Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

70D.Carcinoma of Follicular Epithelium: Radioiodine and Other Treatments and Outcomes

Ernest L. Mazzaferri

Richard T. Kloos

Papillary and follicular thyroid carcinomas, termed differentiated thyroid carcinoma (DTC), typically have a prolonged course and are asymptomatic for long periods. The tumor usually presents as a thyroid nodule and is identified by fine-needle aspiration (FNA) cytology, often when it is confined to the thyroid or has metastasized only to regional lymph nodes, giving an ample opportunity to cure the disease. Distant metastases or tumor that aggressively invades the neck is the presenting manifestation in about 5% of patients with papillary carcinoma and up to 10% with follicular carcinoma, which drastically lowers the likelihood of cure. Choice of therapy rests on an understanding of the natural history of these tumors and on the premise that prognosis can be altered by early intervention. The treatment of choice is surgery, whenever possible, usually followed by radioactive iodine (131I) and thyroxine (T4) therapy, but external radiation and chemotherapy have a role in management of some patients.

Papillary carcinoma comprises about 80% of all thyroid carcinomas, follicular carcinoma about 10%, and Hürthle cell carcinoma about 3% (1). Although these are distinct pathologic entities, their clinical features and outcomes are similar when the tumor is confined to the thyroid. Much of the following discussion refers to DTC, because the approach to treatment of these tumors is similar (2). Where there are substantial differences among the three tumors in treatment, prognosis, or behavior, the differences have been highlighted.


During the years from 1973 to 2003, the incidence of thyroid cancer increased steadily in North America (3) and Europe (4). It is the fastest rising cancer in women in the United States (5). Why this has happened is unknown, but it may be partially the result of exposure of the population to radiation fallout (6). During this same time, the mortality rates of thyroid cancer have declined significantly (~20%) in women (3). This is likely due to early diagnosis and effective treatment in women but not in men. The peak age at the time of diagnosis of thyroid carcinoma is around 45 years in women and 75 years in men (3). At the time of diagnosis, men have 25% more locoregional metastases and more than a 200% greater rate of distant metastases than do women, resulting in thyroid cancer mortality rates that are twice as high in men as in women (3). In the United States, this is the fastest rising cause of cancer death in men (7). These statistics are driven by papillary, follicular, and Hürthle cell carcinomas, which comprised about 95% of thyroid cancers and accounted for about 76% of all thyroid cancer deaths between 1985 and 1995 (1). Yet these thyroid tumors are the most amenable to treatment when identified at an early stage.


Prognosis of DTC is typically so favorable that it is difficult to demonstrate a beneficial effect of therapy unless very large cohorts are studied for several decades. No prospective randomized clinical trials have been done, so that all contemporary views of the efficacy of different treatments are based on retrospective studies.

Several studies shed light on the current practice. A study of 5,583 cases of thyroid carcinoma treated in over 1,500 hospitals in the United States during 1996 found that total or near-total thyroidectomy was performed in the vast majority (~75%) of patients with DTC (8). After surgery at least half were treated with 131I and were given T4 to suppress thyrotropin (TSH), but this was underreported in the study. A report from Germany (9) of 2,376 patients with DTC treated in 1996 indicated that total thyroidectomy was performed in about 90% of the patients and that 131I was almost always administered postoperatively (74% papillary, over 90% follicular). Lymph node dissection was performed in 22% of those with papillary carcinoma.

Current guidelines on the treatment of DTC from the United States (10) and Europe (11) advise total or near-total thyroidectomy followed by 131I ablation of the thyroid remnant for most patients. Although the treatment of children has been more controversial, many clinicians now recommend that they be treated the same as adults (12).


The distinction between aggressive and slow-growing tumors becomes less clear when multiple and opposing prognostic features intermingle to shape the final outcome. The three main features determining prognosis, however, are tumor stage, age at the time of diagnosis, and treatment. The most disagreement stems from the weight clinicians allocate to these variables when planning initial therapy.

Mortality Rates

A study of 53,856 cases of thyroid carcinoma treated in the United States during 1985 to 1995 found 10-year cancer mortality rates of about 7% for papillary carcinoma, 15% for follicular carcinoma, and 24% for Hürthle cell carcinoma (1). Prognosis is less favorable in older patients and among those with certain histologic variants. In our 1,355 patients with DTC whose mean age at diagnosis was only 36 years, the 30-year cancer-specific mortality rates were 6% for papillary and 15% for follicular carcinoma (13). Cancer mortality rates are even lower for children (12), except for those under age 10, in whom the prognosis may be less favorable (14).

Recurrence Rates

Depending on the initial therapy and tumor stage, about 20% to 30% of patients have recurrences over several decades, two thirds of which occur within the first decade after initial therapy (13) (Fig. 70D.1). Although not usually fatal, a neck recurrence is not a trivial event and may be the first sign of a lethal outcome. In our patients who had local recurrences, 74% were in cervical lymph nodes, 20% were in thyroid remnants, and 6% were in trachea or muscle; 7% of this group died of cancer (13). The tumors recurred at distant locations in 21%, most often in the lungs alone (63%); half died of carcinoma. Recurrent tumor caused over half the cancer deaths in our patients. The other deaths were due to recognized persistent disease.

FIGURE 70D.1. Tumor recurrence and cancer death rates from differentiated thyroid carcinoma. A: The vertical bars represent standard errors. Numerators are the number of events during the previous interval, and denominators the number of patients at the beginning of the next time interval. B:Recurrences at 5-year intervals. All recurrences, local recurrences, and distant recurrences are shown for each time interval. [Modified from Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86(4):1447–1463. 2001, with permission.]


Features of the tumor often play a major role in decisions regarding therapy. What follows are summaries considered more or less independently of variations in therapy.

Typical Papillary Tumors

This tumor has distinctive cellular features that can be recognized by fine-needle aspiration biopsy or frozen section in 95% of cases (see Chapter 28) (15). Most are mixed papillary-follicular tumors, while a few have a purely papillary pattern, features that have no bearing on prognosis. Most are unencapsulated tumors that are 2 to 3 cm in diameter and tend to infiltrate the thyroid, but are confined by its capsule. This tumor invades lymphatics and blood vessels and is commonly found in multiple sites within the thyroid and in regional lymph nodes. Those that metastasize to the lung typically appear as diffuse bilateral pulmonary nodules on chest x-ray or are visible only by 131I scans. Hematogenous spread to bone, central nervous system, and other sites can also occur. These features have important prognostic implications, as noted below.

Papillary Carcinoma Variants

Survival rates vary considerably among certain subsets of patients with papillary carcinoma (16). About 10% of papillary carcinomas have a well-defined capsule, which is a particularly favorable prognostic sign, even in tumors with cellular features suggesting otherwise (17). Other variants have a more serious prognosis. Anaplastic tumor transformation, a rare event occurring in fewer than 1% of papillary carcinomas, is associated with p53 oncogene expression and causes death within a year (18). Tall cell papillary carcinomas, which are large tumors in older patients that can be identified by FNA, have up to a 25% 10-year mortality rate (16). The outcome is even worse with columnar-variant papillary carcinoma, which has a 90% mortality rate unless the tumor is encapsulated (17). About 2% of papillary carcinomas are diffuse sclerosing variants that infiltrate the entire gland and may cause a diffuse goiter without a palpable nodule, which may be mistaken for goitrous autoimmune thyroiditis (15). Most metastasize to lymph nodes, and about 25% have distant metastases (15).

