Differentiated thyroid cancer

Introduction

Your patient has a thyroid nodule or an enlarged and abnormal appearing cervical lymph node and a fine needle aspiration (FNA) biopsy is consistent with thyroid cancer. What do you do?

The treatment plan depends on the type of thyroid cancer. Differentiated thyroid cancer (DTC) of thyroid epithelium accounts for more than 90% of thyroid cancers. In areas of sufficient iodine nutrition, about 85% of DTC are papillary, 10% are follicular and 3% are Hurthle cell carcinomas. Recently, it was suggested that noninvasive encapsulated follicular variant of papillary thyroid cancer which represents 15% of papillary cancers should be reclassified as a pre-cancerous transitional lesion between hyperplasia and malignancy. While less aggressive therapy and monitoring for these “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) has been recommended, specific guidelines are yet to be determined.

The DTC retain many of the physiological functions of thyroid cells, including thyrotropin stimulating hormone (TSH) stimulation of growth, iodine uptake, and thyroid hormone production. Papillary thyroid carcinoma tends to be indolent, slow growing, and metastasizes locally by lymphatic spread into cervical lymph nodes. Follicular and Hurthle cell carcinomas tend to be more aggressive and spread hematogenously to distant sites. In iodine-deficient areas, the ratio of papillary to follicular carcinoma is closer to 1:1, rising to ~ 4:1 after improvement in iodine nutrition. Prognosis for papillary and follicular thyroid cancer is the same at each AJCC/UICC stage (I-IV), despite the difference in the methods of metastatic spread.

Approximately 5% of thyroid tumors are medullary thyroid carcinomas, which arises from calcitonin “C” cells that migrate into the thyroid gland during development. These “C” cells are of different embryonic origin than that of thyroid follicular cells and do not come under the category of DTC. These cells do not have the ability to take up iodine and the initial management is only surgery while DTC combines surgery with radioactive iodine (RAI) therapy. The remaining less than 3% of thyroid malignancies include more aggressive tumors, such as primary thyroid lymphoma, anaplastic thyroid carcinoma, and hematogenous metastasis to the thyroid gland from other primary tumor sites.

What is the cause of differentiated thyroid cancer?

Thyroid cancer is the most rapidly increasing cancer in men and women. Since 1975, the incidence of thyroid cancer has increased nearly three times and most of this can be attributed to an increased incidence of papillary thyroid cancer (PTC). The cause of the increased incidence is unknown. It may be in part, but not entirely, from increased incidental detection on imaging studies. There has also been a demonstrable increase in the incidence rate and mortality rate for advanced stage PTC. The incidence rate for thyroid cancer in the US is currently around 22.3/100,000 for women and 7.7/100,000 for men. Based on 2012-2014 rates, the National Cancer Institute estimates that 1.2% of men and women will be diagnosed with thyroid cancer at some time during their lifetime. Although many oncogenes have been found in papillary thyroid cancers (BRAF, RET/PTC, RAS, TRK, TERT) and follicular thyroid cancers (RAS, PTEN, PAX8/PPAR gamma), it is not clear that these mutations alone are carcinogenic or predict disease free survival (DFS) or response to therapy. RET/PTC1 is frequently found in papillary thyroid cancers that occur after external radiation.

Dietary iodine is taken up through the gut and concentrated in the thyroid. In the follicle cells of the thyroid gland, four and three atoms of iodine are incorporated into each molecule of thyroid hormone, L-thyroxine (T4) and triiodothyronine (T3), respectively. TSH is trophic and will increase follicular thyroid cell growth, iodine uptake and production of thyroid hormone precursor.

Who is at risk for developing the differentiated thyroid cancer?

