Staging of Thyroid Carcinoma

The International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have agreed on a staging system in thyroid cancer.^4,5 As stated by the AJCC, “the principal purpose served by international agreement on the classification of cancer cases by extent of disease was to provide a method of conveying clinical experience to others without ambiguity.” The AJCC is based on the TNM system, which relies on assessing three components: (1) the extent of the primary tumor (T), (2) the absence or presence of regional lymph node metastases (N), and (3) the absence or presence of distant metastases (M). The TNM system allows a reasonably precise description and recording of the anatomic extent of disease and provides a reliable estimate of the risk of dying from thyroid cancer, not necessarily risk of recurrence. With the pathologic classification (pTNM) that is based on surgical pathology data, a precise size can be assigned to the primary tumor, extrathyroid invasion is demonstrated, and the histology is unequivocally identified.

A previous classification dating back to 1992, the primary thyroid tumor (T) status was defined according to the size of the primary lesion: T1, greatest diameter 1 cm or smaller; T2, larger than 1 cm but not larger than 4 cm; T3, larger than 4 cm; T4, direct (extrathyroidal) extension beyond the thyroid capsule.⁴ The 2002 TNM classification extended the T1 group to include tumors no larger than 2 cm,⁵ and distinguished between T4a (theoretically resectable) and T4b (unresectable) tumors, for which treatment options and prognosis differ. The most recent TNM classification, published in 2010, defines microcarcinomas as not larger than 1 cm, now classified as T1a, from other small tumors, larger than 1 cm but no larger than 2 cm, now classified as T1b.⁶ This distinction is based on the excellent prognosis of microcarcinoma and on recent data showing that microcarcinoma may be treated with lobectomy or total thyroidectomy with no difference in prognosis, whereas for tumors larger than 1 cm, lobectomy seems to convey a higher risk of recurrence and mortality.^8,9 The most recent classification also subdivides T categories into Ts, solitary tumors, and Tm, multifocal tumors, with the largest tumor focus determining the numerical level of the T stage (the sizes of the foci are not added together).

The classification of regional disease has remained the same over the years, distinguishing only N0 and N1, because of the low impact of nodal disease on overall prognosis. For pathologic N staging, ordinarily six lymph nodes should be found at pathology to qualify for the definition of N0 (although there are few data on central compartment neck dissection supporting this number) and even for smaller number of nodes removed, the pN0 classification still holds. In addition, the prognostic difference between central lymph node metastases and other regional metastases (Na versus Nb) has yet to be validated. In one study, for example, the risk of persistent or recurrent disease appeared to be related to the involvement of the central neck compartment, the number of involved lymph nodes, and the number of lymph nodes with extracapsular spread.⁷ Currently, it is not possible to ascertain whether the modifications included in the 2010 TNM classification will significantly improve its prognostic value or will have a clinical impact on therapeutic strategies.

For purposes of analysis, TNM stage-groups have been described (Table 50-1). The age of the patient is included because of its importance in predicting the behavior and prognosis of thyroid cancer. The stage grouping has not changed from the 2002 classification. According to this staging classification, all patients younger than age 45 years are in stage I, unless they have distant metastases, in which case they are in stage II. Stages III and IV do not exist in this age group. In young patients and especially in children, however, the risk of recurrence is high and may be underestimated by the TNM staging system. For older patients (age 45 years or more) the tumor and node stages have a larger effect on prognosis, most likely in part because of the tumor behavior in this age group. Patients with widespread nodal disease are in stage IVA.

Table 50-1 The Tumor, Node, Metastases (TNM) Scoring System ^4-6

Clinical History

Although PTCs can occur at any age, most occur in patients between 30 and 50 years of age (mean age, 45 years).^12,13 Women are affected more frequently (female predominance, 60% to 80%). Most primary tumors are 1 to 4 cm in size. PTC is frequently multifocal when it occurs in a single lobe, and it is bilateral in 20% to 80% of cases, depending on whether or not the thyroid was meticulously examined. Extrathyroidal invasion of adjacent soft tissues is present in about 15% (range 5% to 34%) at primary surgery, and about one third of PTC patients have clinically or ultrasonographically evident lymphadenopathy at presentation. About 35% to 50% of excised neck nodes have histologic evidence of involvement, and in children nodal involvement may be present in up to 90%. Only 1% to 7% of PTC patients have distant metastases (DM) at diagnosis. Spread to mediastinal nodes is usually associated with extensive nodal involvement in the neck.

