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Objectives

The following module was designed following the objectives of the Canadian Oncology Goals and Objectives for Medical Students for thyroid. Information on epidemiology, risk factors, prevention, screening, presentation, diagnosis, and prognosis for thyroid cancer is provided.

By the end of the tutorial, the following objectives should be addressed:

  1. Understand basic anatomy of the thyroid and nearby structures
  2. Identify common risk factors associated with thyroid cancer
  3. Discuss the importance of genetics as a risk factor for thyroid cancer
  4. Describe the common signs and symptoms of thyroid cancer
  5. Understand the classification and staging of thyroid cancers
  6. Understand general approach to thyroid cancer diagnosis
  7. Understand the laboratory tests, imaging techniques, and biopsy methods used in the investigation of thyroid cancer
  8. Describe management options for thyroid cancer

Anatomy Review

Thyroid Anatomy I
Gray, Henry. (1918). Anatomy of the Human Body (20th edition). Philadelphia and New York. Accessed 13 Dec 19, from https://commons.wikimedia.org/wiki/Gray%27s_Anatomy_plates#/media/File:Gray560.png

Thyroid Anatomy II
Gray, Henry. (1918). Anatomy of the Human Body (20th edition). Philadelphia and New York. Accessed 13 Dec 19, from https://commons.wikimedia.org/wiki/Gray%27s_Anatomy_plates#/media/File:Gray562.png

The thyroid gland is an endocrine gland located anterior to the trachea, just inferior to the larynx. It contains a right and left lobe, isthmus, and occasionally a prominent pyramidal lobe which extends upwards towards the hyoid bone. Each lobe is between 4 to 6 cm in length. The entire gland weighs about 15-25g in adults [1]. The gland consists of follicular cells which take up iodine and produce and store thyroid hormone, as well as parafollicular cells (C-cells) which create calcitonin. Next to the thyroid gland are four parathyroid glands critical to calcium regulation in the body through PTH secretion.

The thyroid blood supply is from the branches of the thyrocervical trunk and the external carotid artery. The recurrent laryngeal nerves runs from the vagus nerve toward the larynx between the trachea and esophagus and is responsible for vocal cord control during breathing and speaking. Surgeons must be careful to protect this nerve during thyroidectomy or lobectomies. The superior laryngeal nerves run downward from the vagus nerve and the external branch supplies the cricothyroid muscle and assists in changing pitch of voice.

The main lymph nodes associated with the thyroid are the central compartment lymph nodes which includes Levels VI and VII. Occasionally, thyroid cancers spread to the lateral neck or retropharyngeal lymph nodes as well. [1]

Epidemiology

Thyroid cancer is a fairly uncommon cancer, however its incidence continues to rise worldwide, mostly as a result of increased use of diagnostic imaging and surveillance [2, 6]. The incidence rate of thyroid cancer is 11.2 per 100,000 population in Canada in 2019 [3]. In 2019, in the province of BC there will be approximately 565 new cases of thyroid cancer diagnoses and 30 patients will die of it based on most recent Health Authority data in 2019 [4]. Although incidence is rising steadily, mortality from thyroid cancer has changed minimally over the past five decades, and therefore, the challenge faced by physicians is to balance the therapeutic approach so patients with lower risk disease or benign thyroid nodules are not over-treated [6].

Thyroid cancers occur most often between 25 and 65 years of age. Women are more than twice as likely to develop thyroid cancer compared to men [2].

Risk Factors

  • Previous radiation exposure, especially in infancy or early childhood [5].
    It is estimated that development of thyroid cancer after radiation therapy is 7% with a latent period report from 4 to 30 years. Radiation to the head and neck or chest not only results in increased thyroid cancer risk but also increase the occurrence of benign changes within the thyroid gland (i.e. colloid nodules, cysts).
  • Female sex
  • Genetic predisposition and hereditary medical conditions
         - Familial adenomatous polyposis (FAP)
          - Gardner syndrome
          - Familial medullary thyroid cancer (FMTC)
          - Multiple endocrine neoplasia (MEN) syndrome
  • Chronically elevated TSH levels may increase thyroid cancer risk
  • History of goiter or family history of goiter may increase risk of developing papillary thyroid cancer

Prevention

Prevention of thyroid cancer involves a diet with adequate amounts of iodine. In North America, most of the populus have adequate iodine as it is added to table salt.