Micropapillary thyroid carcinoma (<1 cm; AJCC/UICC T1a) is very common in adults; the incidence has risen every year for the last decade. These small tumors are found incidentally in up to 24% of patients after thyroidectomy for benign nodular disease. The risk for death is nearly zero in patients with these small tumors demonstrating a typical papillary thyroid histology, absence of extrathyroidal extension, and no lymph node metastases but the risk of recurrence has been variably estimated between 2-6%. The assessment of risk for DTC is difficult because of the high prevalence of small, clinically unimportant disease. There is a 10 fold increase in the risk for DCT in patients of first degree relatives of patients with thyroid carcinoma.

Patients with the PTEN hamartoma tumor syndrome, or Cowden’s syndrome, have an elevated standardized incidence ratio of 72 (95% CI 51-99) for thyroid carcinoma. Other syndromes associated with DTC include familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome and Pendred syndrome. External radiation of the thyroid and exposure to ionizing radiation from nuclear fallout, especially during childhood, and whole body radiation for bone marrow transplantation, are associated with a significantly increased risk for papillary thyroid carcinoma.

What you should be alert for in the history?

Initial evaluation of a thyroid nodule

The history should be focused on family history of thyroid cancer and risk factors for DTC. Risk factors for differentiated thyroid malignancies include a primary relative with DTC, head and neck radiation during childhood, and extremes of age (<30 or >60 years old). Worrisome symptoms include rapid growth of a thyroid mass over several weeks or months. Tracheal compression or invasion by thyroid cancer can result in hoarseness of voice, dyspnea or cough, especially with exertion or in the recumbent position, or hemoptysis. Initially, esophageal compression or invasion by thyroid cancer will cause dysphagia at the level of the lower neck to solids and pills, but not to liquids. Posterior invasion by DTC may result in recurrent laryngeal nerve damage, vocal cord dysfunction, and hoarseness.

What are the characteristic findings on physical examination?

In order to feel a thyroid nodule, it is important to know where it is located in the anterior neck. The thyroid isthmus usually is located anterior to and just below the cricoid cartilage of the trachea. The thyroid gland in young, thin women is often located in the mid-neck, while in older adults, the thyroid is located lower in the neck near the sternal notch. Thyroid nodules can be soft to palpation and may not be easily identified on exam. The thyroid exam should ascertain the length of each lobe, texture (firm or hard) of the gland, whether individual nodules can be felt, the presence or absence of tracheal deviation, and whether the thyroid extends below the clavicles, thus suggestive of a substernal goiter.

The presence of clinically important obstruction is confirmed by the Pemberton’s maneuver. A positive Pemberton’s sign is the development of facial flushing and/or distended jugular veins when both arms are raised at the side of the head for 1 minute. This is evidence of impaired venous outflow from the head and neck and may be associated with arterial or airway compromise from a retrosternal goiter that fills the thoracic inlet. Invasion of tumor outside the thyroid gland can be detected on exam when a nodule does not move up and down with swallowing. Careful exam for adenopathy of the central (paratracheal) area and along the jugular chain (lateral neck) should be performed, especially ipsilateral to the thyroid nodule.

Key laboratory and imaging tests

Recent guidelines by two professional endocrine societies, the American Thyroid Association and the American Association of Clinical Endocrinologists, agree that a diagnosis of DTC is made by fine FNA usually by ultrasound guidance. An assessment of adenopathy should be performed by an ultrasound of the central and lateral neck by professionals trained in performing this exam for thyroid cancer. Sonographic features suggestive of metastatic nodes include loss of fatty hilum, rounded shape, cystic change, calcifications, and peripheral vascularity.

If an abnormal-appearing node is found in the central or lateral neck, a FNA biopsy should be confirmed by ultrasound-guided FNA for cytology and measurement of thyroglobulin in the needle washout. Malignant nodes need to be confirmed by aspiration, as the result directs the extent of nodal dissection during thyroidectomy. Approximately 20-30% of patients will have clinically suspicious metastatic nodes apparent on ultrasound. Other anatomical imaging for metastatic disease in the neck is not routinely necessary.

