What Is the Optimal Initial Treatment of Low-Risk Papillary Thyroid Cancer (and Why Is It Controversial)?

June 11, 2009

Patients with papillary thyroid cancer typically undergo a triad of consecutive initial treatments, comprising surgery, radioiodine therapy, and thyroid hormone suppression of serum thyrotropin (thyroid-stimulating hormone, or TSH).

ABSTRACT: The incidence of papillary thyroid cancer has been rising steadily over the past 3 decades. Most tumors in this setting are regarded as low risk, but recurrence rates are high, producing controversy about initial therapy. Microcarcinomas smaller than 1 cm are generally best treated with lobectomy alone. Total thyroidectomy should be performed for tumors 1 cm or larger or for tumors that have metastasized. Prophylactic central and lateral neck lymph node compartment dissection uncovers unsuspected metastases in about half the patients, which may alleviate the need for postsurgical radioiodine therapy but can be associated with surgical complications. Radioiodine may diminish tumor recurrence but is complicated by injury to nonthyroidal tissues and by dose-related nonthyroidal cancers that occur in a small number of patients. Tumors that are metastatic, invasive, or multifocal or have aggressive histologic features should be treated with radioiodine. Total-body irradiation can be significantly reduced by preparing the patient with recombinant human thyrotropin and by using smaller amounts of radioiodine (~30 mCi). The natural history of papillary cancer is such that patients who achieve disease-free status after total thyroidectomy and radioiodine therapy usually achieve normal life expectancy.

Patients with papillary thyroid cancer typically undergo a triad of consecutive initial treatments, comprising surgery, radioiodine therapy, and thyroid hormone suppression of serum thyrotropin (thyroid-stimulating hormone, or TSH). Each modality, albeit effective, is laced with controversy when applied to the initial treatment of low-risk papillary thyroid cancers. The aim of this article is to address the current controversies surrounding the management of low-risk papillary thyroid cancer in light of the current literature and to provide an analysis of contemporary opinions and recommendations for initial therapy.

The Epidemiologic Controversy


What is optimal surgery for a 2-cm papillary thyroid cancer without preoperatively apparent cervical lymph node metastases?
What is the role, if any, of postoperative radioiodine therapy, and if so treated, should patients undergo thyroid hormone withdrawal or preparation with intramuscular recombinant human TSH?
What is the role of postoperative thyroid hormone suppression of TSH?
What is the optimal means of identifying residual thyroid cancer?

The initial management of thyroid cancer has attracted considerable attention in recent years, mainly because of its relentlessly rising incidence, which increased 2.4-fold from 1973 to 2000.[1] This is almost entirely attributable to a nearly threefold increase in papillary thyroid cancer, which is by far the most common form of the disease, comprising over 80% of all thyroid cancers (throughout this review, percentages are rounded to the nearest integer).[2]

Between 1988 and 2002, when thyroid cancer tumor size was first included in the National Cancer Institute’s Surviellance, Epidemiology and End Results (SEER) database,[1] it became apparent that nearly half the thyroid cancers diagnosed during this period were papillary microcarcinomas 1 cm or smaller, and nearly 90% were papillary cancers 2 cm or smaller.[3] Tumors of this size are widely acknowledged to be associated with low mortality rates, and the overall mortality rates for thyroid cancer during this period remained stable at 0.5 deaths per 100,000 persons in the population.[3]

It was therefore suggested that these trends-combined with the substantial reservoir of occult thyroid cancer in the general population-are a manifestation of the detection of subclinical disease, not an increase in the true occurrence of thyroid cancer.[3] The authors of this study expressed understandable concern that overdiagnosis makes it difficult to identify which patients need treatment. In addition, most of the patients being studied underwent total thyroidectomy, even if the papillary cancer was very small. The authors consequently recommended that a more cautious diagnostic approach (perhaps simply providing follow-up for symptomatic thyroid nodules) is worthwhile, and that papillary cancers smaller than 1 cm could be classified as a normal finding.[3]