Mainly affecting younger persons, about 10% of the tumors found in children following the Chernobyl accident were of this type (19). They are aggressive tumors that may have a poor prognosis; however, with aggressive treatment the prognosis is as good as that of classical papillary carcinoma (20). Follicular-variant papillary carcinomas have typical papillary nuclear features and follicular architecture that may suggest a follicular neoplasm on FNA, although the cellular features may identify this as follicular-variant papillary carcinoma (21); their clinical behavior resembles that of typical papillary more than follicular carcinoma (22).

Follicular Carcinoma Histology

This is usually a solitary encapsulated tumor with a microfollicular histologic pattern that is slightly more aggressive than papillary carcinoma. Widely invasive tumors have a poor prognosis and are easily recognized by their aggressive extension into surrounding tissues. Up to 80% of patients with such tumors develop metastases, and more than 15% die of their disease within 10 years (1,2). However, most follicular carcinomas are minimally invasive encapsulated tumors that closely resemble follicular adenomas, and the distinction can be made only by review of the permanent histologic sections and not by FNA or frozen-section study, which poses a serious management predicament at the time of surgery. The main diagnostic criteria for follicular carcinoma are cells penetrating the tumor capsule or invading blood vessels within or beyond its capsule. The latter has a worse prognosis than capsular penetration alone (23). Still, a few patients with minimally invasive follicular carcinomas, the main type diagnosed in recent years, have distant metastases or die of their disease (24).

The poorer prognosis of follicular carcinoma is more closely related to the patient's older age at the time of diagnosis and advanced tumor stage than its histology alone (13). The survival rates of patients with papillary or follicular carcinomas are similar in patients of comparable age and disease stage (2,13). Both have an excellent prognosis if they are confined to the thyroid, are small tumors (≥1.0 cm), or are minimally invasive (13). Both have poor outcomes if they are widely invasive (papillary carcinoma invading the thyroid capsule and adjacent structures, and follicular carcinoma invading blood vessels and the tumor capsule) or metastatic to distant sites (2,13).

The 30-year survival rate in our series was 76%, and the cancer-specific death rate was 8% in 1,355 patients, of whom 79% had papillary and 21% follicular carcinoma (13). The mortality rate in patients with follicular carcinoma was over twofold that of the patients with papillary carcinoma; however, those with follicular carcinoma were older than patients with papillary carcinoma and had larger tumors and more advanced disease at presentation. Patients with tumors of similar stage had 30-year recurrence and cancer-specific mortality rates that were the same, regardless of the tumor's papillary or follicular histology (13).

Hürthle (Oncocytic) Cell Follicular Variant

These cells may constitute most (>75%) or all of a tumor; such tumors are sometimes classified as Hürthle cell carcinoma or as variants of follicular carcinoma. Although there has been some controversy about their diagnosis, management, and outcome, more recent large series clarify some of these issues. A study of 1,585 cases of Hürthle cell carcinoma found the 10-year cancer mortality rate was 25%, compared with a 15% rate in 5,271 patients with follicular carcinoma (1). Pulmonary metastases occur in 20% to 35% of patients with Hürthle cell carcinoma, about twice that of follicular carcinoma (25). Hürthle cell–variant papillary carcinoma is even less common, but may have higher than usual recurrence and mortality rates (2).

Tumor Size

Papillary carcinomas smaller than or equal to 1 cm, termed microcarcinomas, are often found unexpectedly during surgery for benign thyroid conditions. Although they usually pose no threat to survival and ordinarily require no further surgery (26), about 20% are multifocal and as many as 60% have cervical lymph node metastases that may be the presenting feature (27). Lung metastases occur rarely, except for multifocal tumors with cervical metastases, which are the only microcarcinomas with significant morbidity and mortality (27,28). Otherwise, the recurrence and cancer-specific mortality rates are near zero (26,27). In our series, 30-year recurrence rates with DTC smaller than 1.5 cm were one-third those associated with larger tumors (13). The small tumors rarely metastasized to distant sites and had low cancer-specific mortality rates (0.4% vs. 7% for tumors ≥ 1.5 cm, p < .001) (13). There is a linear relationship between tumor size and cancer recurrence and mortality for both papillary and follicular carcinomas (13) (Fig. 70D.2).

FIGURE 70D.2. Primary tumor size as it affects cancer recurrence (•) and cancer death rates (○) from DTC. Regression lines are for cancer death (solid line) and tumor recurrence (dashed line). Each point represents the percentage of events for tumor size in more than one patient. (Drawn from data in Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86 (4):1447–1463.)

Multiple Intrathyroidal Tumors

Multicentric tumors are found in about 20% of patients with papillary carcinoma when the thyroid is examined routinely and in up to 80% if the thyroid is examined with great care (2). Although regarded as intrathyroidal metastases in the past, multiple distinct RET /PTC gene rearrangements found in the majority of multifocal papillary carcinomas proves that they are individual tumors that arise independently in a background of genetic or environmental susceptibility (29). Their presence cannot be predicted on the basis of clinical risk stratification (30), and is thus not apparent until the final histologic sections of the entire thyroid gland have been studied, which has a bearing on the need to surgically excise the contralateral lobe and to ablate the thyroid remnant with 131I. Among patients undergoing routine completion thyroidectomy for presumed unilateral DTC, about half have a tumor in the contralateral lobe (2,30,31); however, when multifocal disease is present in the thyroid lobe first excised, or when the tumor has recurred in any site, bilateral multifocal tumors are almost always found (32). Thus, the prognosis may be more serious than usual with this feature, even when there are multicentric microcarcinomas. There is a higher incidence of recurrent regional lymph node metastases in multicentric microcarcinomas than in single 1 cm tumors, and the presence of lymph node metastases increases the likelihood of distant metastases from microscopic multicentric tumors (28,33,34). Multicentric microcarcinomas are often found in patients with familial nonmedullary thyroid carcinoma, which tends to be more aggressive than usual (34).

Those who find few recurrences in the contralateral thyroid lobe after hemithyroidectomy argue that multiple microscopic tumors are of little clinical consequence (35). Others find recurrence rates ranging from 5% to 20% in large thyroid remnants and that pulmonary metastases occur more frequently after subtotal than total thyroidectomy (36,37,38). In one study, patients with multiple intrathyroidal tumors had almost twice the incidence of nodal metastases and three times the rate of pulmonary and other distant metastases than those with single tumors, and the likelihood of persistent disease was three times more likely in those with multiple tumors (38). Another study found a 1.7-fold higher risk for recurrence in multifocal compared with unifocal tumors (39). Another study found that the only two parameters significantly influencing tumor recurrence of papillary microcarcinomas were the number of histologic foci (p < .002) and the extent of initial thyroid surgery (27). The 30-year cancer mortality rates among our patients with multiple tumors were two times those in the patients with a single tumor (13). At 30 years, the recurrence rate among 436 patients who had undergone subtotal thyroidectomy was significantly higher than that among 698 patients who had undergone total or near-total thyroidectomy (40% vs. 26%, p < .002); cancer-specific mortality rates were also higher in the subtotal thyroidectomy group (9% and 6%, p = .02) (13).

Lymphocytic Infiltration of Tumor

Lymphocytic infiltration ranging from focal areas of lymphocytes and plasma cells to classic Hashimoto's disease, which is often seen in papillary carcinoma, is associated with a lower than usual tumor stage and may be an independent predictor of a favorable prognosis (40).