The sensitivity of computed axial tomography (CT) scan and positron emission tomography for DTC metastatic to cervical lymph nodes is relatively low (30-40%). In particular, CT scanning with iodinated contrast should not be performed unless the trachea or mediastinum requires assessment, as the high amount of iodine in the contrast will prevent diagnostic imaging and therapy with radioactive iodine for at least 6 weeks. If anatomic imaging is needed, either CT without contrast or MRI with gadolinium contrast can be performed. Without specific symptoms, such as bone pain or hemoptysis, additional imaging (e.g., bone scans and PET scans) are not necessary in the pre-operative evaluation of DTC.

Diagnosis confirmation

The diagnosis of a DTC by FNA cytology of a thyroid nodule, an abnormal neck lymph node, or after post-surgical thyroid histology is highly accurate. Only approximately 2-5% of nodules with a pre-surgical FNA biopsy showing thyroid cancer will be benign on post-surgical histology. Molecular markers, such as BRAF, have been suggested to help guide the extent of the initial thyroidectomy and lymph node dissection. The BRAF mutation is associated with a higher risk of extrathyroidal tumor extension, cervical adenopathy, and worse disease free survival. Currently, there are no studies that demonstrate an improved outcome (disease free survival or mortality) when the extent of surgery is determined by pre-operative BRAF tumor testing.

Management of the disease

The management of thyroid cancer is individualized and must take into account risk factors for death and recurrence. Therapy is tailored based on the combined risk factors of tumor size, histology, extrathyroidal extension, completeness of surgical resection, lymph node involvement, distant metastatic disease, and iodine avidity.

Generally, management should be directed by an endocrine physician with special expertise in thyroid cancer in conjunction with a multi-disciplinary team. The team should include a thyroid surgeon experienced in central and lateral neck dissection and a nuclear medicine physician. Generally, medical and radiation oncologists are not involved in the care of patients with DTC unless the tumor becomes non-iodine avid or radioiodine unresponsive and is locally invasive or widely metastatic.

Our recommendations are largely based on the most recent ATA guidelines. There are many unresolved questions regarding the management of thyroid cancer and the most recent guidelines recommending a reduction in the extent of surgery and radioactive iodine therapy have not all been studied prospectively. As expected, there are practice differences among various thyroid cancer centers.

Initial Surgical Treatment

(i) Pre-operative imaging: Every patient undergoing surgery should have a pre-operative neck ultrasound to assess for metastatic node involvement in the central (paratracheal; level VI) and lateral (jugular chain; level II, III, IV) as previously described. This will determine the need for and extent of neck dissection.

(ii) Thyroid surgery and lymphnode dissection:

Surgery should be performed by a high-volume surgeon thyroid surgeon (performing more than 50 surgeries per year), as complications of surgery including injury to the recurrent laryngeal nerve and hypoparathyroidism, are more common in patients with thyroid cancer compared to patients with benign thyroid disease. The choice of surgery depends on several factors:

• Near-total or total thyroidectomy is the recommended procedure for all patients with thyroid cancer > 4 cm or if there is gross extrathyroidal extension, clinical metastatic nodes or known distant metastases.

• In patients with well differentiated thyroid cancer between 1 and 4 cm and who do not have evidence of extrathyroidal extension or clinical metastatic node involvement, the choice of surgery can either be a lobectomy or near total/total thyroidectomy.

• If patients with a lesion less than 1 cm is planned for surgery, a lobectomy can be performed as the initial procedure unless there is an indication to remove the contralateral lobe including contralateral nodules, history of prior head and neck irradiation, family history of thyroid carcinoma or clinically evident metastatic nodes.

When there is tumor involvement of a nodal compartment confirmed by biopsy, dissection of the compartment with removal of all nodes should be performed. Removal of individual nodes (node or berry picking) is not recommended.

• Therapeutic central or lateral neck dissection should be performed when metastatic nodes are found on pre-operative imaging and confirmed by biopsy or if detected during surgery.

• Prophylactic central neck dissection (when there is no known central compartment lymph node disease before surgery) should be considered for larger tumors (>4 cm), extrathyroidal extension, when there is known metastatic nodes in the lateral neck.