It is additionally important to avoid radiation exposure in childhood unless absolutely necessary.

Signs & Symptoms

The vast majority of thyroid cancers present as thyroid nodules detected by the patient, by the clinician via physical examination, or with imaging of the neck for other disorders [7]. There is a ~5-10% chance of malignancy in thyroid nodules detected in the general population, but men and patients at the extremes of age are at higher risk [7].

Signs & symptoms

  • Painless swelling in neck
  • Enlarged thyroid gland (goiter) or tight collar
  • Persistent cough
  • Late symptoms may include dysphagia, difficulty breathing, hoarseness
  • Symptoms related to distant metastasis, i.e. lungs, bones

Diagnosis

Although over 90% of nodules are small, non-palpable, benign lesions that will never become clinically significant tumors, some patients have non-palpable or palpable lesions that are malignant. Thyroid cancers exhibit a broad range of clinical behaviour - from indolent tumours with low mortality in most cases, to very aggressive malignancies, for example, in anaplastic thyroid cancer [7]. Therefore, identification of malignant thyroid nodules is important, especially those that will cause morbidity if not diagnosed early. To distinguish between low-risk and high-risk patient subsets, a thorough history and physical examination, laboratory investigations, neck ultrasonography, and for appropriately selected patients, fine-needle aspiration (FNA), are needed [6].

History

A full patient history must be collected at first consult including a history of presenting illness, past medical history, past surgical history, medication list, allergies, family history, social history, and a review of systems.

During the comprehensive history, specific thyroid-related history questions would include:

Worrisome findings
  • Rapid increase in nodule size
  • Dysphagia
  • Hoarseness
  • Difficulty breathing
Risk factor screening
  • Previous radiation exposure, especially in infancy or early childhood
  • Known genetic predisposition and hereditary medical conditions (such as FAP, Gardner syndrome, FMTC, MEN syndrome)
  • Past history of elevated TSH/chronically elevated TSH
  • History of goiter or family history of goiter
Signs and symptoms of hypo- or hyperthyroidism

(Note: this should not be used to differentiate benign from malignant nodules, however, hyperthyroidism in the setting of a dominant thyroid nodule is highly suggestive of an autonomously functioning nodule and these “hot nodules” should not undergo fine-needle aspiration (FNA), as they are rarely malignant and FNA findings are often misleading [7])

Physical Examination

General examination
  • Vital signs
  • Weight and height
Thyroid examination

Inspection of the thyroid from the front of the patient - you can sometimes recognize a large thyroid, or see a large nodule

  • Tip the patient’s head back slightly and locate the thyroid cartilage, and the cricoid cartilage
  • Inspect below the cricoid cartilage for the thyroid gland
  • Ask patient to sip water and swallow, with neck slightly extended
  • The thyroid cartilage, cricoid cartilage, and thyroid gland should rise with swallowing, and then return to their resting positions

Palpation of the thyroid, done from behind the patient

  • Flex the neck forward and place fingers on the patient’s neck with the index fingers just below the cricoid cartilage
  • Palpate for the isthmus and ask the patient to swallow a sip of water
  • Examine for the right lobe by turning the patient’s head slightly to the right, while keeping the neck slightly flexed
  • While palpating for the right lobe with your right hand, ask the patient to sip and swallow water again
  • Repeat the same procedure for the left lobe
  • If you feel the thyroid, note the size, shape, and consistency, and identify any nodules (firmness, mobility, size, adherence to surrounding structures), tenderness.
  • (On examination of the neck, the firmness, lack of mobility, and large size of the nodule(s); adherence to surrounding structures; and the presence of lymphadenopathy are important clues indicating an increased probability of carcinoma, however, these features lack specificity for malignancy [7].)
Lymph node examination of the head and neck


Diagnostic pathway

Following history and physical examination, ultrasonography must be performed and depending on the findings, FNA may be required. The American Thyroid Association (ATA) has produced guidelines to assist in decisions for biopsy based on the ultrasound findings as in Table 1 which stratify the appearance and characteristics of the nodule into levels of suspicion for malignancy [8].