Local Tumor Invasion

About 5% to 10% of tumors grow directly into surrounding tissues, increasing both morbidity and mortality. Local invasion, which can occur with both papillary and follicular carcinoma, ranges from microscopic to gross tumor invasion (13). The most commonly invaded structures are the neck muscles and vessels, recurrent laryngeal nerves, larynx, pharynx, and esophagus, but tumor can extend into the spinal cord and brachial plexus. The symptoms are usually hoarseness, cough, dysphagia, hemoptysis, airway insufficiency, or neurologic dysfunction. Extrathyroidal tumor extension is a key risk factor leading to lymph node and distant metastasis (41). The tumor was locally invasive in 115 of our patients (8% of those with papillary and 12% of those with follicular carcinoma); 10-year recurrence rates were 1.5 times and cancer-specific death rates were 5 times those of patients without local tumor invasion, and nearly all with tumor invasion died within the first decade (13).

Lymph Node Metastases

The first sign of thyroid carcinoma may be an enlarged cervical lymph node; in such a patient, multiple nodal metastases are usually found at surgery. About 33% of metastatic lymph nodes from papillary carcinoma are partly cystic (42). The incidence and location of lymph node metastases varies with the tumor type, patient age, and the extent of lymph node surgery. For example, gross lymph node metastases are found in about 36% of adults and in up to 80% of children with papillary carcinoma, and in about 17% with follicular carcinoma (12,43) (TABLE 70D.1). Micrometastases are found even more often. In one series of 119 patients in which 21% were known preoperatively to have lymph nodes metastases, almost 61% were found to have micrometastases after undergoing bilateral lateral neck compartment dissection; 41% were bilateral (44). Another study (45) of 2,551 cervical lymph nodes obtained from 80 patients with papillary thyroid carcinoma also found micrometastases in 60% of the lymph nodes. Tumors located in the upper third of the thyroid were found to metastasize in the direction of upward lymphatic flow, whereas tumors located in the lower third or isthmus metastasized inferiorly (45).



Papillary Carcinoma Metastases

Follicular Carcinoma Metastases



Nodal (%)b

Distant (%)


Nodal (%)

Distant (%)










9 (17)c



7 (15)




45 (53)



24 (32)


aAll patients in 13 series (43).

bRounded to nearest integer.

cIn parentheses are all local recurrences, including those in the contralateral thyroid lobe and other neck structures.

The prognostic importance of regional lymph node metastases is controversial. Some find their presence has no impact on recurrence or survival (46). On the other hand an increasingly larger number of studies find nodal metastases are a risk factor for local or distant tumor recurrence and cancer-specific mortality, especially if there are bilateral cervical or mediastinal lymph node metastases or if tumor invades through the lymph node capsule (13,28, 47,48,49,50). In one study, 15% of patients with and none without cervical node metastases died of disease (p < .02) (51). Another study of patients with distantly metastatic papillary carcinoma reported that 80% had mediastinal node metastases at the time the carcinoma was diagnosed (52). Our patients with papillary or follicular carcinoma who had cervical or mediastinal lymph node metastases had significantly higher 30-year cancer mortality rates than those without them (10% vs. 6%, p < .01).

Distant Metastases

About 10% of patients with papillary carcinoma and up to 25% of those with follicular carcinoma develop distant metastases; half are present at the time of diagnosis (43) (TABLE 70D.1). They occur more often (35%) with Hürthle cell carcinoma and after the age of 40 years (25). Among 1,231 patients reported in 13 studies, 49% of the metastases were to lung, 25% to bone, 15% to both lung and bone, and 10% to the central nervous system or other soft tissues (43). The outcome is influenced mainly by the patient's age, the tumor's metastatic site(s), ability to concentrate 131I, and tumor bulk (53,54). Although some patients survive for decades, especially younger patients, about half die within 5 years regardless of tumor histology (43). In a study from France, survival rates with distant metastases were 53% at 5 years, 38% at 10 years and 30% at 15 years (55). Survival is longest with diffuse microscopic lung metastases seen only on posttreatment 131I imaging and not by x-ray (55,56,57). The prognosis is much worse when the metastases do not concentrate 131I or appear as large lung nodules and is intermediate when the tumors are small nodules on x-ray that concentrate 131I (53,57).

The 3-year survival rate for patients with 18FDG-PET avid tumor metastasis volumes of 125 mL or less is 96% compared with 18% in patients with 18FDG-PET volumes greater than 125 mL (58). Patients with multiple bone or central nervous system metastases have a poor prognosis (57). About half die within 3 years of discovery of the bone metastases (54) and survive about 1 year after the diagnosis of brain metastases (59). A study of 161 patients who died of thyroid carcinoma found that the main causes of death were respiratory insufficiency due to pulmonary metastasis (43%), circulatory failure due to vena cava obstruction by extensive mediastinal or sternal metastases (15%), and airway obstruction (13%) and massive hemorrhage (15%) due to uncontrolled local tumor (60).

Thyroglossal Duct Tumors

Small papillary carcinomas that arise in a thyroglossal duct remnant are typically encapsulated by the cyst and usually are not recognized until the permanent histologic sections are reviewed. Dissection of the tract and removal of the hyoid bone (Sistrunk operation) is adequate for most patients because these tumors rarely metastasize (61). However, one study found a high incidence of intrathyroidal carcinomas in such cases, some with aggressive behavior, suggesting that total thyroidectomy may be justified (62).



Practically every study shows that the age of the patient at the time of diagnosis is an important prognostic variable. Thyroid carcinoma is more lethal after age 40 years. The risk for cancer death increases with each subsequent decade of life, dramatically rising after age 60 years (Fig. 70D.3). However, there is a remarkably different pattern of tumor recurrence: rates are highest (40%) at the extremes of life, before age 20 years and after age 60 years (12,13,43) (Fig. 70D.3). Despite the clear effect of age on survival, there is disagreement about how age should be factored into the treatment plan, especially in children and young adults. Children commonly present with more advanced disease than adults and have more tumor recurrences after therapy, yet their prognosis for survival is good (12). Some believe that young age has such a favorable influence on survival that it overshadows the prognosis predicted by the tumor characteristics (46). The majority, however, believe that the tumor stage and histologic differentiation are as important as the patient's age in determining prognosis and management (10,12,13,63).

FIGURE 70D.3. Age stratified by decade at the time of initial treatment as it affects the percentage of patients with tumor recurrence, distant recurrence, and cancer deaths. (Modified from Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86(4):1447–1463, with permission.)


Men have a less favorable prognosis than women (13,46). The death rates from all types of thyroid cancer reported in the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database are twice as high in men as in women (3). In our study, the risk for thyroid cancer death was about twice as great in men as in women (13). Because of this, men with thyroid carcinoma should be regarded with special concern, especially those over age 50.

Graves' Disease

Thyrotropin receptor antibodies may promote tumor growth in patients with Graves' disease. Some find thyroid carcinoma in almost half of the palpable nodules in patients with Graves' disease (64). The tumors are larger and display more aggressive behavior than usual (64). Some, but not all, find that thyroid carcinoma occurring in patients with Graves' disease is more often invasive and metastatic to regional lymph nodes, even when the primary tumor is small (64,65).


Although the patient's age and tumor stage at the time of diagnosis are the most important variables predicting outcome, their relative importance is debated. Several clinical staging and prognostic scoring systems have been proposed that use age over 40 years as a major feature to identify risk. When more weight is assigned to the patient's age, the relative importance of tumor stage tends to be decreased. This concept, however, does not appear to be widely accepted among practicing physicians because young patients with low prognostic scores often have tumor recurrence. At an international consensus conference in 1987, only 5 of 160 participants treated younger patients more conservatively (66). Similarly, in an international survey of thyroid specialists performed in 1988 (67) and in a survey of clinical members of the American Thyroid Association performed in 1996 (68), age was not used by the majority of respondents in their therapeutic decisions. Current recommendations for the treatment of children now suggest the same therapy as is given to adults with similarly stage tumors (12).