Only a fraction (~ 15%) of patients with PTC are likely to experience relapse of disease, which is located in the neck for three fourths of these patients, and more frequently in lymph nodes than in the thyroid bed or in soft tissue; 80% of recurrences occur during the 5 first years of follow-up. Even fewer patients (~ 5%) have a lethal outcome. Among those with lethal PTC, 20% of deaths occur in the first year after diagnosis, and 80% of the deaths occur within 10 years.^12–16

Multivariate analyses have been used to identify variables predictive of cause-specific mortality. Increasing age of the patient and the presence of extrathyroidal invasion are independent prognostic factors in all studies. The presence of initial DM and large size of the primary tumor are also significant variables in most studies, and some groups have reported that histopathologic grade (degree of differentiation) is an independent variable. The completeness of initial tumor resection (postoperative status) is also a predictor of mortality. The presence of initial neck lymph node metastases, although relevant to future nodal recurrence, does not influence cause-specific mortality. Several scoring systems based on these significant prognostic indicators have been devised and provide prediction of postoperative events comparable to that of the internationally accepted TNM staging system. Each system allows one to assign the majority of PTC patients (80% or more) to a low-risk group, in which the cause-specific mortality at 25 years is less than 2%, and the others (a small minority) to a high-risk group, in which almost all the cancer-related deaths are observed.

Cox model analysis and stepwise variable selection has led to a final prognostic model that includes five variables: distant metastases (DM), age, completeness of resection, local invasion, and size (MACIS). The final score is calculated as follows: 3.1 (if age 39 years or younger) or 0.08 (if age 40 years or older) × age + 0.3 × tumor size (in centimeters) + 1 (if tumor not completely resected) + 1 (if locally invasive) + 3 (if DM are present). The MACIS scoring system permits identification of groups of patients with different risks of dying from PTC. Twenty-year cause-specific survival rates for patients with MACIS scores of less than 6, 6 to 6.99, 7 to 7.99, and 8 + were 99%, 89%, 56%, and 27%, respectively (p < .0001). When cumulative mortality from all causes of death was considered, approximately 85% of PTC patients with MACIS scores below 6 had no excess mortality over rates predicted for control subjects in the general population.¹³

Natural History

FTC tends to occur in older people, with a mean age of over 50, increasing to 60 years for oxyphilic FTC. As in most thyroid malignancies, women outnumber men by more than 2 to 1. Most patients with FTC present with a painless thyroid nodule, with or without background thyroid nodularity. Lymph node metastases to the neck in FTC are so rare that “wherever they are observed, the alternative possibilities of follicular variant papillary carcinoma, oncocytic carcinoma, and poorly differentiated carcinoma should be considered.”³

The tumor size in FTC is usually larger than those seen with PTC. Between 5% and 20% of patients may have DM at presentation. The most common sites for DM in FTC are lung and bone. When a DM is the first manifestation of the disease, definitive proof of its thyroid origin should be obtained, usually by a biopsy of a metastasis, before performing any thyroid surgery.

The nodal recurrence rate for FTC is the lowest for any differentiated thyroid carcinoma, being around 2% at 20 postoperative years, and is higher in patients with Hurthle cell carcinoma, increasing to approximately 15%. Local recurrences at 20 years occur in approximately 20% of FTCs and 30% of Hurthle cell carcinomas, and DM rates are around 25%. The death rates tend to parallel the curves for development of DM, and cause-specific survival rates approximate 80% at 20 postoperative years.^18,19

The risk factors that predict outcome in FTC are largely the same as in PTC: increasing age of the patient, DM at presentation, large tumor size, and the presence of local (extrathyroidal) invasion. The pTNM risk group categorization has proved to be useful in FTC. In addition, vascular invasiveness, lymphatic involvement at presentation, DNA aneuploidy, and oxyphilic histology are potential prognostic variables unique to FTC. The importance of vascular invasion is underscored by a study showing that FTC patients with minimal capsular invasion and no evidence of vascular invasion had 0% cause-specific mortality at 10-years of follow-up.²⁰

Iodine 131 Therapy

¹³¹I is an effective agent for delivering high radiation doses to the thyroid tissue with low spillover to other portions of the body. The radiation dose to the thyroid tissue is related to the tissue concentration of iodine, the ratio between the total tissue uptake and the volume of functional tissue, and the effective half-life of ¹³¹I in the tissue. Thyroid tissue is able to concentrate iodine only after thyroid-stimulating hormone (TSH) stimulation, but even after optimal TSH stimulation, iodine uptake in neoplastic tissue is always lower than in normal thyroid tissue and may not be detectable in about one third of cases (see Chapter 51, Postoperative Radioactive Iodine Ablation and Treatment of Differentiated Thyroid Cancer).²⁴

¹³¹I therapy is a complement to total thyroidectomy in selected patients and should not be considered as a therapeutic means to justify incomplete and insufficient surgery. It is given postoperatively for three reasons. First, it destroys normal thyroid remnants (this is termed ablation), thereby increasing the sensitivity of subsequent ¹³¹I total-body scanning and the specificity of measurements of serum Tg for the detection of persistent or recurrent disease. Second, it may destroy occult or known microscopic carcinoma, thereby potentially decreasing the long-term recurrence rate. Finally, it makes it possible to perform a postablative ¹³¹I total-body scan, a sensitive tool for detecting persistent carcinoma.^1,25

Postoperative ¹³¹I therapy should be used selectively, and not all patients with a diagnosis of follicular cell–derived thyroid carcinoma benefit from routine postoperative radioiodine therapy. In very low risk patients, the long-term prognosis after surgery alone is so favorable that ¹³¹I ablation is not recommended. Routine prophylactic lymph node dissection in all PTC patients also permits selected T1N0 patients to avoid radioiodine administration.²² However, patients with persistent disease and those who are at high risk of recurrence (Table 50-2) are routinely treated with ¹³¹I because such therapy can potentially decrease both recurrence and death rates. Young children are also usually candidates for postoperative radioiodine therapy because they may have extensive neck lymph node involvement and in such case frequently harbor pulmonary metastases that may not be detectable with standard radiographs or even with computed tomography (CT) imaging of the chest. Finally, in the other patients, there is currently no evidence that it may improve the long-term outcome, especially if surgery has been complete.

