Differentiated Thyroid Cancer
*The original source for this chapter was Stephanie Lee, MD. The chapter was revised for this program by David Gerber, MD.
What every physician needs to know:
Differentiated thyroid cancers (DTC) of thyroid epithelium account for more than 90% of thyroid cancer.
In areas of sufficient iodine nutrition, the prevalence of DTC subtypes is as follows:
Hurthle cell 3%
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:follicular carcinoma is closer to 1:1, rising to approximately 6:1 after improvement in iodine nutrition. Prognosis for the different types of DTC 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 carcinoma, which arises from calcitonin “C” cells that migrate into the thyroid gland during development. These “C” cells are of different embryonic origin than thyroid follicular cells and are not a type of DTC.
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 from other primary tumor sites.
Are you sure your patient has differentiated thyroid cancer? What should you expect to find?
For a thyroid nodule identified or suspected by physical examination or incidental imaging finding, the following should be performed:
Measure thyroid stimulating hormone (TSH).
Perform ultrasound of thyroid for nodules, and central and lateral neck for adenopathy.
If TSH is low (5% of thyroid nodules), radioiodine imaging should be performed. If the nodule is hot (i.e., autonomously functioning), the patient should be evaluated and treated for thyrotoxicosis. Hot nodules are rarely malignant and should not be biopsied as many have atypical or worrisome cytopathologic features. If the nodule is cold or warm (5-10% chance of malignancy), an FNA should be considered.
If the TSH is normal or elevated, an FNA should be considered.
The threshold for performing FNA depends on the size and sonographic features of the nodule. In general, the more solid the nodule the lower the size threshold for FNA. Other suspicious radiographic features include
Increased central vascularity
Taller than wide shape
Unilateral adenopathy in the central (level VI) or lateral (levels II, III, IV, V) neck
Which individuals are most at risk for developing differentiated thyroid cancer?:
Micropapillary thyroid carcinoma (<1cm; 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% 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. The assessment of risk for DTC is difficult because of the high prevalence of small, clinically unimportant disease.
DTC can be found in about 10% of first degree relatives of patients with papillary thyroid carcinoma. Patients with the PTEN hamartoma tumor syndrome/Cowden’s syndrome have an elevated standardized incidence ratio of 72 (95% confidence interval 51-99) for DTC (primarily follicular thyroid carcinoma), with an estimated lifetime risk of 35.2% (CI 19.7%-50.7%).
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 of papillary thyroid carcinoma.
What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
After a diagnosis of DTC is made by fine needle aspiration (FNA) biopsy, 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
If an abnormal-appearing node is found in the central or lateral neck, ultrasound-guided FNA for cytology and measurement of thyroglobulin should be performed. Malignant-appearing nodes need to be confirmed by aspiration, as the result directs the extent of nodal dissection during thyroidectomy.
Approximately 20-50% of patients, particularly those with papillary thyroid carcinoma, will have clinically involved metastatic nodes (nodes seen on imaging or detected during surgery). Other anatomical imaging for metastatic disease in the neck is not routinely necessary. The sensitivity of CT, MRI, and PET for DTC metastatic to cervical lymph nodes is relatively low (30-40%).
In particular, computed tomography (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 magnetic resonance imaging (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 preoperative evaluation of DTC. Primary and metastatic foci of differentiated thyroid cancer typically are iodine avid (80-90%) and not hypermetabolic on PET scan. The more aggressive the thyroid cancer, the more likely the tumor will be iodine non-avid and hypermetabolic on PET scan.
The diagnosis of a DTC by FNA cytology of a thyroid nodule, an abnormal neck lymph node or 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. By contrast, 1-2% of benign FNA biopsies are found to be malignant at surgery.
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 preoperative BRAF tumor testing. Therefore, BRAF testing to determine extent of surgery is not recommended.
See Table I. TNM staging of thyroid cancer.
What should the initial definitive therapy for the cancer be?
The management of thyroid cancer is individualized and must take into account risk factors for death and recurrence. Therapy is tailored based on a combination of risk factors:
Completeness of resection
Central versus lateral nodal involvement
Gross invasion of surrounding structures
Presence of distant disease
Therapy should be directed by physicians with experience in initial and long-term management of thyroid cancer. Generally, management should be directed by an endocrine physician with special expertise in thyroid cancer in conjunction with a multidisciplinary team. The team should include a high volume thyroid surgeon (>50 thyroid surgeries/year) experienced in central and lateral neck dissection and a nuclear medicine physician. Generally, medical oncologists and radiation oncologists do not manage DTC patients unless the tumor becomes non-iodine avid or radioiodine unresponsive and is locally invasive and widely metastatic.
