Surgical removal is the treatment of choice for thyroid carcinomas. Neck ultrasound is obtained preoperatively, since suspicious cervical lymphadenopathy is detected in about 25%. Intraoperative thyroid ultrasound by the surgeon also helps assess the extent of the tumor and lymph node involvement, altering surgical treatment in many cases.
For differentiated papillary and follicular carcinoma larger than 1 cm, total thyroidectomy is performed with limited removal of cervical lymph nodes. Surgery consists of a thyroid lobectomy for an indeterminate “follicular lesion” that is 4 cm or smaller. If malignancy is diagnosed on pathology intraoperatively, a completion thyroidectomy is performed. For indeterminate follicular lesions larger than 4 cm that are at higher risk for being malignant, a bilateral thyroidectomy is performed as the initial surgery. Higher-risk lesions include those with an FNA biopsy that shows marked atypia or that are suspicious for papillary carcinoma and those that occur in patients with a history of radiation exposure or a family history of thyroid carcinoma.
For papillary thyroid carcinoma, surgery involves lobectomy alone for cancers smaller than 1 cm in patients under age 45 years who have no history of head and neck irradiation and no evidence of lymph node metastasis on ultrasonography. Other patients should have a total or near total thyroidectomy. The advantage of near-total thyroidectomy for differentiated thyroid carcinoma is that multicentric foci of carcinoma are more apt to be resected. Also, there is less normal thyroid tissue to compete with cancer for 131I administered later for scans or treatment. A central neck lymph node dissection is performed at the time of thyroidectomy for patients with nodal metastases that are clinically evident. A lateral neck dissection is performed for patients with biopsy-proven lateral cervical lymphadenopathy. Neck muscle resections are usually avoided for differentiated thyroid carcinoma. However, patients with the Hürthle cell variant of follicular carcinoma may benefit from a modified radical neck dissection. Metastases to the brain are best treated surgically, since treatment with radiation or RAI is ineffective. Levothyroxine, 0.05–0.1 mg orally daily, is begun immediately postoperatively. About 2–4 months after surgery, patients require reevaluation and often 131I therapy.
Permanent injury to one recurrent laryngeal nerve occurs in 1% and 7% of patients, depending on surgical expertise. Bilateral nerve palsies are rare. Temporary recurrent laryngeal nerve palsies occur in another 5% but often resolve within 6 months. After total thyroidectomy, temporary hypoparathyroidism occurs in 20% and becomes permanent in about 2%. The incidence of hypoparathyroidism may be reduced if accidentally resected parathyroids are immediately autotransplanted into the neck muscles. Thyroidectomy requires at least an overnight hospital admission, since late bleeding, airway problems, and tetany can occur. Ambulatory thyroidectomy is potentially dangerous and should not be done. Following surgery, staging (Table 26–7) should be done to help determine prognosis and to plan therapy and follow-up.
Table 26–7.Staging and prognosis for patients with papillary thyroid carcinoma using MACIS scoring. ||Download (.pdf) Table 26–7. Staging and prognosis for patients with papillary thyroid carcinoma using MACIS scoring.
|Total Score1 - Stage ||Percentage of Patients with Papillary Thyroid Carcinoma ||20-Year Survival |
|< 6.0 = Stage I ||74.2% ||96–99% |
|6.0–6.99 = Stage II ||8.5% ||68–89% |
|7.0–7.99 = Stage III ||9.2% ||55–56% |
|≥ 8.0 = Stage IV ||8.1% ||17–24% |
In pregnant women with thyroid cancer, surgery is usually delayed until after delivery, except for fast-growing tumors that may be resected after 24 weeks gestation; there has been no difference in survival or tumor recurrence rates in women who underwent surgery during or after their pregnancy. Differentiated thyroid carcinoma does not behave more aggressively during pregnancy. However, compared to nonpregnant women, there is a higher risk of complications in pregnant women undergoing thyroid surgery.
B. Active Surveillance for Papillary Thyroid Microcarcinoma
Most papillary thyroid microcarcinomas that are less than 1 cm are indolent with an excellent prognosis. Therefore, for microcarcinomas, an ongoing active surveillance protocol used in some medical centers is to perform a clinical examination and neck ultrasound every 6 months. Such conservative management may be particularly warranted for patients who have a limited life expectancy, a high surgical risk, or very low-risk tumors.
