PTC is the most common type of thyroid cancer, accounting for 70–90% of well-differentiated thyroid malignancies. Microscopic PTC is present in up to 25% of thyroid glands at autopsy, but most of these lesions are very small (several millimeters) and are not clinically significant. Characteristic cytologic features of PTC help make the diagnosis by FNA or after surgical resection; these include psammoma bodies, cleaved nuclei with an "orphan-Annie" appearance caused by large nucleoli, and the formation of papillary structures.
PTC tends to be multifocal and to invade locally within the thyroid gland as well as through the thyroid capsule and into adjacent structures in the neck. It has a propensity to spread via the lymphatic system but can metastasize hematogenously as well, particularly to bone and lung. Because of the relatively slow growth of the tumor, a significant burden of pulmonary metastases may accumulate, sometimes with remarkably few symptoms. The prognostic implication of lymph node spread is debated. Lymph node involvement by thyroid cancer can be well tolerated but appears to increase the risk of recurrence and mortality, particularly in older patients. The staging of PTC by the TNM system is outlined in Table 48-3. Most papillary cancers are identified in the early stages (>80% stages I or II) and have an excellent prognosis, with survival curves similar to expected survival (Fig. 48-3A). Mortality is markedly increased in stage IV disease (distant metastases), but this group comprises only about 1% of patients. The treatment of PTC is described later.
The incidence of FTC varies widely in different parts of the world; it is more common in iodine-deficient regions. FTC is difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures. FTC tends to spread by hematogenous routes leading to bone, lung, and central nervous system metastases. Mortality rates associated with FTC are less favorable than for PTC, in part because a larger proportion of patients present with stage IV disease (Fig. 48-3B). Poor prognostic features include distant metastases, age >50 years, primary tumor size >4 cm, Hürthle cell histology, and the presence of marked vascular invasion.
TREATMENT: Well-Differentiated Thyroid Cancer
SURGERY All well-differentiated thyroid cancers should be surgically excised. In addition to removing the primary lesion, surgery allows accurate histologic diagnosis and staging, and multicentric disease is commonly found in the contralateral thyroid lobe. Lymph node spread can also be assessed at the time of surgery, and involved nodes can be removed. Recommendations about the extent of surgery vary for stage I disease, as survival rates are similar for lobectomy and near-total thyroidectomy. Lobectomy is associated with a lower incidence of hypoparathyroidism and injury to the recurrent laryngeal nerves. However, it is not possible to monitor Tg levels or to perform whole-body 131I scans in the presence of the residual lobe. Moreover, if final staging or subsequent follow-up indicates the need for radioiodine scanning or treatment, repeat surgery is necessary to remove the remaining thyroid tissue. Therefore, near-total thyroidectomy is preferable in almost all patients; complication rates are acceptably low if the surgeon is highly experienced in the procedure. Postsurgical radioablation of the remnant thyroid tissue is increasingly being used because it may destroy remaining or multifocal thyroid carcinoma, and it facilitates the use of Tg determinations and radioiodine scanning for long-term follow-up by eliminating residual normal or neoplastic tissue.
TSH SUPPRESSION THERAPY As most tumors are still TSH-responsive, levothyroxine suppression of TSH is a mainstay of thyroid cancer treatment. Though TSH suppression clearly provides therapeutic benefit, there are no prospective studies that identify the optimal level of TSH suppression. A reasonable goal is to suppress TSH as much as possible without subjecting the patient to unnecessary side effects from excess thyroid hormone, such as atrial fibrillation, osteopenia, anxiety, and other manifestations of thyrotoxicosis. For patients at low risk of recurrence, TSH should be suppressed into the low but detectable range (0.1–0.5 mIU/L). For patients at high risk of recurrence or with known metastatic disease, complete TSH suppression is indicated if there are no strong contraindications to mild thyrotoxicosis. In this instance, unbound T4 must also be monitored to avoid excessive treatment.
RADIOIODINE TREATMENT Well-differentiated thyroid cancer still incorporates radioiodine, though less efficiently than normal thyroid follicular cells. Radioiodine uptake is determined primarily by expression of the sodium iodide symporter (NIS) and is stimulated by TSH, requiring expression of the TSH-R. The retention time for radioactivity is influenced by the extent to which the tumor retains differentiated functions such as iodide trapping and organification. After near-total thyroidectomy, substantial thyroid tissue often remains, particularly in the thyroid bed and surrounding the parathyroid glands. Consequently, 131I ablation is necessary to eliminate remaining normal thyroid tissue and to treat residual tumor cells.