Several issues regarding the epidemiology of small thyroid cancers require further explication. The age of patients at the time of thyroid cancer diagnosis ranges from 4 years to 85 years or older, peaking at 40 to 45 years in women and 50 to 55 years in men.[1] The notion that there is a large reservoir of occult nonthreatening thyroid cancers stems from autopsy studies that report a high prevalence of undiagnosed thyroid cancers.[4] Yet it is highly unlikely that data from autopsy studies from around the world accurately reflect the rates of clinical thyroid cancer in the United States population, considering that the occult thyroid cancer prevalence rate in 20 autopsy series ranges from 2% to 36%.[4] The autopsy study[5] with the highest rate of occult thyroid cancers (36%) found that 67% were discovered in nodular goiters as compared with 24% in otherwise normal thyroid glands, and almost half were in individuals 61 years of age or older.[5] In contrast, clinical cases of thyroid cancer are found with equal frequency in multinodular goiters and single thyroid nodules; furthermore, autopsy studies in younger persons find considerably fewer (2%) occult thyroid cancers.[4]

Case Report: A Young Woman With a Thyroid Nodule


An asymptomatic 20-year-old woman is found to have an asymptomatic thyroid nodule during a routine examination. Her general health has been excellent, and there is no familial history of thyroid disease. She takes no medicine and does not use over-the-counter or recreational drugs. Her medical history reveals no prior significant medical problems, and no one in the family has thyroid disease.

Physical examination is entirely normal except for a 2-cm nodule in the right thyroid lobe. Serum TSH measures 1.5 mIU/L, and routine laboratory tests are normal. Office ultrasonography shows a 1.9 × 8.7 × 2.0 cm mixed hypoechoic/isoechoic right thyroid nodule with irregular borders and scattered 1 to 2 mm calcifications. The thyroid and lateral neck compartments are ultrasonographically normal. Ultrasound- guided fine-needle aspiration biopsy of the thyroid nodule is diagnostic of papillary thyroid cancer.

After explaining the risks and benefits of surgery, you recommend total thyroidectomy and a prophylactic central neck (level VI) compartment dissection. The histopathologic diagnosis of the right thyroid nodule is classic papillary thyroid cancer, and 8 of 10 level VI lymph nodes are positive for tumor. Six weeks after surgery, neck ultrasonography shows no residual tumor in the thyroid bed and no residual cervical lymph nodes. After discussing the various options, you recommend radioiodine remnant ablation.

Also, the gender distribution of thyroid cancers at autopsy is nearly equal,[4] whereas in clinical studies the rate in women is threefold that of men, suggesting ascertainment bias in the autopsy studies. Small thyroid cancers incidentally found at surgery for benign thyroid disease is another matter. The rate of unanticipated microcarcinomas in surgical thyroid specimens is variable, ranging from approximately 2% to 22% in 11 series.[4] This is stronger evidence for a reservoir of very small papillary thyroid cancers in the general population that might explain some of the increase in papillary microcarcinomas, but the eventual outcome of such small tumors cannot be ascertained with certainty.

While overall mortality rates from thyroid cancer have been stable for the past 3 decades, this does not fully describe the outcome in subsets of patients.[6] From 1995 through 2000, the 5-year relative survival rates for thyroid cancer were 97.3% in women and 93.5% in men, which translates into a thyroid cancer mortality rate in men that is more than twice that in women (P < .05).[1] From 1992 through 2001, the annual percent change in death rates decreased 0.03% in women and increased 2.3% in men (P < .05).[1] This was the largest increase in cancer mortality of all malignancies in men in the United States,[1] which can be largely attributed to delayed diagnosis and significantly more advanced tumor stage at the time of diagnosis in men.[1,6] Still, 5-year mortality rates in those age 45 years or younger are very low (approximately 1%).[1]

What are the clinical implications of these epidemiologic findings?

