Thyroid cancer
1. What are the different types of thyroid cancers?
Thyroid cancer can be divided into three broad subtypes: (1) differentiated thyroid cancer (DTC), which includes papillary thyroid cancer (PTC) and its variants, follicular thyroid cancer (FTC) and Hürthle cell carcinoma; (2) medullary thyroid cancer (MTC); and (3) anaplastic thyroid cancer (ATC), which is a form of undifferentiated thyroid cancer. Other miscellaneous types of thyroid cancers include thyroid lymphoma, mucoepidermoid carcinoma, and metastases to the thyroid gland.
2. Describe the epidemiology of thyroid cancer.
Thyroid cancer is one of the few cancers that have increased in both absolute incidence and mortality over the past several decades; an estimated 56,400 new cases were diagnosed and 1780 deaths occurred in 2012. However, the relative survival is actually improved compared with the 1970s, with an average 5-year survival in 97% of patients. Many new thyroid cancer diagnoses have resulted from increased imaging. The detection of tumors smaller than 1.0 cm has accounted for 50% of the increase since the late 1990s. However, up to 20% of the increase in diagnoses is for tumors larger than 2.0 cm, a finding suggesting that enhanced detection of incidental cancers is not the sole cause of the increased incidence. Thyroid cancer is the fifth most common cancer in women, and it affects women three times as often as it does men. However, the mortality rate in men and women is similar, indicating that thyroid cancer tends to be more aggressive in men.
3. What are the risk factors for thyroid cancer?
In the absence of an inheritable genetic syndrome such as multiple endocrine neoplasia type 2 (MEN2), the main risk factors include a family history and exposure to ionizing radiation, especially at a young age (< 15 years old). This latter factor was demonstrated in the aftermath of the Chernobyl nuclear accident, studies of which suggested a dose-related radiation exposure risk of thyroid cancer that was 5- to 20-fold greater than in unexposed children. Relative iodine deficiency may also have been a predisposing factor.
Differentiated thyroid cancer
4. What are the different forms of DTC?
PTC, the most common form of DTC, encompasses about 80% of all thyroid cancer cases. Included under PTC are the follicular variant of PTC (FVPTC) and rarer aggressive subtypes, such as tall cell variant, sclerosing variant, and other poorly differentiated forms of PTC. FTC, the next most common type of DTC, accounts for about 10% to 15% of thyroid cancer cases overall but perhaps fewer in iodine-replete areas of the world. Finally, pure Hürthle cell carcinomas are composed of invasive follicular cells that have a distinctive oxyphilic change and that may be relatively radioiodine resistant compared with other forms of DTC.
5. Which is easier to diagnose based on thyroid fine-needle aspiration (FNA), PTC or FTC?
PTC has distinctive nuclear features such as enlarged, overlapping nuclei with nuclear grooves and intranuclear pseudoinclusions that allow for a cytopathology diagnosis with a positive predictive value (PPV) greater than 95%. In contrast, FTC is functionally defined as the invasion of largely normal-appearing follicular cells through a tumor capsule. Because this cannot be ascertained on a cytology aspirate, pure FTC is difficult to diagnose based on thyroid FNA.
6. How do molecular markers play a role in the diagnosis or prognosis of thyroid cancer?
The discovery and utilization of molecular markers that can be assessed in thyroid biopsy aspirates have enhanced the ability of practitioners to predict malignancy in thyroid nodules that have indeterminate FNA cytology (average malignancy risk ∼25%). Two commercial tests that use different analyses to predict malignancy risk are available. The Afirma test by Veracyte, Inc., uses a microarray analysis on a gene set that has a high negative predictive value (NPV) of 93% and a 40%-50% PPV for suspicious nodules. This test is very useful in predicting benign lesions and for avoiding unnecessary diagnostic surgery. The miRInform test by Asuragen, Inc., evaluates thyroid nodule aspirates for specific DNA mutation markers (KRAS, HRAS, NRAS, and BRAF mutations) and RNA fusion transcripts (RET/PTC1, RET/PTC3, and PAX8/PPARγ) that are specific for thyroid cancer. RAS mutations carry about an 85% PPV for thyroid cancer, but they can also be present in benign follicular adenomas. The other markers of this panel are functionally 100% predictive of malignancy. Their sensitivity is relatively poor, however, because thyroid cancers may harbor genetic alterations not found in this test. BRAF is present in approximately 30% to 60% of PTCs and predicts greater local invasion, lymph node metastases, radioiodine resistance, and an overall worse prognosis than do other mutations found in DTC.