Table 1. Sonographic phattern, their estimated risk of malignancy, and FNA guidance for thyroid nodule as per the 2015 American Thyroid Association Thyroid Nodule Guidelines [8]

Depending on location and the Radiologist, some thyroid ultrasound reports will include an American College of Radiology TI-RADS Score (Thyroid Imaging Reporting and Data System) which produces a score from 0 (benign) to 7 (high suspicious) based on similar imaging findings as discussed in the table above and subsequent FNA or follow-up recommendations [9].

Treatment is subsequently decided based on the pathology, imaging, surgeon preference, and patient factors, and is discussed in a later section. Figure 1 shows a simplified diagnostic pathway as proposed according to the 2015 American Thyroid Association Thyroid Nodule Guidelines [8]. For detailed explanation beyond the level of this module, visit the 2015 ATA Thyroid Nodule Guidelines.

Figure 1. Algorithm of evaluation and management of patients with thyroid nodules based on US pattern and FNA cytology as per 2015 ATA Thyroid Nodule Guidelines

If diagnosis is still unclear after FNA and repeat FNA, then radioactive isotope uptake and scanning should be done to determine whether the nodule is either hot or cold. If the nodule is hot (solitary autonomous nodule) then the patient can merely be observed and have medical treatment as required. On the other hand, if the nodule is not hot (cold), surgical intervention should be recommended. Repeat FNA may be recommended if thyroid nodule fails to regress. If again this proved to be suspicious then surgery should be recommended [8]. Specific management options are discussed under management at a later section.

Once a patient is referred to a thyroid surgeon, routine indirect or direct laryngoscopy is important for preoperative evaluation and also in the assessment of a thyroid nodule. Vocal cord paralysis is generally associated with advanced thyroid malignancy.

Classification

The normal thyroid gland is composed histologically of two main parenchymal cell types: follicular epithelial cells, and C or parafollicular cells [7]. Most thyroid cancers are derived from the follicular cells which give rise to both well-differentiated cancers (papillary, follicular) and anaplastic thyroid cancers. In the young (under 40 years of age), thyroid cancer is usually well-differentiated and the overall prognosis is excellent. On the other hand, anaplastic carcinomas, particularly in older patients, have a significantly poorer prognosis and are rarely cured. From C or parafollicular cells arise medullary thyroid carcinoma (MTC).

Papillary carcinoma

Papillary carcinoma is the most common form of thyroid cancer in Canada compromising over 80% of all diagnosed thyroid Cancers. It is a slow growing subtype and survival rates are high if diagnosed early. It is often single lobular. Metastases most commonly involve cervical lymph nodes and, less commonly, the lungs [7].

Follicular carcinoma

Follicular carcinoma is the second most common type of thyroid cancer after papillary carcinoma. It arises from follicular cells responsible for thyroid hormone production. It is slow growing and survival rates are high if diagnosed early. Follicular carcinoma is often treated with radioactive iodine since this tumor is most likely to capture radioactive iodine. When metastasized, however, follicular thyroid cancers tend to metastasize hematogenously to distant sites, in particular, to lung and bones.

Anaplastic carcinoma

Anaplastic carcinoma is the least common type of cancer (<1%) and occurs more often in middle ages and elderly patients [6]. It is the most aggressive type and is fast growing with early spread. A metastatic work-up often reveals locoregional disease and distant metastases, most commonly to the lungs followed by bones and brain. Anaplastic thyroid cancer often arises from and can coexist with differentiated thyroid cancer, but can also occur de novo. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with symptoms such as hoarseness, dysphagia, and dyspnea. It is often too advanced to surgically resect at diagnosis and therefore treated with radiation therapy alone. The cure rate of anaplastic carcinoma is very low. 

On presentation, most patients with anaplastic thyroid cancer have a large, firm palpable mass in the thyroid with or without cervical adenopathy, and patients often develop hoarseness, dysphagia, and dyspnea. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with the aforementioned symptoms. [6]

Medullary carcinoma

Medullary carcinoma arises from parafollicular neuroendocrine cells of the thyroid (C-cells) which are responsible for the production of calcitonin. It is uncommon and constitutes 1-2% of thyroid cancers [6]. It is slow growing and survival rates are high if diagnosed early. It may spread to lymph nodes or metastasize elsewhere. It generally occurs on one side of the thyroid only. MTC is the most prominent clinical diagnosis in multiple endocrine neoplasia (MEN) 2A and MEN 2B - a quarter of medullary thyroid cancer cases occur in patients with an inherited MEN syndrome.