Mortality rates for thyroid microcarcinomas and tumors smaller than 2 cm are very low. Identifying patients who are likely to remain disease-free without therapeutic intervention, however, is another matter. A large study of watchful waiting found that careful observation without surgery might be acceptable for incidentally discovered low-risk papillary microcarcinomas but that careful and systematic surgery should be performed for invasive tumor or lymph node metastases.[7] A study[8] of over 2,000 patients with microcarcinoma followed for up to 40 years found that younger patients with smaller tumors have a better prognosis than older patients with larger tumors (6 to 10 mm). In all, 40% of patients older than 55 years had a recurrence after 30 years of follow-up, as compared with less than 10% of younger patients.

To avoid this problem of microcarcinomas, the American Thyroid Association (ATA) evidence-based guidelines[9] recommend performing fine-needle aspiration biopsy (FNAB) for tumors 1 cm or larger unless the patient is at high risk for thyroid cancer (such as those with a history of head and neck radiation), in which case tumors > 5 to 9 mm can be considered for FNAB. Even then, the natural history of the smaller tumors in an individual patient is uncertain.

Tumor Staging Systems

TABLE 1


TNM Classification System for Differentiated Thyroid Cancer

Problems inherent to thyroid cancer staging systems complicate initial management decisions. According to the 6th edition of the American Joint Commission on Cancer (AJCC) tumor-node-metastasis (TNM) staging system,[10] patients under 45 years old with papillary thyroid cancer are classified as stage I (low risk) if there are no distant metastases, regardless of the tumor size, invasion, or locoregional metastases (Table1); stage II is defined by distant metastases. Patients age 45 years or older are classified as stage I if the primary tumor is smaller than 1 cm and is limited to the thyroid without metastases, and are classified as stage II if the primary tumor is larger than 1 cm but not larger than 4 cm and limited to the thyroid. The criteria for stages III and IV in older patients are shown in Table 1.

A number of other prognostic staging systems also have been used to predict the outcome of papillary cancer[11]; however, none account for more than a small portion of the uncertainty in predicting thyroid cancer outcome, and there is no statistically significant superiority of any system over that of the AJCC TNM classification.[11,12] There also are statistically significant differences between papillary and follicular thyroid cancer assessed in different tumor staging systems, with each possessing its own set of independent prognostic factors for cause-specific survival,[13] underscoring the inadequacy of these staging systems in individual patients. The ATA guidelines[9] suggest that TNM staging should be used for all reports of the treatment and outcome of patients with thyroid cancer because the classification is universally available and widely accepted.

Current risk stratification systems rely almost exclusively on clinical, pathologic, and imaging data obtained during the initial evaluation and therapy. Still, none adequately incorporate various histologic subtypes of thyroid cancer, or other variables that might alter prognosis such as mitoses, areas of tumor necrosis, or molecular characteristics of the primary tumor. Moreover, the current staging systems are static representations of the patient at the time of presentation and are not easy to modify as new data become available during follow-up. It is important to recognize that prognosis shifts over time, depending on the inherent biologic properties of the tumor and its response to therapy, which provide much more practical information than does static postoperative assessment. How should clinical risk be assessed?

FIGURE 1


Thyroid Cancer Recurrence and Mortality

The primary problem with planning therapy for papillary cancer according to staging systems is that virtually all patients under age 45 years with papillary thyroid cancer are identified as being at low risk only on the basis of cancer-induced mortality. Although survival rates are typically favorable in this group, the disease in young patients is often marked by one or more recurrences before the patient can be rendered free of disease. Current staging systems are insensitive to tumor recurrence, a major source of morbidity that seriously impacts the patient’s quality of life. There is little doubt that persistent or recurrent posttreatment locoregional recurrences are a major part of the management of papillary cancer (Figure 1).

The ATA guidelines[9] define low-risk patients as having none of the following tumor characteristics: (1) local or distant metastases; (2) residual macroscopic tumor; (3) tumor invasion of locoregional tissues or structures; (4) aggressive histology such as tall cell, insular, columnar cell carcinoma, or vascular invasion; and (5) radioiodine (131I) uptake outside the thyroid bed on the first posttreatment whole body scan. This is a much more flexible definition of outcome, which is more closely related to the actual evolution of this disease.