C. Levothyroxine Suppression of Thyroid-Stimulating Hormone
Levothyroxine is prescribed for differentiated thyroid cancer in doses to achieve a target serum TSH: (1) For initial TSH suppression in high to medium risk patients, the target serum TSH is below 0.1 milli-international units/L while avoiding clinical hyperthyroidism; (2) For initial TSH suppression in low-risk patients, for persistent indolent disease, and for 5–10 years after remission in high-risk patients, the target TSH is between 0.1 and 0.5 milli-international units/L; (3) For patients who are free of disease and at low risk for recurrence, the target TSH is 0.5–2 milli-international units/L.
D. Radioactive Iodine (131I) Therapy for Differentiated Thyroid Cancer
Differentiated thyroid cancers variably retain the normal thyroid's ability to respond to TSH, secrete thyroglobulin, and concentrate iodine. There are two reasons to treat patients with 131I after thyroidectomy: (1) thyroid remnant ablation for patients at high risk for recurrence and (2) treatment of metastatic thyroid cancer. 131I is usually administered 2–4 months after surgery. However, the indications and optimal activity (dose) for 131I therapy for differentiated thyroid cancer remain controversial, since there is an overwhelmingly good prognosis for most patients with differentiated thyroid cancer.
Before receiving 131I therapy, patients should follow a low-iodine diet for at least 2 weeks. The low iodine diet consists of avoiding the following: iodized table salt, sea salt, fish, shellfish, seaweed, commercial bread, dairy products, processed meats, canned or dried fruit, canned fruit juices, highly salted soups and snack foods, black tea, instant coffee, food coloring with Red Dye #3, egg yolks, multivitamins with iodine, or topical iodine. Patients must not be given amiodarone or intravenous radiologic contrast dyes containing iodine. In all women of reproductive age, pregnancy must be excluded prior to RAI scanning or therapy. Despite restriction of dietary iodine, differentiated thyroid cancer frequently lacks sufficient RAI avidity to allow RAI therapy. Thyroid cancers with a BRAF mutation, including 60% papillary thyroid cancers, tend to have poor RAI avidity. With BRAF mutations, the BRAF V600E oncoprotein stimulates the MAPK pathway, suppressing the expression of genes required for iodine uptake and retention. Vemurafenib is a BRAF inhibitor that induces RAI uptake in 40% of BRAF-positive thyroid cancer metastases, allowing 131I therapy.
1. RAI thyroid remnant ablation
A low activity1 of 30 mCi (1.1 GBq) 131I is sometimes given for “remnant ablation” of residual normal thyroid tissues after surgery for differentiated thyroid cancer in patients without known metastases. However, 131I remnant ablation is not required for patients with low-risk stage I papillary thyroid carcinomas or carcinomas that are smaller than 1 cm (whether unifocal or multifocal), except for patients with unfavorable histopathology (tall-cell, columnar cell, insular cell, Hūrthle cell, or diffuse sclerosing subtypes). There are several advantages to thyroid remnant ablation using 131I: (1) There is usually remnant normal tissue that can produce thyroglobulin (a useful tumor marker). (2) It may destroy microscopic deposits of cancer. (3) The post-therapy scan may visualize metastatic cancer that would otherwise have been invisible.
2. RAI treatment of metastases
Therapy with 131I improves survival and reduces recurrence rates of differentiated thyroid cancer for patients with stage III–IV cancer and those with stage II cancer having gross extrathyroidal extension. RAI therapy is also given to patients with stage II cancer who have distant metastases, a primary tumor larger than 4 cm, or primary tumors 1–4 cm with lymph node metastases or other high-risk features. Brain metastases do not usually respond to 131I and are best resected or treated with gamma knife radiosurgery. A post-therapy whole-body scan is performed 2–10 days after 131I therapy. About 70% of small lung metastases resolve following 131I therapy; however, larger pulmonary metastases have only a 10% remission rate.
Staging with RAI scanning or 18FDG-PET/CT scanning assists with determining the activity of 131I to be administered. Treatment protocols vary among institutions. Generally, patients with higher-risk stage I cancer or stage II cancer are treated with 131I activities of 50–100 mCi (1.8–3.7 GBq). Patients with stage III–IV cancers typically receive 131I activities of 100–150 mCi (3.7–5.5 GBq). Repeated treatments may be required for persistent RAI-avid metastatic disease. Patients with differentiated thyroid carcinoma who have little or no uptake of RAI into metastases (about 35% of cases) should not be treated with 131I. Patients with asymptomatic, stable, RAI-resistant metastases should receive levothyroxine to suppress serum TSH and should be carefully monitored for tumor progression.