Eight schemes for clinically staging DTC are summarized in TABLE 70D.2 (69,70,71,72,73,74,75,76). When applied to the papillary carcinoma data from the Mayo Clinic, four of the schemes that use age (EORTC, TNM, AMES, AGES) were effective in separating low-risk patients in whom cancer-specific mortality was 1% at 20 years from high-risk patients in whom it was 30% to 40% at 20 years (73). Twenty-year survival rates for patients with MACIS of less than 6, 6 to 6.99, 7 to 7.99, and 8+ were 99%, 89%, 56%, and 24%, respectively (74). A study that categorized 269 patients with papillary carcinoma according to five different prognostic scoring schemes found that some patients in the lowest risk group for each scheme died of cancer (70). This is particularly true of the schemes that simply categorize risk dichotomously as low or high (69,77). Moreover, these schemes do not consider tumor recurrence and are inaccurate in predicting disease-free survival. The latest American Joint Committee on Cancer (AJCC) TNM staging system (76) for thyroid cancer (TABLE 70D.2), classifies even more patients as being at low risk than did the former version. Staging systems derived from multivariate analyses that do not take into account the effects of therapy assume that treatment does not alter outcome. This is likely incorrect and suggests that none of the prognostic schemes permit clear decisions to be made for individual patients at the time of surgery based on risk group.


 Staging System and Rating Schemes

Variable at Time of Diagnosis







University of Chicagoc

Ohio State Universityb

Patient characteristics













 Tumor characteristics

   Cell type












   Grade (histologic)



    Extrathyroidal extension









   Lymph node metastases





   Distant metastases









Therapy characteristics

   Incomplete resection






aT, primary tumor, T1, ≤2 cm; T2, >2–4 cm; T3, >4 cm; T4a, any size tumor to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve; T4b tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels; all anaplastic tumors are considered T4. T4a intrathyroidal anaplastic carcinoma surgically resectable; T4b extrathyroidal anaplastic carcinoma surgically unresectable; regional lymph nodes are the central compartment, lateral cervical and upper mediastinal lymph nodes. N1a, metastases to level IV (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes); N1b, metastases to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes; M0, distant metastases absent; M1, distant metastases present.

bBoth papillary and follicular carcinoma.

cOnly papillary carcinoma.


 Papillary or Follicular

 TNM Stage

< 45 years

≥45 years


































T4b+Any N+M0

T4b+Any N+M0



Any T+Any N+M1

Any T+Any N+M1

TNM staging varies with cell type and age. Undifferentiated (anaplastic) carcinomas are stage IV. EORTC (72). Age in years +12 if male, +10 if medullary, +10 if poorly differentiated follicular, +45 if anaplastic, +10 if extending beyond thyroid, +15 if one distant metastasis, +30 if multiple distant metastases.

AMES (Age-Metastasis-Extent-Size) (69). High risk is female >50 years of age, male > 40 years, tumor > 5 cm (if older age), distant metastases, substantial extension beyond tumor capsule (follicular) or gland capsule (papillary).

AGES (Age-Grade-Extent-Size) (73). Calculated from 0.5 × age in years (if > 40), +1 (if grade 2), +3 (if grade 3 or 4), +1 (if extra thyroidal), +3 (if distant spread), +0.2× maximum tumor diameter. MACIS (Metastasis-Age-Completeness of resection, Invasion-Size) (74). MACIS = 3.1 (if ≤39 years of age) or 0.08 × age (if ≥40 years of age), +0.3 × tumor size (in centimeters), +1 (if incompletely resected), +1 (if locally invasive), +3 (if distant metastases present).

NTCTCS (National Thyroid Cancer Treatment Cooperative Study) (71). Staging variables (part A) not scored quantitatively.

University of Chicago system for papillary carcinoma (47). Staging variables (part A) not scored quantitatively.

The Ohio State system for papillary or follicular carcinoma (13).

Data from American Joint Committee on Cancer. Manual for staging of carcinoma, 6th ed. Chicago: Springer-Verlag, 2003.

Ohio State University Staging System

This classification scheme is shown in Tables 70D.2 and 70D.3 (13). Stage 4 patients were significantly older than the others. After a median follow-up of almost 17 years, tumor recurrence and cancer-specific mortality rates were progressively and significantly greater with each tumor stage (TABLE 70D.3). Based on regression modeling on 1,501 patients, excluding those who presented with distant metastases and including therapy, the likelihood of death from thyroid carcinoma was increased if age is at least 40 years, the tumor is a folllicular thyroid cancer, tumor size is at least 1.5 cm, local tumor invasion or regional lymph node metastases were present, or therapy had been delayed for at least 12 months. It was reduced in women, by surgery more extensive than lobectomy, by 131I remnant ablation, and by 131I and T4 therapy for metastases (TABLE 70D.4).



Stage 1

Stage 2

Stage 3

Stage 4

Tumor size (cm)

< 1.5

1.5–4.4a (or)

≥4.5 (or)


Cervical metastases





Multiple thyroidal tumors (>3) any size





Local tumor invasion





Distant metastases





No. of patients (%)

170 (13)

948 (83)

204 (15)

33 (2)

Age (mean yr)







< .05


No. of recurrence n (%)c

10 (8)

210 (31)

59 (36)

10 (62)





No. of deaths from carcinoma (%)c


34 (6)

19 (14)

17 (65)





aIncludes tumors < 1.5 cm with cervical metastases and palpable tumors of uncertain size confined to the thyroid; any tumor that fulfills one of the three criteria for size, cervical metastases, or multiple intrathyroidal tumors is considered stage 2.

bWilcoxon rank-sum test comparing stage with preceding lower stage (left).

c30-year recurrence or carcinoma death rate, log rank test comparing stage with preceding lower stage (left). NS, not significant



Hazard Ratio


95% Confidence Interval

All cancer recurrence





   Local tumor invasion




   Lymph node metastasesb




   Follicular histology




   Tumor sizec




   Thyroid remnant 131I ablationd




   Therapy with 131Id




   Surgery more than lobectomye




Distant metastasis recurrence





   Follicular histology




   Lymph node metastasesc




   Local tumor invasion




   Tumor sized




   Thyroid remnant 131I ablatione




   Therapy with 131Ie




   Surgery more than lobectomyf




Cancer mortality





   Time to treatmentb




   Follicular histology




   Lymph node metastasesc




   Tumor sized




   Local tumor invasion




   Female (vs. male)




   Thyroid remnant 131I ablatione




   Surgery more than lobectomyf




   Therapy with 131Ie




aAge stratified as less than 40 years versus 40 years and older for cancer mortality, and by decade for recurrences and distant recurrences.

bTime to treatment ≤12 months versus >12 months.

cLymph node metastases present versus absent.

dTumor diameter stratified into 1-cm increments from tumors smaller than 1 cm to >5 cm.

eRemnant ablation is the use of 131I in patients with uptake only in the thyroid bed and no evidence of residual tumor; therapy with 131I is postoperative treatment of patients with known residual disease.

fBilateral thyroid surgery versus lobectomy with or without isthmusectomy From Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86 (4):1447–1463, with permission.

The rigid application of staging systems in support of conservative treatment for low-risk patients may lead to inadequate initial therapy. Aggressive disease may occur in patients who appear to be at low risk at the time of diagnosis (13,27). Hundahl et al (1) reported 96% and 68% relative 10-year survival rates for patients categorized as low and high risk, respectively, according to the AMES classification; however, almost two thirds of the cancer deaths in this series occurred in the low-risk group because they outnumbered high-risk patients almost 15:1.


