Papillary Thyroid Cancer: Monitoring and Therapy

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The last 10 years have seen a major paradigm shift in the management of thyroid cancer, with greater reliance on serum thyroglobulin and neck ultrasonography, and less emphasis on routine diagnostic whole-body radioactive iodine scanning for detection of recurrent disease. As our follow-up tests become more sensitive for detection of recurrent disease, we are finding many asymptomatic patients who have low-level persistent disease many years after initial therapy that may or may not benefit from additional testing and therapy. These difficult issues have been addressed by at least five different sets of guidelines published recently by various thyroid specialty organizations around the world. In this article, the authors compare and contrast the recommendations from the various guidelines in an attempt to define areas of consensus and explore possible reasons for differing recommendations.

Section snippets

Initial presentation

Thyroid cancer is diagnosed in women two to three times more often than in men. Although it can present at any age, the median age at diagnosis is close to 45 years of age. Most patients present with an asymptomatic painless mass in the thyroid that is detected by the patient or their health care provider. Thyroid function tests are almost uniformly normal [10].

Although fine-needle aspiration has the highest sensitivity and specificity for identification of malignant thyroid nodules, several

Clinical guidelines

Over the last few years, several thyroid cancer specialist organizations around the world have published guidelines specifically addressing the pertinent management issues in thyroid cancer [11], [24], [25], [26], [27], [28]. In the following sections, we explore the similarities and differences in the recommendations provided in these various guidelines to determine where there is uniform agreement and where we continue to have areas of controversy. Because each of the guidelines includes an

Risk stratification

Risk stratification is the cornerstone of treatment and follow-up recommendations. Over the years, a relatively small group of clinical and histopathologic factors have been shown to be significant predictors of disease-specific mortality and usually risk of recurrence [29], [30]. These include patient factors such as age at diagnosis and gender and tumor-related factors such as size of the primary tumor, extent of extrathyroidal invasion, specific tumor histology, and distant metastases (Table

Goals of initial therapy

As outlined in the ATA guidelines [25], the goals of initial therapy are to surgically remove all evidence of gross disease in the neck while minimizing treatment and disease-related morbidity. In situations where radioactive iodine remnant ablation is required, complete surgical removal of the normal thyroid tissue facilitates the efficacy of RAI in destroying the remaining microscopic normal remnant and any metastatic disease that may be present. Furthermore, our initial therapies, if

Primary surgical considerations regarding extent of thyroid resection

Because of the high prevalence of metastatic cervical lymph node involvement in differentiated thyroid cancer, several of the guidelines recommend routine preoperative ultrasonographic evaluation of neck lymph nodes to properly plan surgical intervention [11], [25], [26]. Preoperative ultrasound (US) identifies suspicious cervical adenopathy in 20% to 30% of cases and in some cases alters the planned surgical approach [38], [39]. Because US is used in nearly all patients as routine follow-up in

Primary surgical considerations regarding extent of lymph node resection

Compartment-oriented lymph node dissections are recommended in all the guidelines for patients who have known lymph node metastases detected on preoperative staging or intraoperatively. The guidelines uniformly agree that functional neck dissection is preferred over “berry picking” and that radical neck dissection is rarely indicated. All the guidelines note that this approach decreases the risk of recurrence in low-risk patients and may prolong survival in high-risk patients.

The BTA and the

Radioactive iodine remnant ablation

The use of radioactive iodine in the postthyroidectomy setting to destroy residual thyroid bed tissue has become known as radioactive iodine remnant ablation (RRA). Because RRA has been shown in selected patients to decrease recurrence rates [22], [42], [43], [44], [45], [46] and decrease disease-specific mortality [22], [42], [44], [45], [46], it must also have a tumoricidal effect beyond destroying the microscopic residual thyroid cells remaining after a total thyroidectomy. Often, this

Details of radioactive iodine remnant ablation

Most of the guidelines recommended a low iodine before RRA, but the duration varied from 1 to 4 weeks (Table 7). The ATA and ETA noted that thyroid hormone withdrawal or recombinant human TSH (rhTSH) stimulation was acceptable for routine RRA [25], [26], whereas the NCCN, BTA, and AACE did not discuss the possible use of rhTSH as preparation for remnant ablation [11], [24], [27].

With regard to diagnostic whole-body scanning before ablation, there was general concern for stunning with higher

Role for external beam irradiation in initial therapy

In the setting of initial therapy, external beam radiation is seldom necessary in patients who have papillary thyroid cancer [52]. The guidelines are in agreement that external beam radiation therapy (EBRT) is most often used for unresectable tumors that do not concentrate RAI or for older patients (>45 years) who have evidence of gross extrathyroidal extension of the tumor into surrounding structures that are likely to have microscopic or small-volume macroscopic disease that is not amenable

Role of thyroid-stimulating hormone suppressive therapy

Suppression of TSH with supraphysiologic doses of levothyroxine to decrease the rate of progression and recurrence of thyroid cancer has been a cornerstone of treatment for more than 40 years [53], [54]. Retrospective studies suggest that TSH suppression to less than 0.1 mU/L may be beneficial in high-risk patients [55], [56], but the benefit of aggressive TSH suppression is much less clear in low-risk patients. Although all would agree that it is wise to avoid prolonged elevations in TSH, the

Serum thyroglobulin

As newer assays with improving sensitivities have become commercially available over the last 10 to 20 years, serum Tg determination has become the primary marker of differentiated thyroid cancer [57]. Although Tg is an excellent marker for well differentiated thyroid cancer, poorly differentiated tumors can produce Tg poorly and can evidence clinically significant recurrent disease with minimal Tg elevations [58]. Not all thyroid cancer recurrences that are detected with high-resolution US,

Follow-up strategy for detecting persistent/recurrent disease

Follow-up paradigms for detecting recurrent disease are usually based on whether the patient is considered high risk or low risk for death from disease. Although these approaches are useful, it may be more instructive to base the follow-up strategy on an understanding of the biology of the tumor and likely sites of recurrence. For example, a 25-year-old woman with a 3-cm papillary thyroid cancer involving several lymph nodes at diagnosis is likely to have a well differentiated tumor that should

Treatment options for persistent/recurrent disease

In the setting of clinically recurrent thyroid cancer, each of the guidelines endorses consideration of additional surgery if lesions are resectable and consideration of additional RAI if the lesions are likely to be RAI avid. Likewise, each guideline agrees that EBRT is usually only considered if the recurrent disease is not surgically resectable and is likely to be unresponsive to RAI. Therefore, initial investigations searching for persistent/recurrent disease should focus on neck US and

Treatment options for distant metastases

Although distant metastases are present in only 3% to 5% of patients who have papillary thyroid cancer at diagnosis, they can become evident in as many as 9% to 10% of patients who have papillary thyroid cancer and in as many as 20% of patients who have follicular thyroid cancer during the course of follow-up. In young patients, the pulmonary metastases often present as small, military, diffuse lesions throughout both lungs that usually respond well to repeated doses of RAI [69]. RAI is much

Summary

The last 10 years have seen a number of major paradigm shifts in the management of thyroid cancer. This is largely secondary to the more widespread use of highly sensitive detection tools, such as neck ultrasonography, highly sensitive Tg assays, and 18 FDG PET scanning in routine clinical practice. In addition, the ability to offer RAI studies, radioactive iodine remnant ablation, and stimulated Tg measurements with rhTSH rather than traditional thyroid hormone withdrawal has allowed many

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