Near-total or total thyroidectomy is the recommended procedure for all patients with differentiated thyroid cancer (DTC). An exception may be patients with micropapillary thyroid carcinomas found incidentally after lobectomy for benign nodular disease. Completion thyroidectomy is suggested for all patients with a DTC greater than 1cm found after lobectomy, especially if there are additional nodules seen in the contralateral lobe by ultrasound, metastatic lymph nodes, a family history of DTC, or a history of head and neck radiation.
Typically, DTC initially metastasizes to paratracheal (central or level VI) nodes and then sequentially to the lateral neck (lateral to the jugular and carotid artery) nodes. Risk of recurrent disease rises when the number of lymph nodes found at surgery is greater than 2-5 or if there is extrathyroidal invasion of the tumor outside the thyroid. Risk of death rises in the presence of lateral neck nodes (AJCC/UICC stage IVA), gross invasion into surrounding structures (AJCC/UICC stage IVB), or distant metastases (AJCC/UICC stage IVC).
Removal of individual nodes (node or berry picking) is not recommended. When there is tumor involvement of a nodal compartment, dissection of the compartment with removal of all nodes should be performed. Therapeutic central or lateral neck dissection (removing all nodes without removal of normal structures) should be performed when pathologic nodes are found on preoperative imaging (and confirmed by biopsy) or detected during surgery. Prophylactic central neck dissection (no known disease before surgery) should be performed with larger tumors (>4cm), when there are known metastatic nodes in the lateral neck or when there is distant disease. Prophylactic lateral neck dissection is not recommended as it does not change the risk of mortality.
Recently, studies have examined the impact of microscopic metastases of DTC in cervical lymph nodes. In general, it is felt that microscopic (<0.2cm and not found by imaging or during surgery) does not impact recurrence or mortality and should not upgrade a patient with a small tumor to AJCC/UICC stage III (nodal metastases in the paratracheal, level VI area) or AJCC/UICC stage IV (lateral or mediastinal nodes).
Surgery should be performed by a high-volume surgeon experienced in thyroid surgery, as the complications of surgery (injury to the recurrent laryngeal nerve, hypoparathyroidism) are more common in patients with thyroid cancer compared to patients with benign thyroid disease.
Long-term follow-up of DTC includes:
Selecting and maintaining an appropriate level of TSH suppression by exogenous thyroid hormone (levothyroxine) administration
Periodic serum thyroglobulin levels
Periodic neck ultrasound exams
Because TSH is a growth factor for thyroid cells, the 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 as follows:
Persistent disease: <0.1mIU/L
Radiographically disease-free but at high risk for recurrence (e.g., thyroglobulin positive but imaging negative): 0.1-0.5mIU/L
Disease-free with low risk of recurrence: ~0.3-2mIU/L (lower half of reference range)
Potential toxicities of TSH-suppressive doses of levothyroxine include:
Cardiac tachyarrhythmias (especially in elderly)
Bone demineralization (especially post-menopausal women)
Symptoms of thyrotoxicosis
To achieve a TSH <0.1mIU/L, a levothyroxine dose of greater than 1.6mcg/kg is typically required. For patients who remain disease free for several years, TSH levels may be maintained within the reference range. Adequate daily intake of calcium (1200mg/day) and vitamin D (1000 units/day) is recommended during TSH suppression.
In the absence of antigen (i.e., no residual thyroid cancer or thyroid remnant after thyroidectomy and RAI ablation), the serum thyroglobulin level generally falls with time. Patients with persistent or progressive disease will show thyroglobulin levels that rise with time. 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. A patient after thyroidectomy and radioiodine ablation with a rising thyroglobulin antibody titer is at high risk for tumor recurrence. 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. A new assay, the thyroid cancer monitoring assay, uses protease digestion to destroy interfering thyroglobulin antibodies and to digest thyroglobulin into specific peptide fragments. The sensitivity, specificity, and reproducibility of this assay in general clinical practice have not yet been assessed.
Radioiodine therapy (RAI)
The American Thyroid Association guidelines currently recommend the selective use of radioactive iodine in patients with DTC.