• Prophylactic lateral neck dissection is not recommended as it does not change the risk of mortality.

If the initial surgery is a lobectomy, a completion thyroidectomy should be offered to the patient if a bilateral surgery would have been the initial choice had the diagnosis of thyroid cancer been known prior to surgery.

(iii) Post-op management: During the immediate post-op period, patient should be monitored for hypocalcaemia. While all patients undergoing a total or subtotal thyroidectomy will require thyroid hormone replacement, the need for thyroid hormone withdrawal in preparation for radioactive iodine therapy in certain patients may affect this. Patients who undergo a lobectomy do not need to be started on thyroid hormone replacement immediately, but may have the need in the future based on TSH levels. Lab work at 6 weeks post op should include TSH levels and thyroglobulin levels to help determine further management.

Initial risk stratification and management

Initial therapy after surgery is determined by AJCC TMN staging which predicts the risk of death and the American Thyroid Association (ATA) risk assessment that predicts the risk of tumor recurrence.

(i) Risk Stratification

The ATA guidelines provides an Initial Risk Stratification System for DTC classifies disease into low, medium and high risk of disease recurrence or persistence. In reality, the risk of recurrence is a continuum determined by different variables. If patients receive radioactive iodine therapy, this may affect the initial staging and ATA risk assessment based on the findings of the post therapy scan.

Risk of recurrent disease rises when the nodes is >3 cm, the number of lymph nodes found at surgery is >5 or if there is extrathyroidal invasion of the tumor outside the thyroid. Risk of death rises when nodes are found in the lateral neck (AJCC/UICC stage IVA) or there is gross invasion (AJCC/UICCstage stage IVB) or distant metastases (AJCC/UICCstage stage IVC).

The most recent ATA 2015 thyroid cancer guidelines have suggested modifications to the risk stratification system based on additional variables including extent of lymph node involvement and degree of vascular invasion in follicular thyroid cancer. These modifications have yet to be validated.

(ii) Radioiodine (RAI) therapy

The American Thyroid Association guidelines currently recommend the selective use of radioactive iodine in patients with DTC. RAI is not recommended for patients with ATA low risk disease and is recommended for all patients with DTC with known distant metastases, gross extrathyroidal extension of the tumor and incomplete tumor resection. Selected patients in the ATA intermediate risk group with microscopic invasion into perithyroidal tissue, vascular invasion, lymph node metastases, extrathyroidal extension or aggressive histology may be offered postoperative radioiodine ablative therapy (Figure 1).

Figure 1.

RAI ablation is done in the presence of a high serum TSH level, which increases the iodine uptake into the tumor and allows delivery of higher doses of therapeutic radiation. This can be achieved with thyroid hormone withdrawal or the use of recombinant human TSH when RAI treatment is done for remnant ablation or adjuvant therapy. In patients with high risk for recurrence undergoing adjuvant therapy or treatment for gross residual disease, thyroid hormone withdrawal is the preferred method if there are no contraindicating comorbidities. It is also recommended that the RAI is administered after the patient has been on a diet low in iodine. Iodine is found in many foods, including iodized salt, dairy products, egg yolks, and some breads. High levels of non-radioactive iodine will reduce the amounts of RAI entering the tumor, resulting in a reduction in the effectiveness of the RAI therapy.

For remnant ablation after a total thyroidectomy, a low dose of 30 to 50 mCi is sufficient. An intermediate or moderate dose (75 to 125 mCi) or high dose (150-200 mCi) of RAI may be given for persistent or incompletely resected disease, local and distant metastatic disease, or aggressive histologies (tall cell, insular, columnar cell variants), providing that there is evidence that the metastases will concentrate the RAI. A post-therapy whole body scan should be performed with a gamma camera 2-10 days after the RAI therapy for staging purposes. About 10-15% of patients are staged at a higher level after the post-therapy scan if it is positive for additional disease.