Initial Thyroid Surgery

The natural history of papillary thyroid cancer is such that patients who achieve disease-free status after total thyroidectomy and 131I therapy usually reach normal life expectancy.[14] Yet despite slow tumor growth and favorable prognosis for survival with small papillary thyroid cancers, the most challenging problem is controlling locoregional recurrences.[15] Whether this is best accomplished with surgery or 131I-or whether patients with small papillary cancers should be treated at all-has been the substance of ongoing debate, especially concerning patients with tumors smaller than 2 cm.[3,6] The optimal extent of surgery has been debated for decades, with some opting for total thyroidectomy[15] and others for lobectomy or subtotal thyroidectomy,[16] particularly for younger patients with small tumors. This is a critical decision. The extent of initial surgery for papillary thyroid cancer sets the stage for subsequent adjunctive therapy.

What is the optimal extent of initial thyroid surgery?

FIGURE 2


Cumulative Thyroid Cancer Recurrence Rates

The debates concerning the extent of thyroid surgery have been largely silenced by a recent study of the AJCC National Cancer Data Base by Bilimoria et al,[17] including 52,173 patients with papillary thyroid cancer who were surgically treated from 1985 through 1988.[17] The operations were classified as either total thyroidectomy (bilateral resection) or lobectomy (unilateral resection). In all, 43,277 patients (83%) had total thyroidectomy and 8,946 (17%) had lobectomy. The tumors were smaller than 1 cm in 24%, 1 to 2 cm in 30%, and larger than 2 cm in 46% of the patients. At the time of diagnosis, metastases were found in lymph nodes in almost 35% of the patients, and 2% had distant metastases. Unfortunately, information concerning 131I therapy was missing in approximately two-thirds of the patients.

Recurrence rates were almost 6% at 5 years and 9% at 10 years, increasing significantly by 1 cm tumor increments (P < .001, Figure 2). The 10-year cancer-specific survival rates declined with increasing tumor size; however, survival was statistically worse only for patients with tumors larger than 4 cm (P < .0001, Figure 3). Multivariate analysis found that lobectomy was associated with a 57% higher risk of recurrence (P = .001) and a 21% higher risk of cancer death (P = .027) compared with total thyroidectomy.

FIGURE 3


Cumulative Thyroid Cancer Mortality Rates

To determine the threshold size that affected outcomes, tumor size was stratified by 1-cm increments up to 4 cm for the Cox analysis. For patients with tumor size less than 1 cm, there was no difference in recurrence or survival between total thyroidectomy and lobectomy. However, for patients with tumors 1 cm or larger, lobectomy was associated with a 15% higher risk of recurrence (P = .04) and a 31% higher rate of cancer death (P = .04), as compared with that of total or near-total thyroidectomy. To evaluate the possibility of a confounding effect of larger tumors upon the analysis, patients with tumors 1 to 2 cm in size were examined separately. In this group, patients who underwent lobectomy had a 24% higher risk of recurrence (P = .04) and a 49% higher risk of 10-year cancer mortality compared with those who had a total thyroidectomy (P = .04).

ATA recommendation R26[9] is that the surgical procedure for patients with thyroid cancer larger than 1 cm should be a near-total or total thyroidectomy unless there are contraindications to this surgery (near-total thyroidectomy is removal of all thyroid tissue, leaving amounts of thyroid tissue < 1 cm to spare the recurrent laryngeal nerves and parathyroid glands). The guideline further suggests that thyroid lobectomy alone may be sufficient treatment for small (< 1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases. The ATA classifies that as an “A” recommendation (ie, their guidelines task force “strongly recommends” it).[9]