Delay in Therapy

The median time from the first detection of the tumor—nearly always a neck mass—to initial therapy in our patients was 4 months, but ranged from less than 1 month to 20 years (13). Delay in diagnosis correlated with cancer mortality (Fig. 70D.4). The median delay was 18 months in those patients who died of carcinoma compared with 4 months in those still living (p < .001). The cancer mortality rate was 4% in patients who underwent initial therapy within a year, as compared with 10% in the others; the 30-year cancer mortality rates in these two groups, respectively, were 6% and 13% (p < .001).

FIGURE 70D.4. Percentage of cancer deaths according to time (on a logarithmic scale) from the first manifestation of the tumor to initial therapy. Each data point represents one to three patients. (Drawn from data in Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86 (4):1447–1463.)

Extent of Surgery

Clark discusses surgery for thyroid carcinoma in detail in Chapter 80, but it will be briefly summarized here because the extent of surgery has an impact on the subsequent medical therapy. Recurrence rates are high with large thyroid gland remnants. For example, in one study (78) of patients with papillary carcinoma, tumor recurrence rates during the first 2 years after surgery were about fourfold greater after unilateral lobectomy than after total or near-total thyroidectomy (26% vs. 6%, p = .01). In a subsequent report from the same institution, patients with papillary carcinoma whose AGES score was 4 or more had a 25-year cancer mortality rate almost twice as high after lobectomy than after bilateral thyroid resection (65% vs. 35%, p = .06) (79). In a study of AMES low-risk patients from the same institution, 20-year rates for local recurrence and nodal metastases were, respectively, 14% and 19% after unilateral lobectomy, which were significantly higher (p = .001) than the 2% and 6% rates after bilateral lobar resection (80). The researchers concluded that bilateral lobar resection probably represents the preferable initial surgical approach to patients with low-risk papillary thyroid carcinoma (80). In another study of patients with papillary carcinoma (47), near-total thyroidectomy decreased the risk for death from tumors larger than 1 cm and decreased the risk for recurrence as compared with lobectomy or bilateral subtotal thyroidectomy. We found that recurrence and cancer death rates were both about 50% lower after near-total or total thyroidectomy as compared with less surgery in patients with stage 2 and 3 tumors (13) and that surgery more extensive than lobectomy was an independent variable that reduced the likelihood of carcinoma mortality rate by 50% (TABLE 70D.4). Thus, there is abundant evidence that microscopic residual disease remaining after initial surgery leads to high recurrence and carcinoma mortality rates.

Thyroxine Therapy

Effects of Thyrotropin Suppression on Tumor Growth

The idea that TSH stimulates both the iodine transport and growth of thyroid carcinoma forms the basis for the wide use of T4 in treating this disease. Like normal thyroid tissue, most papillary and follicular carcinomas contain functional TSH receptors, but whether postoperative T4 alone improves survival is less certain. There have been no prospective randomized trials of this question, but there is evidence that TSH stimulates tumor growth. Tumors in patients with Graves' disease may be more aggressive, presumably as a result of stimulatory effects of circulating TSH receptor antibodies (64). Rapid tumor growth sometimes follows T4 withdrawal in preparation for 131I therapy. Moreover, T4 given as an adjuvant to surgical and 131I therapy is effective. Tumor recurrence rates are higher if T4 is not given after surgery. After 30 years' follow-up, we found that there were significantly fewer recurrences in patients treated with T4as compared with no adjunctive therapy (Fig. 70D.5, p < .01) and there were fewer cancer deaths in the T4 group (6% vs. 12%, p < .001) (13).

FIGURE 70D.5. Recurrence rates of differentiated thyroid carcinoma in 1,439 patients without distant metastases treated with surgery and no medical therapy (n = 101), or surgery and T4 alone (n = 783), surgery and T4 with 131I (n = 503) for remnant ablation or treatment of metastases, or surgery and external radiation (n = 52). The vertical bars represent standard errors. [Drawn from data in Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86 (4):1447–1463.)

Potential Adverse Effects of Thyroxine Therapy

Patients with thyroid carcinoma are usually treated with T4 to lower TSH secretion below normal, thereby deliberately causing subclinical if not overt thyrotoxicosis (see Chapter 88). One potential consequence of this is bone mineral loss, even in children (12). It especially contributes to osteoporosis in postmenopausal women with thyroid carcinoma (81,82,83), which may be prevented by estrogen or antiresorptive therapy. However, using the smallest T4dose necessary to suppress TSH has no significant effects on bone metabolism and bone mass in men or women with thyroid carcinoma (84).

Cardiovascular abnormalities, well recognized in endogenous subclinical thyrotoxicosis, also occur in patients taking suppressive doses of T4 and may be ameliorated by beta-adrenergic blockade. Subclinical thyrotoxicosis causes an increased risk for atrial fibrillation (85), a higher 24-hour heart rate, more atrial premature contractions, increased cardiac contractility and ventricular hypertrophy, systolic and diastolic dysfunction, and increased cardiovascular mortality (86,87,88,89).

Thyroxine Dose

Patients with thyroid carcinoma who have undergone total thyroid ablation require more T4 than those with spontaneously occurring primary hypothyroidism. In one study, the average dosage of T4 that resulted in an undetectable basal serum TSH concentration and no increase in serum TSH after thyrotropin-releasing hormone (TRH) was 2.7 ± 0.4 (SD) µg/kg/day (90). Younger patients needed larger doses than older patients did, and TSH suppression was more likely when the therapy had been prolonged. In a comparative study of patients with thyroid carcinoma and patients with non-carcinoma-related hypothyroidism, the dose of T4 needed to reduce serum TSH concentrations to normal was 2.11 and 1.62 µg/kg/day, respectively (91). These results suggest that some T4 is secreted from residual thyroid tissue in patients who have spontaneously occurring hypothyroidism.

One study found that a constantly suppressed TSH (≤0.05 µU/mL) was associated with a longer relapse-free survival than when serum TSH levels were always 1 µU/mL or greater, and that the degree of TSH suppression was an independent predictor of recurrence (92). Another large study found that disease stage, patient age, and 131I therapy independently predicted disease progression, but that the degree of TSH suppression did not (93).

As a practical matter, the most appropriate dose of T4 for most patients with thyroid carcinoma reduces the serum TSH concentration to just below the lower limit of the normal range. Some prefer greater suppression, for example, serum TSH concentrations between 0.05 to 0.1 µU/mL in low-risk patients and less than 0.01 µU/mL in high-risk patients (81), and a few advocate the latter target for all patients. However, there is no published evidence that maintaining serum TSH concentrations less than 0.01 µU/mL has benefits, and it does have some risks.

Iodine 131 Therapy

Sodium Iodide Symporter

Therapy with 131I requires optimal uptake of iodine by tumor cells, which is difficult because iodide is concentrated much less avidly by DTC than by normal thyroid tissue. Yet some studies of papillary thyroid carcinoma reported increased sodium iodide symporter (NIS) activity (94), whereas others reported reduced NIS activity and heterogeneous immunohistochemical NIS staining (95). There is a clinical correlation between immunohistochemical NIS staining and the ability of a tumor to concentrate 131I (96). A more recent study (97) suggests that NIS is absent in about 30% and clearly expressed or even overexpressed in the rest of the thyroid cancer cells, but that malignant transformation often interferes with the proper targeting or retention of NIS to the plasma membrane. An improved response to 131I therapy might result from enhanced NIS expression, function, and targeting to the plasma membrane.