RAI ablation therapy is recommended for ALL patients with:
Known distant metastases
Gross extrathyroidal extension of the tumor
Primary tumor size >4cm
RAI ablation therapy is recommended for SELECTED patients with:
Primary tumors 1-4cm confined to thyroid
High-risk histologies (tall cell variant, columnar cell, or poorly differentiated features)
Cervical LN metastases
RAI ablation therapy is NOT routinely recommended for patients with:
Unifocal or multifocal microcarciniomas (<1cm) confined to thyroid
RAI ablation (30-100mCi) is performed 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. Remnant ablation can be performed following thyroxine withdrawal with endogenous TSH elevation or injections of recombinant human TSH (rhTSH) to achieve an elevated serum TSH level. It appears that the clinical outcome is similar between these two treatment modalities. Recent randomized trials show equal rates of remnant ablation with 30 or 100 mCi administered with rhTSH injection or with hypothyroidism. It is also recommended that the RAI be 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 RAI therapy.
Higher doses of RAI (100-250mCi) may be given for persistent microscopic disease, 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 is not recommended to treat patients with non-iodine avid DTC (RAI scan negative), with the exception of a single empiric dose 100-200mCi to localize persistent progressive disease. Under this circumstance, 18FDG-PET/CT scanning should be considered for localizing metastases, especially if the serum thyroglobulin level is >10ng/mL or in patients with aggressive histologies that typically do not take up RAI (i.e., Hurthle cell thyroid or anaplastic thyroid carcinomas).
Complications of RAI
It has been recognized that significant complications of RAI can occur, including:
Dose-dependent sialadenitis (up to 54% of patients develop dry mouth)
Chronic parotid gland swelling and discomfort
Increased tooth decay and loss
Bone marrow suppression (rare with doses <200mCi)
Pulmonary fibrosis (in patients with widespread pulmonary metastases who receive large doses to the lungs)
Second primary malignancies, primarily those of the GI tract and leukemia (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)
Adjunctive external beam radiation therapy
External beam radiation therapy is used in DTC as a palliative treatment for locally advanced or otherwise unresectable disease in patients older than 45 years. 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 (often with glucocorticoid therapy to minimize radiation-related tumor expansion).
There is no data which demonstrates that conventional cytotoxic chemotherapy is effective. The 2009 American Thyroid Association guidelines suggest that patients with progressive, non-iodine avid or non-iodine responsive disease should bypass traditional chemotherapy and be entered into a clinical trial with a targeted multikinase therapy. These recommendations are likely to be changed in the next version of the guidelines anticipated to be published in 2014. Doxorubicin may act as a radiosensitizer and could be considered for patients with locally advanced disease receiving external beam therapy.
Targeted multikinase (anti-angiogenic tyrosine kinase inhibitor) therapy
While most patients with DTC are adequately treated with surgery and RAI therapy, a minority of patients have persistent biochemical (measurable serum thyroglobulin with negative imaging studies) and structural (gross tumor seen on imaging) disease.
Biochemical evidence of persistent tumor without evidence of active growth does not require treatment, but should be monitored for progression with periodic serum thyroglobulin levels and neck ultrasound exams. It is not necessary to ablate non-progressive biochemical disease (stable serum thyroglobulin levels) without evidence of structural disease.
In patients with serum thyroglobulin levels arising from non-iodine avid macroscopic disease, clinical trials have shown that multikinase therapies (axitinib, motesanib, pazopanib, sorafenib, and others) in phase II/III studies have been effective at stabilizing the progressive disease. Despite these advances, only a minority of patients achieve true radiographic response, and there have been no reports of patients with a complete response. However, disease control rate approaches 80% of patients treated with these agents, alone or in combination.
In November 2013, the first tyrosine kinase inhibitor, sorafenib, was FDA approved for use in progressive, non-iodine avid differentiated thyroid cancer. The pivotal randomized, double-blind phase 3 trial demonstrated a significantly longer median progression-free survival in the sorafenib group (10.8 months) compared to placebo group (5-8 months). This improvement in progression-free survival was seen regardless of tumor BRAF mutation status.