Initial Surgery for Cervical Lymph Node Metastases

FIGURE 4


Cervical Lymph Node Compartments

Ongoing controversy surrounds the optimal initial management of papillary lymph node metastases.[18,19] The neck is divided into seven contiguous lymph node compartments that are identified by roman numerals I to VII (Figure 4). Compartment VI creates the greatest concern for surgical complications and unsuspected lymph node metastases, which are found in 50% to 65% of patients.[20,21] Still, lymph node metastases occur nearly as often in the ipsilateral lateral cervical compartment levels III and IV, with fewer metastases in level II, while a small number skip past the usual path of metastasis and are found in contralateral compartments III and IV.[22]

Lymph node metastases are most common at the extremes of age. They are found in 25% to 60% of both low- and high-risk patients, depending on the extent of the compartment dissection.[23,24] Children with papillary thyroid cancer present with even more extensive lymph-node metastases, ranging from 50% to 90% at the time of diagnosis.[25-28] Children nonetheless have a relatively favorable outcome after initial therapy, with disease-free survival rates of 80% at 5 years and 60% at 10 years, providing they are adequately treated with total thyroidectomy and 131I ablation.[25,26,29] Children and adolescents have a good prognosis with prolonged survival, even when extensive regional disease or lung metastases are present at the time of diagnosis, but very long-term follow-up is needed to appreciate the impact of the disease in children.[30,31] It is best to think of outcome in young patients in terms of normal life expectancy, which casts a different light on survival and recurrence rates.

It has been widely held that lymph node metastases from papillary thyroid cancer increased local recurrence rates without affecting survival; however, newer studies suggest otherwise. A study of almost 10,000 patients found 14-year all-cause survival rates of 79% and 82% in patients with and without lymph-node metastases, respectively (P < .05).[32]

Another study[33] of 33,088 patients with papillary cancer lymph node metastases found a 46% increased risk of cancer-specific death in patients age 45 years or older compared with patients who did not have lymph node metastases (P < .001).[33]

Metastatic lymph nodes that remain after initial therapy are the most common cause of recurrence.[23,24] Moreover, the larger the number of cervical lymph node metastases, the more serious the long-term outcome in terms of tumor recurrence and distant metastases.[34] This occurs in both children and adults with papillary thyroid cancer, and in adults with papillary microcarcinomas < 1 cm.[8,20,23,35]


No further therapy other than levothyroxine
Maintain TSH < 0.1 mU/L indefinitely
Radioiodine therapy with 30 mCi
Radioiodine therapy with 100 mCi

The treatment of lymph node metastases rests on a fine balance of the risks and benefits of both lymph node surgery and the use of postoperative 131I. The ATA guidelines[9] suggest systematic lymph node dissection, which refers to an en bloc dissection of anatomic node compartments, as opposed to selectively excising lymph-nodes, often referred to as “berry-picking,” which is not recommended. Therapeutic lymph-node dissection is removal of malignant lymph nodes identified before or at the time of surgery, whereas prophylactic dissection refers to excision of lymph nodes that are considered normal preoperatively and at the time of surgery.

ATA recommendation R27[9] suggests that therapeutic central-compartment (level VI) or lateral neck compartment dissections should accompany total thyroidectomy to provide clearance of disease from the central neck (B recommendation, “based on fair evidence”).[9] Recommendation R27a suggests that prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary cancer with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4), which is a category C recommendation (“expert opinion”); and recommendation 27c suggests that near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2) noninvasive clinically node-negative papillary thyroid cancers (C recommendation).[9]

Yet the verification of this recommendation lies in identifying lymph node metastases preoperatively or at the time of surgery. The ATA guidelines suggest preoperative cervical ultrasonography in all patients undergoing thyroidectomy. Although this identifies suspicious cervical lymph nodes in up to half the cases,[36,37] altering the surgical approach in many patients, neck ultrasonography has important limitations. It may fail to identify extracapsular lymph node invasion deep in the neck and small lymph node metastasis within the central compartment (VI), which may lower the sensitivity of ultrasonography to 35% or more.[38,39]