Therapeutic 131I has been used for over 50 years for patients with papillary and follicular thyroid carcinoma, both to ablate any remaining normal thyroid tissue and to treat residual thyroid carcinoma. It has gained wide use in part because it is the most effective systemic therapy, and because recurrence rates are high in patients treated with surgery and T4 alone. Although eliminating residual normal thyroid tissue greatly simplifies follow-up and facilitates tumor detection, the explicit indications for its use continue to provoke debate (73).

Ablation of Residual Normal Thyroid Tissue

Routine thyroid remnant ablation with 131I, although questioned by some (73), is widely used and has appeal for several reasons. First, it may destroy occult microscopic carcinoma within the thyroid remnant or elsewhere (2,30). Second, it enables later detection of recurrent or persistent disease, particularly in the neck and lung, by imaging studies (63). Third, it greatly facilitates the value of serum thyroglobulin (Tg) measurements during follow-up. Few metastases can be visualized by 131I scanning when appreciable amounts of normal thyroid tissue remain after surgery. Moreover, serum Tg concentration—the most sensitive marker of recurrent or persistent disease—is less reliable with large thyroid remnants (98). Accordingly, 131I is commonly used postoperatively to ablate thyroid gland remnants even in patients without known residual disease who have a very good prognosis (25,99,100). We found tumor recurrences in 7% of patients treated with 29 to 50 mCi (1,073–3,750 MBq) and in 9% after 51 to 200 mCi (1,887–7,400 MBq) 131I given to ablate thyroid remnants. Both rates were significantly lower than that in patients receiving no 131I ablation (Fig. 70D.6).

FIGURE 70D.6. Tumor recurrence (±SEM) 16.7 years (median) after thyroid surgery and 131I ablation of uptake in the thyroid bed compared with those treated with thyroid hormone alone. The numerator is the number of patients with recurrence, and the denominator is the number of patients in each time interval.  All recurrences.  Distant metastasis recurrences. Probability values are from log rank statistical analysis of 40-year life-table data. (From Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer.  2001;86(4):1447–1463, with permission.)A:B:J Clin Endocrinol Metab

Iodine 131 Therapy for Thyroid Remnant Ablation

For many years, remnant ablation was performed with 75 to 150 mCi (2,775–5,550 MBq). However, clinicians began using 25 to 30 mCi (925–1,110 MBq) to avoid hospitalization, which is no longer necessary because of a change in federal regulations that permits the use of much larger 131I doses (in this chapter, the term “dose” is used to describe 131I activity and not the radiation dose expressed in rad) in ambulatory patients. Smaller doses of 131I (< 30 mCi, 1,110 MBq) can ablate thyroid remnants if the amount of thyroid tissue remaining after surgery is small. It has appeal because of the lower cost and the lower whole-body radiation dose. In a randomized prospective study of this question, the first dose ablated thyroid bed uptake in 81% of patients given 30 mCi (225 MBq) and in 84% treated with 100 mCi (3,700 MBq) (101).

Others have found that larger 131I doses are necessary to ablate normal thyroid tissue and to treat residual microscopic carcinoma. Using a dosimetry approach, the 131I must deliver about 30,000 rad (300 Gy) to ablate normal thyroid tissue (102).Using this approach, less than half the patients could be successfully treated with 30 mCi (102). A meta-analysis found a statistically significant advantage for a single high 131I dose (75–100 mCi) over a single low (30–50 mCi) dose such that for every seven patients treated, one more would have successful thyroid ablation given a high rather than a low dose (103). The meta-analysis also found that the size of the thyroid remnant is important. Another study found that an average of 86.8 mCi (3,212 MBq) was more successful in ablating the thyroid remnant after near-total thyroidectomy than less extensive surgery (90% vs. 22) (102). Stated in different terms, 94% of patients had successful ablation when the surgeon left less than 2 g of thyroid tissue as compared with a 68% success rate when the remnant was larger (102).

Some researchers did not find lower recurrence rates after 131I ablation of the thyroid remnant. At the Mayo Clinic, the recurrence rates were about the same in 220 patients treated with surgery and 131I ablation and 726 patients treated with surgery alone (13.3% vs. 9.6); 10-year cancer-specific mortality rates were 3% and 2% in the two groups, respectively. These results contrast with those reported by others who found a more favorable effect of 131I ablation. Indeed, 131I remnant ablation conferred a survival benefit even in patients with Hürthle cell carcinoma (25).

Most researchers reported that tumor recurrence rates are lowered with 131I remnant ablation. In one study, postoperative 131I ablation of residual thyroid tissue decreased recurrence rates for tumors larger than 1 cm and reduced the risk for death in patients with stage I or II disease who had tumors larger than 1 cm (47). Among 831 patients with DTC in another series, pulmonary metastases developed in 58; they occurred in 11% after partial thyroidectomy, whereas the rate was reduced by more than half (5%) when subtotal thyroidectomy was supplemented with 131I and was only 1.3% after total thyroidectomy and 131I (38). Among 321 patients treated in 13 Canadian hospitals with 131I mainly to ablate residual normal thyroid tissue in those with microscopic residual papillary or follicular carcinoma, local disease was controlled significantly more often with either postoperative external radiotherapy or 131I therapy, or both together, than with T4 alone ( < .001) (104). Survival at 20 years with microscopic residual disease treated by surgery alone was less favorable (~40) than after treatment with either p131I or external radiation (~90%,  < .01), but p131I treatment of patients without obvious residual disease did not increase survival significantly (104). In a later study from Canada of 382 patients with DTC, initial thyroid 131I ablation after total thyroidectomy was associated with a significantly lower rate of local relapse that was independent of tumor stage (105). A study from Italy of 48 children who underwent near-total (44 patients) or partial (4 patients) thyroidectomy followed by 131I ablation found only one tumor recurrence during an average follow-up of 5 years (106). Thyroid 131I bed ablation has been shown to confer a survival benefit in patients with Hürthle cell carcinoma (25) and to reduce the tumor recurrence rates in patients with either papillary microcarcinomas or macrocarcinomas (20,107).

We studied 230 patients with no obvious residual disease who were given 131I postoperatively to ablate presumably normal thyroid remnants (2). The 40-year rates of all recurrences and distant recurrences in patients treated with remnant ablation were each less than one-fourth that of patients treated with T4 alone ( < 0.0001) (2) (Fig. 70D.6). The cancer death rate of those treated with Tp4 alone was fourfold that of patients treated with 131I ablation. In turn, the distant metastasis rates and cancer death rates were about 150% higher in patients not given T4 postoperatively than it was in those treated with T4 (Fig. 70D.6). Thyroid remnant ablation had an independent and favorable prognostic impact on tumor recurrence, distant metastases, and carcinoma deaths (Fig. 70D.6, TABLE 70D.4).

Patient Preparation

One must closely adhere to a protocol that ensures optimal preparation for 131I scanning and therapy (Fig. 70D.7). To maximize 131I uptake, total body 131I scans are performed 4 to 6 weeks after surgery. At the time of the scan, the serum TSH concentrations should be above 30 µU/mL, and the total body iodine pool should be as low as possible. Urine iodine levels should be obtained if there is any question about iodine contamination from medications or iodinated contrast materials in the previous months leading up to therapy.