It has been recognized that significant complications of RAI can occur, including dose-dependent sialadenitis (up to 54% of patients with dry mouth), chronic parotid gland swelling and discomfort, and increased tooth caries and tooth loss. RAI therapy is associated with second primary malignancies, primarily those of the GI tract and leukemia (with a relative risk of ~1.19). However, the absolute increase in numbers of cancers is small (4.6 excess cases per 10,000 person-years at risk).

(iii) Initial thyroid hormone suppression therapy and TSH goal

Because TSH is a known growth factor for thyroid cells, thyroid hormone (levothyroxine) dose is adjusted until the TSH is suppressed below the normal range. The American Thyroid Association guidelines suggest that the TSH goal for patients should be adjusted based on their risk of persistent or recurrent disease and risk of death from thyroid cancer:

• In patient with ATA low risk disease who undergo a lobectomy or in those who undergo total thyroidectomy with an undetectable suppressed Tg, the goal TSH should be between 0.5 to 2 mU/L. If the Tg is >0.2 mg/dl, the TSH goal should be between 0.1 to 0.5 mU/L.

• In patient with ATA intermediate risk disease, the goal TSH level can be around 0.1 to 0.5 mU/L.

• For those with ATA high risk disease including those with distant metastasis, gross extrathyroid extension and large metastastic nodes, the TSH should be maintained less than 0.1 mU/L.

Long-term follow up and monitoring response to therapy

Long-term follow up of tumor includes periodic serum thyroglobulin levels and neck ultrasounds for recurrent tumor and continual reassessment of response to therapy.

(i) Response to therapy

Following the initial therapy, during each follow up visit, the patient’s response to therapy based on thyroglobulin levels and imaging data obtained should be performed. The response to therapy helps guide subsequent decisions on the appropriate level of TSH suppression and further work up.

• Excellent response to therapy: no biochemical (suppressed Tg < 0.2 ng/mL or stimulated Tg <1 ng/mL) or structural evidence of disease. Surveillance for recurrent disease may be done less frequently over time in these patients.

• Biochemical incomplete response: Negative imaging and elevated Tg levels (suppressed Tg >1 ng/mL or stimulated Tg >10 ng/dL or rising anti-Tg levels). Patients in this group with rising Tg levels will require additional imaging and possibly further therapy.

• Structural incomplete response: Evidence of persistent or new local or metastatic disease. Depending on multiple factors the patient may be monitored with close follow up versus offered additional therapy.

• Indeterminate response: nonspecific findings on imaging or Tg levels in the indeterminate range (detectable Tg, but less than 1 ng/mL when suppressed and less than 10 ng/mL when stimulated). Patients with anti-Tg antibodies that are stable or declining in the absence of structural disease are also included in this category. In these patients, any non-specific imaging finding should be followed and trends in Tg and anti-Tg antibody levels should be monitored.

(ii) Thyroglobulin measurement

In the absence of antigen (i.e., no residual thyroid cancer or thyroid remnant after thyroidectomy and RAI ablation), the serum thyroglobulin antibody titer generally falls with time. Patients with persistent or progressive disease with show thyroglobulin antibody titers that rise with time due to continued antigen stimulation of the immune system.

However, 10-15% of patients with DTC will have thyroglobulin antibodies that will prevent the current immunometric (IMA) test from accurately measuring serum thyroglobulin. In these cases, serum thyroglobulin antibody levels may be used as a surrogate tumor marker. It may also be helpful to request thyroglobulin measurement by a different assay method, such as by radioimmunoassay (RIA). This assay is not as sensitive as the IMA assay, but generally has less interference by thyroglobulin antibodies.

(iii) Neck ultrasound and other imaging

Initial neck ultrasounds should be performed every 6 to 12 months to look for persistent or new evidence of structural disease in the neck. The most common site of recurrent disease in papillary thyroid cancer is cervical lymph nodes.