Total thyroidectomy with prophylactic level VI lymph node dissection done by a very experienced surgeon is the optimal means of surgically removing all tumors in the neck, but can result in hypoparathyroidism or unintended laryngeal nerve damage.
Radioiodine (131I) therapy is the optimal means of destroying residual microscopic thyroid cancer, but is associated with damage to non-thyroidal tissues and carries a small risk for causing nonthyroidal cancers and leukemia.
Following thyroid surgery that leaves no evidence of residual tumor, small amounts of 131I (~30 mCi) and preparation with recombinant human TSH significantly reduces total-body irradiation and permits follow-up with thyroglobulin to accurately identify occult tumor.
Patients can be reliably assured to be free of disease when all of the following are present: no clinical and ultrasound evidence of tumor, and undetectable serum thyroglobulin during both TSH suppression and stimulation without antithyroglobulin antibodies. TSH can be maintained in the low normal range by thyroid hormone when the patient is free of disease

White et al[19] conducted a systematic review using evidence-based criteria and found no prospective randomized studies to explain the impact on outcome of central lymph node dissection in patients with papillary thyroid cancer. The authors concluded that systematic compartment-oriented central lymph node dissection may decrease recurrence of papillary cancer and likely improves disease-specific survival (C recommendation). They also noted that adding central (level VI) lymph node dissection to total thyroidectomy can significantly reduce serum thyroglobulin (Tg) levels.[19] They found a higher than usual rate of permanent laryngeal nerve injury and hypoparathyroidism with compartment-oriented central lymph node dissection. This must be weighed against the fact that reoperation in the central neck compartment for recurrent papillary cancer substantially increases the risk of hypoparathyroidism and unintentional laryngeal nerve injury compared with total thyroidectomy with or without central lymph node dissection (C recommendation). This finding alone may support a more aggressive initial operation in the central neck.[19]

Until recently, only one strong study supported prophylactic compartment dissection. In this trial, 160 patients with papillary cancer had systematic (prophylactic) compartment-oriented dissection of lymph node metastases, which improved recurrence (P < .0001) and survival (P < .005) rates, especially for patients with T1 to T3 tumors.[40]

A very recent study from Paris by Bonnet et al[39] provides important new information on systematic (prophylactic) lymph node metastases. In this retrospective study of 115 consecutive patients ranging in age from 17 to 73 years (mean, 48.5), all had papillary cancers smaller than 2 cm, ranging from 1 to 19 mm (mean, 12.5). Patients were selected for study on the basis of tumor size and a negative preoperative neck ultrasound examination (preoperative T1, ,N0, M0, stage I). All underwent total thyroidectomy and bilateral prophylactic dissections of the central neck (level VI) and ipsilateral lateral neck (levels III and IV). Further lateral neck dissection was based on the results of frozen section analysis of metastatic involvement of ipsilateral lateral levels III and IV.

The main finding of the study was that 42% of the patients had lymph node metastases, 45% of which were in the central compartment and 57% involving the lateral compartment. Almost 40% of the tumors would have been missed if the surgery had involved only the central neck. In 29% of the patients, tumors extended beyond the thyroid capsule. The final surgery was extensive: all 115 patients had bilateral level VI dissections, 96 (94%) had ipsilateral systematic level III to IV dissections (which were bilateral in 6%), and 11% had ipsilateral level II, III, IV and V dissections because tumor was in the superior thyroidal pole. Only one patient had permanent unilateral vocal cord paralysis (0.9%), and another had permanent hypoparathyroidism (0.9%).

In this study, prophylactic lymph node dissection had an important impact on selective remnant ablation. Radioiodine was not administered in 42% of patients with tumors less than 20 mm in diameter without metastatic lymph nodes, and 58% of the patients were treated with 131I as a result of lymph node metastasis, extracapsular thyroid invasion, or unfavorable histologic subtype. At the 1-year follow-up, all of the patients had negative neck ultrasound examinations and 97% had an undetectable serum Tg during either TSH suppression or recombinant human thyrotropin-α (Thyrogen [rhTSH]) stimulation, indicating there was no evidence of residual tumor. Only one patient had persistent foci of 131I uptake after therapy.