FIGURE 70D.7. Protocol for patient preparation for 131I scan after initial thyroidectomy or at yearly follow-up intervals. Liothyronine (T3) is given to alleviate symptoms of hypothyroidism. Recombinant human thyrotropin () used in preparation for rhTSH131I ablation of normal thyroid bed tissue is an off-label use of the drug, but it is as effective as thyroxine (T4) withdrawal if 100 mCi 131I is used or T4 is withdrawn for several days before and after treatment with 30 mCi 131I. Another option is to give no thyroid hormone and just measure serum TSH about 3 weeks postoperatively. Serum TSH should increase above 30 µU/mL before the scan is done.

Triiodothyronine (T3) may be given immediately after surgery. In a young adult the dosage is 100 µg/day in divided doses; older patients are given 50 to 75 µg/day. The T3 is given for 4 weeks, then discontinued for 2 weeks. Other options include withdrawal of T4 for 4 weeks, or to give no thyroid hormone postoperatively and just measure serum TSH after about 3 to 4 weeks. Serum TSH should increase above 30 µU/mL. Although the protocol that uses T3ensures the fewest symptoms, most patients develop overt hypothyroidism during the last week or two if they have undergone complete thyroidectomy. Furthermore, concern over stimulation of tumor growth during these weeks of TSH elevation remains a possibility.

Recombinant Human Thyrotropin

Intramuscular administration of recombinant human thyrotropin (rhTSH) stimulates thyroidal 131I uptake and Tg release while the patient continues T
4 therapy, thus avoiding symptomatic hypothyroidism (108). Now approved for diagnostic use, rhTSH has been tested in two large international multicenter studies. The first showed that rhTSH stimulates 131I uptake for diagnostic whole-body scanning (DxWBS), but the sensitivity of scanning after its administration was less than after the T4 withdrawal (108). A second multicenter international study tested the results of two dosing schedules of rhTSH on the DxWBS images and serum Tg levels compared with those obtained after T4 withdrawal. The 131I DxWBS method was more carefully standardized in this study than the first one (109). The DxWBS images in the second study were slightly better after T4 withdrawal than rhTSH stimulation, but the differences were not statistically significant. The combination of DxWBS and serum Tg measurements detected 93% of the patients with tumor or tissue limited to the thyroid bed and detected 100% of those with metastases (109). There were no important differences between the two- and three-dose regimens. For diagnostic studies, 0.9 mg rhTSH is given intramuscularly every day for 2 days followed by a minimum of 4 mCi of 131I on the third day and a DxWBS and Tg measurement on day 5 (Fig. 70D.7). DxWBS 131I images must be acquired after a minimum scan time of 30 minutes or 140,000 counts. A serum Tg of 2 ng/mL or higher 72 hours after the last rhTSH injection indicates that thyroid remnant tissue or carcinoma is present, which may be identified on the rhTSH-stimulated DxWBS (109), especially in high-risk patients (110). The drug is well tolerated. Mild headache and nausea are its main adverse effects, but rhTSH is associated with significantly fewer symptoms and dysphoric mood states than occur with T4 withdrawal.

Although not yet approved for therapeutic purposes, rhTSH given according to the same protocol used for diagnostic studies has been shown to successfully prepare patients for 131I remnant ablation. Complete ablation, defined as an absence of uptake on a 5 mCi 131I DxWBS image 10 to 14 months after treatment, was achieved in 84.2% of patients prepared with T4 withdrawal and 86.5% of those given rhTSH, who were treated, respectively, with an average of 126 and 119 mCi of 131I (100). Another study found that 30 mCi 131I given 48 hours instead of 24 hours after the last rhTSH injection failed to ablate the thyroid remnant when rhTSH was given (111). Still another study showed that 30 mCi of 131I was successful when T4 was stopped the day before the first injection of rhTSH and started again the day after the 131I was administered, which was associated with a decline in urine iodine levels attributed to the approximate 50 µg iodine content in a daily dose of T4 compared with the 5 µg content of 131I (112).

Low-Iodine Diet

A daily diet of about 50 µg of iodine can increase 131I uptake in normal subjects and can double the rad (Gy) per 100 mCi (3,700 MBq) of 131I administered (113). However, total body radiation after therapeutic 131I may be increased up to 70% as the result of delayed iodine clearance. Although this diet can be tedious for the patient, a daily iodine intake of 50 µg can be achieved by restricting the use of iodized salt, dairy products, eggs, and seafood (TABLE 70D.5). Patients should check the labels of prepared foods for algae derivatives, all breads for iodates, and avoid all red-colored foods and medicines, and should avoid eating in restaurants if possible. The diet is typically started 2 weeks before 
131I scanning and continued for several days thereafter. More complex regimens that include diuretics can be used, but are usually unnecessary unless tumor 131I uptake is very low.




Avoid the following foods for 2 weeks prior to your radioactive iodine test and until your thyroid scan and treatment, if needed, are completed:

1. Iodized salt, sea salt

2. Milk or other dairy products, including ice cream, cheese, yogurt, etc.

3. Eggs

4. Seafood, including fish, shellfish, kelp, or seaweed

5. Foods that contain the additives carrageenan, agar-agar, algin, alginate

6. Cured and corned foods (ham, lox, corned beef, sauerkraut)

7. Breads made with iodate dough conditioners

8. Foods and medications containing red food dyes

9. Chocolate

10. Molasses

11. Soy products (soy sauce, soy milk)

Additional guidelines:

   Avoid restaurant foods since there is no reasonable way to determine which restaurants use iodized salt.

   Foods that contain small amounts of milk or eggs may be used.

   Noniodized salt may be used as desired.

   Consult your doctor before discontinuing any red-colored medication.

Sample meal patterns:




Orange juice

Turkey sandwich

London broil

Cream of wheat

Lettuce and tomato

Mushroom sauce

Whole wheat toast

Italian dressing


Fresh apple

Green beans


Graham crackers

Cucumber vinaigrette

Iced tea

Small roll with margarine

Lemon sherbet

Iced tea


From Pineda JD, Lee T. Robbins J. Treating metastatic thyroid cancer  1992;6:433–442, with permission.Endocrinologist


This drug enhances tumor 131I retention. At pharmacologic levels, it decreases the release of iodine from both the thyroid and tumors (114). Given at a dosage of 400 to 800 mg daily (10 mg/kg) for 7 days, lithium increases uptake in metastatic lesions while only slightly increasing 131I uptake in normal tissue. Serum lithium concentrations should be measured daily and maintained between 0.8 and 1.2 n. Radiation of tumors with a biologic half-life of iodine of less than 6 days is enhanced without increasing that to other organs. It should be considered when treating patients with metastases, particularly those that concentrate M131I poorly.

Whole-Body Iodine 131 Scans

A DxWBS is only useful when there is little or no remaining normal thyroid tissue. Large amounts of normal thyroid tissue often prevent the TSH from rising above 30 µU/mL, and scanning should be postponed until the remnant is eliminated. DxWBS images are usually obtained 48 hours after the oral administration of 2 to 5 mCi (74 MBq) of 131I. However, 2 mCi (74 MBq) doses of 131I may fail to show thyroid bed or tumor uptake on the DxWBS, whereas larger doses have a sufficiently harmful effect to interfere with subsequent uptake of therapeutic doses of 131I on the posttreatment whole-body scan (RxWBS), particularly in thyroid remnants and cervical lymph nodes (115). This effect, referred to as “thyroid stunning,” occurs with 3 mCi doses and becomes progressively greater with larger 131I doses, but is not produced by 123I. An increase in serum Tg is observed for about 2 weeks after a scanning dose of 131I, which in one study was associated with more frequent incomplete ablation than that in patients without an increase in serum Tg levels (116). More recent studies, however, suggest that stunning may not impair 131I ablation (115). Moreover, tumors not visualized on the DxWBS, regardless of the scanning 131I dose, not infrequently are visualized on the RxWBS images obtained after large therapeutic 131I doses (2,117). Of perhaps greater importance are more recent studies suggesting that DxWBS is usually not necessary, even before the first postoperative 131I treatment, in low-risk patients who are clinically free of residual tumor (117,118).