Commercially available TKIs that have been studied in thyroid cancer:
Sorafenib 400mg PO bid (taken without food)
Sunitinib 50mg PO daily 4 weeks on/2 weeks off (taken with or without food)
Pazopanib 800mg PO daily (taken without food)
Axitinib 5mg PO bid (taken with or without food)
Vandetanib (approved for medullary thyroid cancer) 300mg PO daily (taken with or without food)
Cabozantinib (approved for medullary thyroid cancer) 140 mg PO daily
Class adverse effects include GI symptoms, hand-foot syndrome, hypertension, and potential for bleeding/thrombosis. Additionally, vandetanib has also been associated with prolonged QTc, Torsades de Pointes, and sudden death; regular EKG monitoring is mandated. Pazopanib has been associated with severe, fatal hepatotoxicity. Cases of cardiomyopathy have been described with sunitinib and sorafenib.
What should you tell the patient and the family about prognosis?
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.
Follow-up surveillance and therapy/ management of recurrences.
History and physical, TSH, thyroglobulin and antithyroglobulin antibodies at 6 and 12 months, then annually in patients who have no evidence of macroscopic disease
Periodic neck ultrasound
In high-risk patients, patients with previous RAI-avid metastases, or patients with abnormal thyroglobulin levels, consider TSH-stimulated radioiodine imaging. High-risk patients who are iodine-non-avid with abnormal thyroglobulin level should be considered for TSH-stimulated PET imaging.
Management of recurrences
Consider RAI* therapy
Surgery if resectable
If radioiodine imaging positive, RAI* therapy alone or after surgery
If radioiodine imaging negative, external beam radiation therapy alone or after surgery
Local treatment (surgery, radiation therapy) as needed for palliation
RAI* if positive uptake
Systemic therapy with small molecule kinase inhibitors or chemotherapy if progressive and either non-iodine avid or unresponsive to radioiodine therapy
Thyroid cancer is the most rapidly increasing cancer in men and women. It is the 5th most common cancer in women and the most common cancer in women under 45 years old. The yearly incidence rate has doubled since 1970. Nearly two-thirds of cases are found in people <55 years of age. The current incidence rate for thyroid cancer is 16.4/100,000 for women and 5.6/100,000 for men.
Based on 2006-2008 rates, the National Cancer Institute estimates that 0.97% of men and women or 1 in 104 people will be diagnosed with thyroid cancer at some time during their lifetime. It is anticipated that there will be 62,980 new cases discovered in 2014. The increase in incidence is primarily from papillary thyroid carcinoma, as the incidence of other types of DTC (follicular and Hurthle) has been relatively stable.
Although many oncogenes have been found in papillary thyroid cancers (BRAF, RET/PTC, RAS, TRK) and follicular thyroid cancers (RAS, PTEN, PAX8/PPAR), it is not clear that these mutations alone are carcinogenic. RET/PTC1 is frequently found in papillary thyroid cancers that occur after external radiation, while a BRAF mutation is most common in older patients (45%) with papillary thyroid carcinoma. The cause of the increased incidence of DTC is unknown, but may be, in part, from increased incidental detection on imaging studies.
Dietary iodine is taken up through the gut and concentrated in the thyroid. In the follicle cells of the thyroid gland, 4 and 3 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, production of thyroid hormone precursor, thyroglobulin, and release of thyroid hormone into the circulation. The postoperative management of thyroid cancer relies on the thyroid cancer cell maintaining these differentiated functions.
Thyroid irradiation is the only modifiable cause of 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 (e.g., by the use of a “thyroid shield” during dental X-ray procedures).
What other clinical manifestations may help me to diagnose differentiated thyroid cancer?
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
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 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 liquids. Posterior invasion by DTC may result in recurrent laryngeal nerve damage, vocal cord dysfunction, and hoarseness.
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 and just below the cricoid cartilage of the trachea. Thyroid glands in young, thin women are 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 beyond the thyroid gland can be detected on exam when a nodule does not move up and down with swallowing. Careful examination for adenopathy of the central (paratracheal) area and along the jugular chain (lateral neck) should be performed, especially ipsilateral to the thyroid nodule.
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- Differentiated Thyroid Cancer
- *The original source for this chapter was Stephanie Lee, MD. The chapter was revised for this program by David Gerber, MD.
- What every physician needs to know:
- Are you sure your patient has differentiated thyroid cancer? What should you expect to find?
- Which individuals are most at risk for developing differentiated thyroid cancer?:
- What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?
- What should the initial definitive therapy for the cancer be?
- What should you tell the patient and the family about prognosis?
- Follow-up surveillance and therapy/ management of recurrences.
- What other clinical manifestations may help me to diagnose differentiated thyroid cancer?