What is the optimal surgical management of lymph node metastases?

The implications of such a large number of preoperatively undetected occult lymph node metastases and tumor invasion in patients with low-risk tumors cannot be ignored, nor can the complications of central-compartment dissection be disregarded. The safest and most thorough surgical approach seems to be total thyroidectomy with bilateral prophylactic level VI and ipsilateral levels III and IV lymph node compartment dissection, which must be performed by a highly experienced surgeon. This is associated with the lowest risk for surgical complications and the highest yield of malignant lymph nodes.[19]. Whether patients will accept such extensive surgery for a tumor widely regarded as low risk for mortality is another matter. The other two alternatives are watchful waiting for tumors smaller than 1 cm, or postoperative 131I therapy. Both are clearly second choices.

Efficacy and Risks of Iodine-131 Therapy

Postoperative 131I therapy is administered with the intent of eradicating small amounts of normal residual thyroid tissue, referred to as remnant ablation, with the further intent of destroying unrecognized occult residual tumor, ie, adjunctive tumor therapy. A systematic review and meta-analysis of the effectiveness of remnant ablation[41] concluded that 131I may be beneficial in decreasing recurrence, but the results were inconsistent for some outcomes.[41] An updated pooled analysis of remnant ablation[42] found a 2% lower risk of recurrent tumor in the form of distant metastases (95% confidence interval = 4%–1%; P < .0005).

On the favorable side, 131I remnant ablation facilitates follow-up with serum Tg measurements, a key test in identifying patients with residual tumor, and 131I destroys normal and malignant follicular cells that have functional sodium/iodine symporters. On the less favorable side, 131I poses a risk for radiation injury to many body tissues such as salivary glands, oral tissues, lacrimal ducts, stomach, breast, bone marrow, and other areas, which increases the long-term risk of 131I-induced nonthyroidal second cancers. The risk increases with the amount of 131I administered.[43] A European study[44] found a linear relationship between second nonthyroidal malignant solid tumors or leukemias and cumulative doses of 131I greater than about 500 mCi. The authors estimated that, as compared with the general population, 100 mCi of 131I administered to 10,000 patients will induce an excess of 54 solid malignant tumors and 3 leukemias during 10 years of follow-up.

Still, it is unknown whether a single 100-mCi treatment of 131I increases the risk of second nonthyroidal cancers or whether this requires very high cumulative amounts of 131I.[43,45] ATA recommendation R36 advises that the minimum activity of131I (30 to 100 mCi) necessary to achieve successful remnant ablation should be used, particularly for low-risk patients.[9] A recent study[46] confirmed that preparation with rhTSH significantly decreases whole-body irradiation by about 30%, including that to organs such as the stomach.[47] Administering 30 mCi for remnant ablation after rhTSH preparation thus substantially decreases whole-body irradiation from remnant ablation.[48]

What is the safest recommendation concerning remnant ablation?

Whether postoperative 131I should be administered is a matter of judgment and dependent on the patient’s views about such treatment. The adverse effects of 131I therapy can be significantly reduced by preparing the patient with a 2-week low-iodine diet and TSH stimulation with rhTSH instead of thyroid hormone withdrawal, using the smallest amount of 131I that is effective (30 mCi). This minimizes the risk of adverse effects, while providing a therapeutic effect equal to that of 50 to 100 mCi of 131I. The patient then can be assured that total-body irradiation with this approach will be as low as currently possible.