7. Describe the staging of DTC.
The American Thyroid Association (ATA) recommends the American Joint Commission on Cancer (AJCC) staging system. Thyroid cancer is the only cancer that has age as a component of stage (Table 37-1). According to the AJCC system, if a patient is less than 45 years old, stage II disease is the highest stage possible, and then only if distant metastases are present outside the neck. Conversely, in patients who are 45 years old or older, intrathyroidal tumors up to 2 cm are stage I and tumors 2 to 4 cm are stage II. Any locoregional metastases raise the stage to so-called high-risk disease at stage III. Stage IV tumors either have gross invasion into extrathyroidal neck structures or distant metastases.
TABLE 37-1.
STAGING SYSTEM FOR DIFFERENTIATED THYROID CANCER
From American Joint Committee on Cancer (AJCC): Cancer staging manual, ed 6, New York, 2002, Springer.
8. How do PTC and FTC generally metastasize?
PTC typically spreads to locoregional lymph nodes. Outside the neck, the most common site of distant metastases is the lungs, with basilar miliary spread. FTC classically has hematogenous spread and a relatively high rate of bone metastases. Aggressive thyroid cancer of any type can have direct extension or invasion into extrathyroidal soft tissue, fascia, and muscle.
9. How often do metastases occur?
In adults, locoregional lymph node metastases occur as often as 30% to 60% of the time, whereas distant metastases are much rarer, occurring in only 2% to 4% of patients. In pediatric thyroid cancer, the presentation is more aggressive. Regional lymph metastases occur in 60% to 80% of these patients, and distant metastases occur in 10% to 20%.
10. What is the primary treatment for thyroid cancer?
Surgical resection is the primary treatment. The greatest predictor of a successful operation (cancer removal and avoidance of complications) is the surgeon’s experience. High-volume thyroidectomy practices consistently have excellent outcomes with minimal complication rates.
11. What determines the extent of the initial surgical procedure?
Ideally, the first thyroid cancer operation is the last. Preoperative neck ultrasound (US) is an invaluable tool for identifying the extent of lymph node metastases in the anterior lateral cervical lymph node chains. US is superior to computed tomography (CT) and magnetic resonance imaging (MRI) because it identifies malignant features of lymph nodes beyond size alone. For known thyroid cancer larger than 1 cm, or when lymph node metastases are detected preoperatively, a near-total thyroidectomy with lymph node resection is the procedure of choice. If the primary tumor is smaller than 1 cm, a hemithyroidectomy may be adequate. The need for prophylactic central neck lymph node dissection (prophylactic because central neck lymph nodes cannot be visualized with an intact thyroid in place) is controversial because of the lack of studies demonstrating improved survival with prophylactic central neck dissection.
12. What is the role of radioactive iodine in thyroid cancer therapy?
Radioiodine can be used for ablating any remnant thyroid tissue after thyroidectomy and can be considered adjuvant therapy after surgery for any locoregional lymph node or distant metastases.
13. Should all patients with thyroid cancer receive radioiodine?
No. Radioiodine therapy is indicated for patients with distant metastases, tumors with gross extrathyroidal extension, and tumors larger than 4.0 cm. Radioiodine therapy is not indicated for unifocal tumors smaller than 1.0 cm because there is no known survival advantage or decrease of recurrence. For thyroid cancers of medium size, patient-specific selection is indicated for determining whether to use radioiodine therapy.
14. How are patients prepared for radioactive iodine therapy?
Thyroid-stimulating hormone (TSH) stimulates iodine uptake into thyroid cells; therefore, TSH should be elevated to enhance uptake into functional thyroid tissue (remnant or DTC tissue). TSH can be elevated by withdrawing thyroid hormone therapy and thereby rendering the patient hypothyroid (usually a 3-week withdrawal from levothyroxine [LT4] alone without a triiodothyronine [T3
