma: today and tomorrow. Expert Rev Mol Diagn. 2005;5:573-84.
  2. The Cancer Genome Altas Research Network. Integrated Genomic Characterization of Papillary Thyroid Cancer. Cell. 2014;159:676-90.

Patient Evaluation

Learning Objectives 
  1. List the potential symptoms and physical findings associated with hyperthyroidism.
  2. List the potential symptoms and physical findings associated with hypothyroidism.
  3. Describe the basic laboratory evaluation of a patient with thyroid disease.
  4. Understand that hyperthyroidism can be a result of an acute thyroiditis, Hashimoto’s thyroiditis, toxic solitary nodule, toxic multinodular goiter, or Graves’ disease
  5. Understand that distinguishing characteristics of Graves’ disease are the following findings:
    • Elevated thyroid stimulating immunoglobulin (TSI)
    • Exophthalmos
    • Periorbital edema
    • Pretibial myxedema
  6. Understand that Hashimoto’s thyroiditis has the following findings:
    • Elevated antithyroid peroxidase antibodies: 
  7. List the potential symptoms and physical exam findings in a patient with a thyroid nodule.
    • Importance of neck node and laryngeal examination 
  8. Describe the distinguishing features that should heighten the concern for malignancy.
  9. Know the importance of radiation exposure and family history in patient assessment.
References 
  1. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.
  2. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24:1670-751. 
  3. Haugen, BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. 
     

Measurement of Functional Status

Learning Objectives 
  1. Understand that preoperative radiographic and laboratory evaluation of gland function is not generally abnormal in nodular thyroid disease, but that TSH and total calcium are most cost-effective.
  2. Understand the importance of evaluating airway and pulmonary status.
References 
  1. Ringel MD, Mazzaferri E. Subclinical thyroid dysfunction--can there be a consensus about the consensus? J Clin Endocrinol Metab. 2005;90:588-90.

Imaging

Learning Objectives 
  1. Understand that ultrasonography should be the initial imaging study of a patients with thyroid disease.
  2. Be able to sonographically describe a thyroid nodule. 
  3. Be able to risk stratify a thyroid nodule based upon it sonographic charactieristics.
  4. Describe indications for other cross sectional imaging studies for patients with thyroid disease.
  5. Know that radioactive iodine uptake scans should only be obtained in patients that are hyperthyroid.
  6. Understand the role of post-treatment and surveillance I-131 radioactive iodine scans in the management of patients with well-differentiated thyroid cancers.
  7. Discuss the indication for PET/CT in the management of patients with thyroid cancer.
References 
  1. Haugen, BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. 
  2. Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, Cronan JJ, Beland MD, Desser TS, Frates MC, Hammers LW, Hamper UM, Langer JE, Reading CC, Scoutt LM, Stavros AT.  ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee. J Am Coll Radiol. 2017;14:587-595.

Pathology

Learning Objectives 
  1. Describe the Bethesda system for assessing thyroid FNA.
  2. Discuss the options for molecular testing in patients with indeterminate thyroid nodules by FNA.
  3. Understand the pathologic findings of the benign diseases of the thyroid.
  4. Recognize the pathologic and clinical implications of NIFTP.
  5. Understand the pathologic findings of the different types of thyroid cancer.
  6. Recognize that non-thyroid primary malignancies can occur in the thyroid.
  7. Know that frozen section pathologic analysis is usually unable to determine whether a follicular neoplasm is malignant.
  8. Understand the role of frozen section pathology when managing thyroid nodules and cancer.
References 
  1. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009;19:1159-65. 
  2. Smith RB, Ferris RL. Utility of Diagnostic Molecular Markers for Evaluation of Indeterminate Thyroid Nodules. JAMA Otolaryngol Head Neck Surg. 2016 May 1;142(5):421-2. 
  3. Haugen BR, Sawka AM, Alexander EK, Bible KC, Caturegli P, Doherty GM, Mandel SJ, Morris JC, Nassar A, Pacini F, Schlumberger M, Schuff K, Sherman SI, Somerset H, Sosa JA, Steward DL, Wartofsky L, Williams MD. American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Thyroid. 2017 Apr;27(4):481-483. 
  4. Callcut RA, Selvaggi SM, Mack E, Ozgul O, Warner T, Chen H. The utility of frozen section evaluation for follicular thyroid lesions. Ann Surg Oncol. 2004;11:94-8.
     

Medical Therapies

Learning Objectives 
  1. Know the medical management of hyperthyroidism or hypothyroidism (spontaneous or iatrogenic)
  2. Understand that the options for thyroid hormone replacement therapy for hypothyroidism includes the following:
    • Levothyroxine (Synthroid, Levoxyl, Tirosint) = T4
    • Liothyroxine (Cytomel) = T3
    • Liotrix (Thyrolar) = T4/T3 (4:1 ratio)
    • Armour Thyroid = desiccated porcine thyroid gland
  3. Understand that the drug option for treatment of hyperthyroidism includes the following:
    • Beta blockers
    • Thionamides - Agents to decrease thyroid hormone production
      • Methimazole (Tapazole)
      • Propylthiouracil (PTU)
  4. Describe how radioactive iodine ablation works to treat hyperthyroidism
    • Oral 131I concentrates in thyroid tissue and ablates thyroid tissue within 6–18 weeks.  
    • Patients are typically on drug therapy prior to avoid thyroid storm.
  5. Understand the role of radioactive iodine, external beam radiation therapy, and chemotherapy in the management of thyroid cancer. 
     
References 
  1. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.
  2. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24:1670-751. 
  3. Haugen, BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. 