Staging

The American Joint Committee on Cancer (AJCC) uses different tumor-node-metastasis (TNM) classification for differentiated and anaplastic thyroid cancer, and for medullary thyroid cancer. For the purposes and level of this module we will provide the staging for only the differentiated and anaplastic thyroid cancers below in Figure 2. For specific staging guidelines, see AJCC 8th edition TNM classification [10]:

Figure 2. AJCC 8th edition updated TNM staging for differentiated and anaplastic thyroid carcinoma. Please note that there are specific and separate TNM staging for medullary thyroid cancer discussed in detail in the AJCC 8th edition manual and not covered in this module.

There are additionally separate stage groupings based on AJCC 8th edition staging guidelines for differentiated, medullary, and anaplastic carcinomas seen in Table 2.


Table 2. AJCC 8th edition specific stage groupings for differentiated, anaplastic, and medullary carcinoma

Management

Management of thyroid cancer can be highly individualized and treatment may differ depending on patient, center, or physician factors. The details of management decision is beyond the scope of this module, however, general approaches and treatment options will be briefly reviewed.

The pathological assessment of the thyroid tumor is of paramount importance as it will not only give the degree of differentiation of the tumor but will assess multicentricity, the extent and site of nodal involvement and the completeness of the surgical resection. Overall, surgery is the mainstay of the majority of thyroid subtype treatments. 

Surgery

Surgery is the primary mode of therapy for patients with differentiated thyroid cancer and should be performed by an experienced thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve (RLN) injury.

Operative management can include either a thyroid lobectomy or a total thyroidectomy. The choice to pursue either depends on extent of disease, patient factors, and presence of comorbid conditions:

  • For tumors < 1cm without extrathyroidal extension and no lymph node involvement: thyroid lobectomy is preferred unless there are clear indications to remove the contralateral lobe (i.e. clinically evidence thyroid cancer in the contralateral lobe, previous history of head and neck radiation, strong family history of thyroid cancer)
  • For tumors 1 - 4 cm in size without extrathyroidal extension and no lymph nodes: either total thyroidectomy or thyroid lobectomy can be performed and would be chosen either based on patient preference, ultrasound abnormalities in contalateral lobe, or on a decision that radioiodine therapy may be beneficial adjuvantly.
  • Any tumors greater or equal to 4 cm, extrathyroidal extension, or metastases deem a total thyroidectomy is recommended.
  • Additionally, total thyroidectomy should also be performed in all patients with any history of childhood head and neck radiation, and in multifocal papillary microcarcinoma (> 5 foci) [8].

Post-operative thyroid hormone is generally not started for patients who received a lobectomy, however, is started for patients who received a total thyroidectomy.

Intra-operatively, careful search for lymph nodes in the area must be made and all obvious nodes removed. More extensive resection is required for different types and sizes of tumors and its spread to surrounding lymph nodes [5]. 

Radioactive Iodine Therapy

131-Iodine ablation may be used adjuvantly after surgery to target remaining thyroid tissue where recurrence may occur, or to treat already recurring or metastasized disease. In studies showing a benefit with 131-I ablation, patients with larger tumors, multifocality, residual disease, and nodal metastasis seem to benefit from treatment [7]. Therefore, the recent treatment guidelines recommend consideration of adjuvant 131-Iodine ablation in postoperative findings of [6]:

  • Large tumor sizes (>= 4cm)
  • FTC with extensive vascular invasion
  • Microscopic or gross extrathyroid extension
  • Central or lateral compartment neck lymph node metastases
  • Distant metastases

Only papillary and follicular cancers will take up iodine, and only 50% of less of these tumors are able to take up enough iodine for it to be therapeutic.

Hormonal Treatment

Treatment with thyroxine is important in management of patients with thyroid carcinoma. The aim of such treatment is to suppress TSH stimulation of the thyroid which can be achieved by maintaining the serum T4 at the upper limit of normal. The starting dose of thyroxine is 1 mcg/lb/day. The level will equilibrate in one month and then the T4 and TSH can be checked. The dosage can then be altered to achieve the desired level.