Postoperative Management With Levothyroxine

Levothyroxine suppression of TSH, which is known to stimulate follicular cell growth when elevated, comprises the last of the three phases of initial therapy. There is a strong association between thyroid hormone suppression therapy and reduction of major adverse clinical events.[9] Still, the optimal degree of TSH suppression by levothyroxine (LT4) is still unknown, especially in high-risk patients rendered free of disease.[9]

What are current recommendations for TSH suppression? ATA recommendation R49a suggests that for patients with persistent disease, the serum TSH should be maintained below 0.1 mU/L indefinitely in the absence of specific contraindications (B recommendation, fair evidence). R49b suggests maintaining the TSH levels at 0.02 to 0.5 mU/L for patients who are clinically and biochemically free of disease but who presented with high-risk disease (C recommendation). R49c suggests that the TSH may be kept in the normal range (0.3–2 mU/L) in patients who are free of disease, especially those at low risk for recurrence (B recommendation). Finally, R49d also suggests maintaining the TSH levels in the normal range for patients who have not undergone remnant ablation, are clinically free of disease, and have undetectable suppressed serum Tg and normal neck ultrasound (C recommendation).

Follow-up Criteria for the Absence of Persistent Tumor

The ATA[9] and European Thyroid Association (ETA)[49] provide explicit recommendations concerning verification of the absence of residual thyroid cancer. In patients who have undergone total or near-total thyroidectomy and thyroid remnant ablation, disease-free status comprises all of the following: (1) no clinical evidence of tumor, (2) no imaging evidence of tumor (no uptake outside the thyroid bed on the initial posttreatment whole-body scan, or, if uptake outside the thyroid bed had been present, no imaging evidence of tumor on a recent diagnostic radioiodine scan and neck ultrasound), and (3) undetectable serum Tg levels during TSH suppression and stimulation in the absence of interfering antibodies. The use of newer immunometric Tg assays with functional sensitivities as low as 0.01 µg/L have been recommended as a substitute for TSH-stimulated serum Tg measurements. However, the specificity of such assays is very low, thus causing a high rate of false-positive results.[9,50]

What follow-up evaluations should be performed for low-risk patients?

Most patients don’t want to hear that they are at low risk of dying from their tumor; they want to be assured that they are free of disease. The majority of patients can achieve disease-free status. The impact of surgery is assessed 5 to 6 weeks postoperatively. If the patient has had total or near-total thyroidectomy with level VI, III, and IV lymph node compartment dissections, there is a good chance that there will be no residual disease, providing the tumor was not invasive, regionally metastatic, or multifocal, and did not have aggressive histopathologic characteristics (such as tall cell carcinoma). If any of these features are found at surgery, 131I is usually administered.

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Levothyroxine
Radioiodine (131I)
Thyrotropin-α (rhTSH, Thyrogen)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

At 6 to 12 months after surgery and 131I therapy, the majority of patients with low-risk tumors should undergo neck ultrasonography and measurements of serum Tg and anti-Tg antibodies (TgAb). Tg is synthesized only by normal or well-differentiated malignant follicular cells. Accordingly, incremental changes in Tg levels reflect tumor mass, providing Tg is measured in the same laboratory by the same method. Approximately 25% of patients have detectable serum TgAb levels, which invariably produce false-negative Tg results. Quantitative TgAb measurements can serve as a surrogate marker reflecting a change in tumor mass. The diagnostic accuracy of both Tg and TgAb levels are most reliable when measured serially over time; the positive predictive value of Tg is only about 50% with a single measurement, but rises to 80% with serial measurements.[51] Nevertheless, a single rhTSH-stimulated Tg less than 1 µg/L in the absence of TgAb has an approximately 98% to 99.5% likelihood of identifying patients who are completely free of tumor on follow-up.[9] False-positive serum Tg results can be caused by the presence of serum heterophile antibodies, which occurs in about 3% of patients, falsely increasing the serum Tg result. This phenomenon can usually be recognized by running the test in another laboratory.

The new 2009 ATA Management Guidelines for Patients With Thyroid Nodules and Differentiated Thyroid Cancer will be available within the next few months. The guidelines can be obtained without cost at http://www.thyroid.org/index.html.

Financial Disclosure:Dr. Mazzaferri has received lecturing honoraria from Genzyme.

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