Pharmacology

Learning Objectives 
  1. List other medications that may be used in the treatment of hyperthyroidism, such as:
    • Glucocorticoids: decrease the conversion of T4 into T3 peripherally
    • Lithium: Blocks thyroid hormone (T4) release
    • Cholestyramine: Lowers T4 and T3 more rapidly than methimazole 
    • Carnitine: a peripheral antagonist of thyroid hormone

Surgical Therapies

Learning Objectives 
  1. Describe the role of surgery for benign conditions of the thyroid gland.
    • Hashimoto’s disease
    • Graves’ disease
    • Solitary toxic nodule
    • Multinodular toxic goiter  
    • Compressive goiter
  2. Discuss surgical decision making in indeterminate nodules of the thyroid.
  3. Understand the role of thyroid lobectomy vs. total thyroidectomy for well-differentiated thyroid carcinoma
  4. Describe the extent of surgery for medullary thyroid cancer.
  5. Recognize the characteristics of a patient with anaplastic thyroid cancer that may benefit from surgery.
  6. Understand the special considerations when performing surgery for goiter.
  7. Know the indications for central and lateral neck dissections for patients with well-differentiated and medullary thyroid cancer.
  8. Recognize the options of video-assisted and robotic thyroidectomy.
  9. Understand the role of surgery in recurrent disease.
References 
  1. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan;26(1):1-133. 
  2. Chen AY, Bernet VJ, Carty SE, Davies TF, Ganly I, Inabnet WB 3rd, Shaha AR. Surgical Affairs Committee of the American Thyroid Association. American Thyroid Association statement on optimal surgical management of goiter. Thyroid. 2014 Feb;24(2):181-9. 
  3. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG. American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma.  Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610.
  4. Stack, BC Jr, Ferris RL, Goldenberg D, Haymart M, Shaha A, Sheth S, Sosa JA, Tufano RP. American Thyroid Association Surgical Affairs Committee. American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. Thyroid. 2012 May;22:501-8.
  5. Agrawal N, Evasovich MR, Kandil E, Noureldine SI, Felger EA, Tufano RP, Kraus DH, Orloff LA, Grogan R, Angelos P, Stack BC Jr, McIver B, Randolph GW. Indications and extent of central neck dissection for papillary thyroid cancer: An American Head and Neck Society Consensus Statement. Head Neck. 2017;39:1269-1279. 
  6. Scharpf, J , Tuttle M, Wong R, Ridge D, Smith R, Hartl D, Levine R, Randolph G. Comprehensive management of recurrent thyroid cancer: An American Head and Neck Society consensus statement: AHNS consensus statement. Head Neck. 2016;38:1862-1869. 
     

Staging

Learning Objectives 
  1. Know the 8th edition AJCC staging system for the different types of thyroid cancer.
    • Well-differentiated thyroid cancer
    • Medullary thyroid cancer
    • Anaplastic thyroid cancer
  2. Understand the concept of dynamic risk stratification for well differentiated thyroid cancers.
  3. Understand the importance of calcitonin doubling time for medullary thyroid cancer.

Case Studies

  1. A 36 year-old female with anxiety, palpitations, and propostions.
  2. A 43 year-old female with a palpable thyroid nodule.
  3. A 61 year-old female with a thyroid nodule and ipsilateral lymphadenopathy with a FNA suspicious for papillary thyroid cancer.
  4. A 55 year-old male with a history of medullary cancer s/p thyroidectomy and central neck dissection with a calcitonin of 105 pg/nl.
     

Complications

Learning Objectives 
  1. Know the incidence for the most common complications that may occur during a thyroidectomy:
    • Hypocalcemia
    • Hematoma
    • Recurrent laryngeal nerve injury
    • Superior laryngeal nerve injury
  2. Know the signs and symptoms of hypocalcemia associated with iatrogenic hypoparathyroidism.
  3. Describe the treatment of acute and chronic hypocalcemia associated with iatrogenic hypoparathyroidism
  4. Know the signs and symptoms of superior laryngeal nerve injury.
  5. Describe the treatment options for superior laryngeal nerve injury.
  6. Know the signs and symptoms of recurrent laryngeal nerve injury.
    • Unilateral vs. bilateral
  7. Describe the treatment options for recurrent laryngeal nerve injury.
    • Unilateral vs. bilateral
  8. Understand that a risk of iatrogenic hyperthyroidism related to excessive thyroid hormone therapy:
    • Accelerated bone loss (measure with bone density scan)
    • Atrial fibrillation or flutter
    • Clinical hyperthyroidism
References 
  1. Dedivitis RA, Aires FT, Cernea CR. Hypoparathyroidism after thyroidectomy: prevention, assessment and management. Curr Opin Otolaryngol Head Neck Surg. 2017;25:142-146.
  2. Weiss A, Lee KC, Brumund KT, Chang DC, Bouvet M. Risk factors for hematoma after thyroidectomy: results from the nationwide inpatient sample. Surgery. 2014;156:399-404.
  3. Lynch J, Parameswaran R. Management of unilateral recurrent laryngeal nerve injury after thyroid surgery: A review. Head Neck. 2017;39:1470-1478.

Review

References 
  1. What is the appropriate evaluation of a patient with suspected hyperthyroidism?
  2. Which patients with thyroid nodules should undergo fine-needle aspiration biopsy?
  3. What is the appropriate extent of surgery for patients with differentiated thyroid cancer limited to the thyroid gland?
  4. What are the indications for neck dissection in patients with medullary thyroid cancer?
  5. What factors determine the need for adjuvant therapy in differentiated thyroid cancer?
  6. What is the appropriate surveillance for patients with differentiated and medullary thyroid cancer?
Resources 

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