Indications The use of therapeutic doses of radioiodine remains an area of controversy in thyroid cancer management. However, postoperative thyroid ablation and radioiodine treatment of known residual PTC or FTC clearly reduces recurrence rates but has a smaller impact on mortality, particularly in patients at relatively low risk. This low-risk group includes most patients with stage 1 PTC with primary tumors <1.5 cm in size. For patients with larger papillary tumors, spread to the adjacent lymph nodes, FTC, or evidence of metastases, thyroid ablation and radioiodine treatment are generally indicated.
131I Thyroid Ablation and Treatment As noted earlier, the decision to use 131I for thyroid ablation should be coordinated with the surgical approach, as radioablation is much more effective when there is minimal remaining normal thyroid tissue. A typical strategy is to treat the patient for several weeks postoperatively with liothyronine (25 μg bid or tid), followed by thyroid hormone withdrawal. Ideally, the TSH level should increase to >50 mU/L over 3–4 weeks. The level to which TSH rises is dictated largely by the amount of normal thyroid tissue remaining postoperatively. Recombinant human TSH (rhTSH) has also been used to enhance 131I uptake for postsurgical ablation. It appears to be at least as effective as thyroid hormone withdrawal and should be particularly useful as residual thyroid tissue prevents an adequate endogenous TSH rise.
A pretreatment scanning dose of 131I (usually 111–185 MBq [3–5 mCi]) can reveal the amount of residual tissue and provides guidance about the dose needed to accomplish ablation. However, because of concerns about radioactive "stunning" that impairs subsequent treatment, there is a trend to avoid pretreatment scanning and to proceed directly to ablation, unless there is suspicion that the amount of residual tissue will alter therapy. A maximum outpatient 131I dose is 1110 MBq (29.9 mCi) in the United States, though ablation is often more complete using greater doses (1850–3700 MBq [50–100 mCi]). Patients should be placed on a low-iodine diet (<50 μg/d urinary iodine) to increase radioiodine uptake. In patients with known residual cancer, the larger doses ensure thyroid ablation and may destroy remaining tumor cells. A whole-body scan following the high-dose radioiodine treatment is useful to identify possible metastatic disease.
Follow-Up Whole-Body Thyroid Scanning and Thyroglobulin Determinations An initial whole-body scan should be performed about 6 months after thyroid ablation. The strategy for follow-up management of thyroid cancer has been altered by the availability of rhTSH to stimulate 131I uptake and by the improved sensitivity of Tg assays to detect residual or recurrent disease. A scheme for using either rhTSH or thyroid hormone withdrawal for thyroid scanning is summarized in Fig. 48-4. After thyroid ablation, rhTSH can be used in follow-up to stimulate Tg and 131I uptake without subjecting patients to thyroid hormone withdrawal and its associated symptoms of hypothyroidism as well as the risk of tumor growth after prolonged TSH stimulation. Alternatively, in patients who are likely to require 131I treatment, the traditional approach of thyroid hormone withdrawal can be used to increase TSH. This involves switching patients from T4 to the more rapidly cleared hormone liothyronine (T3), thereby allowing TSH to increase more quickly. Because TSH stimulates Tg levels, Tg measurements should be obtained after administration of rhTSH or when TSH levels have risen after thyroid hormone withdrawal.
In low-risk patients who have no clinical evidence of residual disease after ablation and a basal Tg <1 ng/mL, increasing evidence supports the use of rhTSH-stimulated Tg levels 1 year after ablation, without the need for radioiodine scanning. If stimulated Tg levels are low (<2 ng/ml) and, ideally, undetectable, these patients can be managed with suppressive therapy and measurements of unstimulated Tg every 6–12 months. The absence of Tg antibodies should be confirmed in these patients. On the other hand, patients with residual disease on whole-body scanning or those with elevated Tg levels require additional 131I therapy. In addition, most authorities advocate radioiodine treatment for scan-negative, Tg-positive (Tg >5–10 ng/mL) patients, as many derive therapeutic benefit from a large dose of 131I.
In addition to radioiodine, external-beam radiotherapy is also used to treat specific metastatic lesions, particularly when they cause bone pain or threaten neurologic injury (e.g., vertebral metastases).
New Potential Therapies Kinase inhibitors are being explored as a means to target pathways known to be active in thyroid cancer, including the Ras, BRAF, epidermal growth factor receptor, vascular endothelial growth receptor, and angiogenesis pathways. Partial responses have been seen in small trials using motesaniv, sorafenib, and other agents, but the efficacy of these agents awaits larger studies.