External Irradiation

External irradiation has a definite role as an adjuvant to surgery or as treatment in the following circumstances:

  1. As an adjuvant treatment following surgery and radioactive iodine ablation when the surgical resection has been incomplete and residual microscopic or macroscopic disease is left behind which does not take up the radioisotope
  2. As a palliative treatment for inoperate unresected tumors or anaplastic carcinomas
  3. As a palliative treatment for symptomatic metastasis.

Chemotherapy

The role of chemotherapy in thyroid cancer is limited. The single chemotherapeutic agent most commonly used for thyroid cancer is doxorubicin (Adriamycin) with partial response rates of 30% and up to 45% in some series. For surgically unresectable local disease that has not responded to radioiodine, the best treatment may be a combination of hyperfractionated radiation treatments plus Adriamycin. Response rates of more than 80% have been reported using this regimen, but even in this situation, complete responses are rare and limited in duration.

Follow-up

Initial follow-up is generally undertaken by an endocrinologist, surgeon, or at a cancer centre. Thereafter, most patients are referred back to the care of their family physician [5].

The follow-up is variable from centre to centre and from patient to patient, however, generally it is recommended a visit every 3 to 4 months for the first two years. If there is no evidence of recurrence after 2 years then visits should be every 6 months for the next two years, with annual visits thereafter.

Initial investigations may include neck ultrasonography (every 6 - 12 months), TSH levels, and serum thyroglobulin (Tg) levels on thyroid hormone suppression (every 3 to 6 months for the first year). Iodine scanning is typically continued until there is no evidence of uptake in the neck or elsewhere and only repeated if the thyroglobulin starts to rise of recurrence or metastasis is clinically detected.

If a patient is high risk and demonstrate either a biochemical or structural incomplete response to therapy, additional imaging can be considered, including MRI, CT, and FDG-PET. Gross residual disease in cervical lymph nodes identified by physical examination or ultrasonography should be confirmed by FNA and surgical resection considered. Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk.

Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, however, recurrences may occur many years or even decades later, particularly in patients with papillary cancer. Therefore, ongoing follow-up after one year post-treatment is guided by individual assessment of the patient’s response to therapy during the first year of follow-up [5].

References

  1. Mohebati, A., and A. R. Shaha. 2012. Anatomy of thyroid and parathyroid glands and neurovascular relations. Clin Anat 25 (1):19-31. doi:10.1002/ca.21220.
  2. Thyroid. (2016). BC Cancer Agency. Retrieved 13 Dec 2019, from http://www.bccancer.bc.ca/health-info/types-of-cancer/head-neck/thyroid
  3. Canadian Cancer Statistics 2019. (2019). Canadian Cancer Society. Retrieved 13 Dec 2019, from https://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2019-EN.pdf?la=en
  4. Statistics by Cancer Type - Thyroid. (2019). BC Cancer Agency. Retrieved 13 Dec 2019, from http://www.bccancer.bc.ca/statistics-and-reports-site/Documents/Cancer_Type_Thyroid_2016_20190426.pdf
  5. Head & Neck Cancer Management Guidelines. (2003). BC Cancer Agency. Retrieved 13 Dec 2019, from http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-management-guidelines/head-neck/head-neck
  6. Cabanillas, Maria E., David G. McFadden, and Cosimo Durante. 2016. Thyroid cancer. The Lancet 388 (10061):2783-2795. doi:10.1016/s0140-6736(16)30172-6.
  7. Carling, T., and R. Udelsman. 2014. Thyroid cancer. Annu Rev Med 65:125-137. doi:10.1146/annurev-med-061512-105739.
  8. Haugen, B. R., E. K. Alexander, K. C. Bible, G. M. Doherty, S. J. Mandel, Y. E. Nikiforov, F. Pacini et al. . 2016. 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 26 (1):1-133. doi:10.1089/thy.2015.0020.
  9. Tessler, F. N., W. D. Middleton, E. G. Grant, J. K. Hoang, L. L. Berland, S. A. Teefey, J. J. Cronan et al. . 2017. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee. J Am Coll Radiol 14 (5):587-595. doi:10.1016/j.jacr.2017.01.046.
  10. Amin, M. B., S. edge, F. Green, D. R., Byrd, R. K. Brookland. American Joint Committee on Cancer. Thyroid - Differentiated and Anaplastic Carcinoma. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. 881-898.

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