Some patients have elevated serum thyroglobulin levels but a negative whole-body RAI scan and a negative neck ultrasound. In such patients, an 18F-FDG PET/CT scan is obtained. If all scans are negative, the patient has a good prognosis and empiric therapy with 131I is not useful.
3. Recombinant human TSH (rhTSH)-stimulated 131I therapy
Recombinant human thyroid-stimulating hormone (rhTSH, Thyrogen) is given to increase the sensitivity of serum thyroglobulin for residual cancer and to increase the uptake of 131I into residual thyroid tissue (thyroid remnant “ablation”) or cancer. Thyrogen must be kept refrigerated and is administered according to the following protocol: Levothyroxine replacement is held for 2 days before rhTSH and for 3 days afterward. For 2 consecutive days, rhTSH (0.9 mg/day, reconstituted with 0.2 mL sterile saline) should be administered intragluteally (not intravenously). On the third day, blood is drawn: serum TSH is assayed to confirm that it is greater than 30 milli-units/L; serum hCG is measured in reproductive-age women to exclude pregnancy; and serum thyroglobulin is measured as a tumor marker. RAI is then administered at the prescribed activity (see above).
Thyrogen should not be administered to patients with an intact thyroid gland because it can cause severe thyroid swelling and hyperthyroidism. Hyperthyroidism can also occur in patients with significant metastases or residual normal thyroid. Other side effects include nausea (11%) and headache (7%). Thyrotropin has caused neurologic deterioration in 7% of patients with CNS metastases.
4. Thyroid-withdrawal stimulated 131I therapy
Thyroid withdrawal is sometimes used because of its lower cost, despite the discomforts of becoming hypothyroid. Levothyroxine is withdrawn for 14 days and the patient is allowed to become hypothyroid; high levels of endogenous TSH stimulate the uptake of RAI and production of thyroglobulin by thyroid cancer or residual thyroid. Just prior to 131I therapy, the following blood tests are obtained: serum TSH to confirm it is greater than 30 milli-units/L, serum hCG in reproductive-age women to screen for pregnancy, and serum thyroglobulin as a tumor marker. Three days after 131I therapy, levothyroxine therapy may be resumed at full replacement dose.
5. Side effects from 131I therapy
National Cancer Institute surveillance data for thousands of patients with thyroid cancer indicate that patients with differentiated thyroid cancer, treated with only surgery, have a 5% increased risk of developing a second non-thyroid malignancy (especially breast cancer). Patients with thyroid cancer who receive 131I therapy have a further increased risk of developing a second non-thyroid malignancy (especially leukemia and lymphoma). The risk of second cancers peaks about 5 years following 131I therapy.
RAI therapy can cause gastritis, temporary oligospermia, sialadenitis, and xerostomia. Radioiodine therapy can cause neurologic decompensation in patients with thyroid brain metastases; such patients are treated with prednisone 30–40 mg orally daily for several days before and after 131I therapy. Cumulative doses of 131I over 500 mCi (18.5 GBq) can cause infertility, pancytopenia (4%), and leukemia (0.3%). Pulmonary fibrosis can occur in patients with diffuse lung metastases after receiving cumulative 131I activities over 600 mCi (22 GBq). The kidneys excrete RAI, so patients receiving dialysis require only 20% of the usual 131I activity.
E. Other Therapies for Differentiated Thyroid Cancer
Patients with osteolytic metastases to bone from differentiated thyroid cancer may be treated with one of two anti-bone resorptive drugs: (1) zoledronic acid, 4 mg intravenously; or (2) denosumab, 120 mg subcutaneously. The frequency and duration of therapy are individualized according to each patient’s symptoms and response. These drugs must be used judiciously; there is an increased risk of atypical femur fractures and osteonecrosis of the jaw with prolonged therapy with either drug.
Patients with aggressive differentiated thyroid cancers may have metastases that are refractory to RAI therapy. Recurrence in the neck may be treated with surgical debulking and external beam radiation therapy. Patients with RAI-refractory differentiated thyroid cancer metastases that are advanced and rapidly progressive may be treated with certain tyrosine kinase inhibitors. Vandetanib and sunitinib induce partial responses in about 40%, while lenvatinib induces partial responses in about 65%. However, median progression-free survival has been only about 18 months and all tyrosine kinase inhibitors can cause serious adverse reactions, so the patient and clinician must decide whether this chemotherapy is worthwhile.