Table 50-2 Indications for ¹³¹I Treatment in Patients with Papillary, Follicular, or Hurthle Cell Thyroid Carcinoma after Initial Definitive Near-Total Thyroidectomy

Postoperatively, no levothyroxine (LT4) treatment is given for 4 to 6 weeks, but triiodothyronine (LT3) can be substituted for at least 3 to 4 weeks and then discontinued for 2 weeks before radioiodine studies. At that time, the serum TSH level should be greater than an empirically determined level of 25 to 30 mU/L. At this level of TSH, an undetectable serum Tg level indicates a very low risk of finding of persistent disease or subsequent recurrence.²⁵ Intramuscular injections of rhTSH (0.9 mg for 2 consecutive days, with ¹³¹I administered 1 day after the second injection) given while continuing LT4 treatment may achieve an effective stimulation of radioiodine uptake by normal thyroid remnants, with ablation rates similar to those obtained with withdrawal.²⁷ Its use prevents hypothyroidism and maintains quality of life, induces a lower radiation exposure to the body, and permits an earlier discharge from the hospital.^28,29 In addition, short-term recurrence rates have been found to be similar in patients prepared with thyroid hormone withdrawal or rhTSH, even in those with initial lymph node involvement.³⁰ rhTSH is approved for remnant ablation in the United States, Europe, and many other countries around the world.

In case of an incomplete thyroidectomy, neck uptake may be measured with a tracer activity of ¹³¹I or ¹²³I, but the activity used should be small enough to avoid stunning—that is, a decrease of thyroid uptake with the subsequent high activity of radioiodine—that is possibly due to a decrease in NIS (sodium/iodide symporter) expression in irradiated cells.^31,32 High uptake (> 10%) and high risk of persistent disease should lead to completion surgery. ¹³¹I therapy can be administered to patients for whom surgery can be considered complete, with no such pretherapy scanning because of its low impact on the decision to ablate, because of concerns over ¹³¹I-induced stunning, and because usually 24-hour uptakes are considerably less than 10%.³³

A total body scan is performed 3 to 7 days after the treatment activity and is highly informative in patients with a low uptake (< 1%) in the thyroid bed. Additional metastatic foci have been reported in 10% to 26% of patients scanned following high-dose radioiodine treatment as compared with the diagnostic scan. ¹³¹I single-photon emission computed tomography (SPECT)/CT fusion imaging may provide superior lesion localization after remnant ablation.^34,35

Total ablation (defined as no visible uptake) may be verified by a ¹³¹I total-body scan 6 to 12 months later, typically with 2 to 5 mCi (74 to 185 MBq). However, a follow-up ¹³¹I total body scan is no longer routinely performed when the postablation scan has been informative (low uptake of remnants only), because it does not afford any further information as to prognosis.³⁶ Successful ablation is currently defined as an undetectable serum Tg level following rhTSH stimulation and a normal neck ultrasonography, usually performed 9 to 12 months after ablation.^1,25 Total ablation is achieved after the administration of either 100 mCi (3700 MBq) or 30 mCi (1100 MBq) in more than 80% of patients who had at least a near-total thyroidectomy, after preparation with either withdrawal or rhTSH.³⁷ After less extensive surgery, ablation is achieved in only two thirds of patients with 30 mCi (1100 MBq). Therefore, a near-total or total thyroidectomy should be performed in all patients who are to be treated with ¹³¹I. In addition, in high-risk patients, a high activity (100 mCi or more) should be administered with the aims of ablating normal thyroid remnants and irradiating residual neoplastic tissue. Total ablation requires that a dose of at least 300 Gy (30,000 rad) be delivered to thyroid remnants.³⁸ In certain cases, dosimetric study can allow a more precise estimate of the ¹³¹I dose to be administered while avoiding the administration of excessive activities.³⁹

External Beam Radiation Therapy

External beam radiation therapy to the neck and mediastinum is indicated only for older patients (> 45 years) with extensive PTC in whom complete surgical excision is impossible and in whom the tumor tissue does not take up ¹³¹I (see Chapter 52, External Beam Radiotherapy for Thyroid Malignancy).^40,41 Retrospective studies have shown that in these selected patients, radiotherapy decreases the risk of neck recurrence. The target volume encompasses the thyroid bed, bilateral neck lymph node areas, and the upper part of the mediastinum. Typically, 50 Gy (5000 rad) are delivered in 25 fractions over 5 weeks, with a boost of 5 to 10 Gy applied to any residual macroscopic focus.