Other modalities of imaging that are not routinely recommended but may be considered include a radioiodine whole body scan (WBS), CT/MRI, bone scans and FDG-PET scanning. A WBS may be considered 6 to 12 months after RAI therapy particularly in patients with intermediate or high risk of recurrence. It may be particularly useful when patients have abnormal uptake outside the bed on the initial post therapy scan, in patients in whom significant thyroid remnant could have affected uptake in remnant tissue and in patients with concerning Tg or Tg antibody levels who have a negative or indeterminate neck ultrasound finding. Cross-sectional imaging of the neck and chest with CT/MRI is helpful in cases of bulky neck nodal disease or when invasion of tumor into surrounding structures is suspected and requires further assessment. A CT of the chest and/or FDG-PET is indicated in patients with elevated Tg levels, ie > 10 ng/ml with a negative RAI scan.

(iv) TSH suppression during long-term follow up

Based on the patient’s response to therapy, the recommendations for long-term TSH suppression will vary. The patient’s age, menopause status, presence of osteoporosis and cardiovascular co-morbidities should be taken into consideration.

• TSH goal of 0.5 to 2 mU/L can be considered in those patients with an excellent or indeterminate response especially those with a low risk for recurrence. Patients who have not received RAI therapy with a normal ultrasound, low Tg levels and Tg and anti-Tg antibodies that are not rising may also be maintained at this TSH level.

• TSH goal of 0.1 to 0.5 mU/L may be appropriate for patients with high risk disease but with an excellent or indeterminate response to therapy for about 5 years.

• TSH goal <0.1 mU/L should be sought in all patients with a structural incomplete response to therapy.

Management of persistent or recurrent disease

The management of persistent or recurrent disease is dependent on various factors including the location, size, rate of growth, radio iodine and FDG avidity and Tg doubling time.

• Malignant neck lymph nodes above a certain size threshold (>8 mm in the central neck and >1 cm in the lateral neck) that have been proven abnormal by FNA or nodes which are invasive can be considered for surgical removal.

• Ethanol injection of a metastatic node or radiofrequency or laser ablation of metastatic disease is an alternative to surgery and may be considered if the patient is a poor surgical candidate.

• In tissue that has demonstrated radioiodine avidity, additional RAI therapy can be considered.

• Adjunctive external beam radiation therapy: External beam therapy is used in DTC as a palliative treatment for locally advanced or otherwise unresectable disease. It is used when there is gross residual tumor and additional surgery or RAI would be ineffective. Expansile bone lesions associated with severe pain, fracture or neurological complications may also be treated with external beam radiation and glucocorticoid therapy to minimize radiation-related tumor expansion.

• Chemotherapy: The American Thyroid Association guidelines suggest that in patients with non-iodine avid or non-iodine responsive disease, initial observation is an acceptable option. However if the disease is progressive or symptomatic, the patient should be entered into a clinical trial with a targeted multikinase therapy rather than considering traditional chemotherapy. If the patient cannot participate in a clinical trial, then treatment by an oncologist with one of the FDA-approved tyrosine kinase inhibitors should be considered.

• Bisphosphonate or denosumab should be used in patients with diffuse or symptomatic bone metastasis in RAI refractory disease.

Prevention/Avoidance

Thyroid irradiation is the only modifiable risk factor for DTC. Therapeutic radiation is necessary and should not be avoided because of thyroid exposure. Diagnostic radiation in which the thyroid is not the object of examination should be limited when possible (for example, by the use of a “thyroid shield” during dental x-ray procedures.)

What is the prognosis of differentiated thyroid cancer?

Thyroid malignancies usually are slow growing. The cause-specific 5-year survival is 97% and the 10 year survival is 93%. However, a small number of cancers are aggressive. These may demonstrate local invasion into the trachea, esophagus, and recurrent laryngeal nerve causing respiratory symptoms, cough, hemoptysis, dysphagia and hoarseness. Distant metastatic disease typically travels hematogenously to the lungs and bone. Often pulmonary disease is asymptomatic, but bone disease may result in pain and pathological fractures.

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