False-Positive Iodine 131 Scans

False-positive scans may be due to body secretions, pathologic transudates and inflammation, nonspecific mediastinal uptake, and uptake by thymus or tumors of nonthyroidal origin (118). Misleading scans can be caused by physiologic secretion of 131I from the nasopharynx, salivary and sweat glands, stomach, genitourinary tract, and from skin or hair contamination with urine, sputum, or tears. Pulmonary transudates and inflammation due to cysts, as well as lung lesions caused by fungal and other inflammatory disease, may produce false-positive scans. Diffuse physiologic hepatic 131I uptake is often seen on the RxWBS. The result of 131I-labeled Tg, hepatic uptake in the RxWBS images is related to the 131I dose, ranging from 40% with 30 mCi to 70% with 150 to 200 mCi of 131I (119). Diffuse hepatic 131I uptake without visible uptake in the thyroid bed usually represents extrahepatic metastases, not occult liver metastases (119).

Tumor Uptake of Iodine 131

The effect of 131I therapy is related to the tumor's capacity to concentrate iodine. Even after meticulous preparation and large 131I doses, many thyroid carcinomas do not concentrate 131I in amounts sufficient for therapy. This is more common after the age of 40 years and in those with Hürthle cell tumors. For example, among 101 patients with distant metastases, 60% of papillary, 64% of follicular, and only 36% of Hürthle cell carcinomas concentrated 131I (120). More recent series report similarly low 131I uptake in Hürthle cell carcinoma (25). However, DTC lung or bone metastases in younger patients are more likely to trap 131I (25,55).

Efficacy of Iodine 131 Therapy for Macroscopic Residual or Recurrent Disease

Although some studies find that total thyroidectomy and 131I therapy does not have a favorable effect on outcome (121), long-term studies generally report a beneficial effect of 131I therapy. For example, a long-term study of 1,599 patients with DTC treated between 1948 and 1989, 131I therapy was the single most powerful prognostic indicator for increased disease-free survival (122). Low-risk patients had significantly fewer recurrences and lower death rates after 131I and T4 therapy than with T4 alone, whereas 131I therapy conferred only a slight advantage to high-risk patients.

Multivariate analyses show 131I to have an independent prognostic effect when administered either to ablate the thyroid remnant or to treat metastases (2,25,107). In our study, 131I given either to ablate the thyroid bed or to treat metastases each independently lowered the rates of all recurrences, distant recurrence, and cancer deaths (TABLE 70D.4). In studies with somewhat shorter follow-up than ours, multivariate analyses have shows that 131I therapy lowers death rates in patients with bone (49,54) and lung (123) metastases providing they concentrate 131I, and reduces locoregional recurrences, whether given to treat metastases or to ablate the thyroid remnant (36,105,107).

Therapeutic Iodine 131 Dosimetry

Of the three dosimetry methods available, the most widely used and simplest is to administer an empiric fixed dose. Most clinics use this method regardless of the percentage of 131I uptake in the thyroid remnant or metastatic lesion. Hospitalization was required in the past to administer therapeutic doses of 131I larger than 30 mCi (1,110 MBq) in the United States, but is no longer necessary as long as the exposure to the public is calculated to be less than 5.0 mSv (124). From 30 to 100 mCi 131I (1,110–3,700 MBq) is given to ablate a thyroid remnant (125). Lymph node metastases that are not excised are treated with 100 to 175 mCi (3,700–6,475 MBq). Tumor extending through the thyroid capsule and invading the neck is treated with 150 to 200 mCi (5,550–7,400 MBq), which typically will not induce radiation sickness or produce serious damage to other structures, although sialadenitis and xerostomia are common (126). Diffuse pulmonary metastases that concentrate 50% or more of the test dose of 131I, which is very uncommon (127), are treated with 150 mCi 131I (5,550 MBq) or less to avoid lung injury that may occur when more than 80 mCi (2,960 MBq) are retained in the whole body 48 hours after the dose. Distant metastases are usually treated with 200 mCi (7,400 MBq) 131I.

A second approach is to use quantitative dosimetry methods to predict radiation doses to target tissues (e.g., thyroid remnant or metastases) and dose-limiting nontarget tissues (e.g., bone marrow, the lungs in those with diffuse pulmonary metastases, and the whole body). Lesional dosimetry is favored by some because radiation exposure from arbitrarily fixed doses of 131I can vary considerably. If the calculated lesional dose is less than 3,500 rad (35 Gy) when reaching radiation limits in nontarget tissues, it is unlikely that the tumor will respond to 131I therapy (102,124). Conversely, doses that will deliver 30,000 rad (300 Gy) to the thyroid remnant or 8,000 to 12,000 rad (80–120 Gy) to metastatic foci are likely to be effective. To make these calculations it is necessary to estimate tumor size.

In a third approach, which is based on dose-limiting toxicities to nontarget tissues, an upper 131I dose is calculated to deliver a maximum of 200 rad (2 Gy) to the whole blood while keeping the whole body retention less than 120 mCi (4,440 MBq) at 48 hours, or less than 80 mCi (2,960 MBq) when there is diffuse pulmonary uptake. Some limit the maximum administered dose to 300 mCi (1,100 MBq) (128). In a more recent study (129) in which up to 300 rad (3 Gy) was delivered to the bone marrow, all patients developed transient bone marrow suppression that was severe enough in four to require hospitalization. Five patients with lung micrometastases had a Tg level of less than 1 ng/mL after treatment, but whether this could have been achieved with lower 131I doses is uncertain.

Dosimetry is complicated and is performed in a limited number of large medical centers that have a dedicated team of physicists, nuclear medicine technologists, and physicians with thyroid cancer expertise. It is often reserved for patients with distant metastases or unusual circumstances such as concurrent renal failure. Comparison of outcomes between empiric fixed dose methods and dosimetric approaches is difficult and unreliable. Moreover, prospective randomized trials to address the optimal therapeutic approach have not been done (130). Those in favor of high-dose therapy cite the positive relationship between the total 
131I uptake per tumor mass and outcome (131), but this has not been confirmed (132,133).

After a therapeutic dose of 131I is administered, oral fluid intake should be large enough to increase urine output and avoid bladder radiation injury. Also, the patient should suck on lemon drops to stimulate salivary flow to minimize the risk for radiation-induced sialadenitis. Constipation should be treated with cathartics to reduce colon and gonadal radiation. Radiation safety procedures must be followed carefully to minimize the risk for exposure to family members and personnel handling these patients. T4 therapy is resumed 24 hours after 131I therapy. It may take up to 2 months for serum TSH levels to decline to normal or below when T4 doses of 100 to 200 µg are given, but this may be expedited by giving 300 to 400 µg of T4 daily or 50 to 100 µg of T 3 daily in divided doses for several days. The use of rhTSH stimulation for imaging or therapy alleviates these untoward effects of iatrogenic hypothyroidism.

 Choice of Therapy

An approach used in our clinic and consistent with the guidelines of the National Comprehensive Cancer Network (NCCN) (10), the American Thyroid Association (ATA) (134), the American Association of Clinical Endocrinologists (AACE) (135), and the British Thyroid Association (BTA) (11) is summarized in TABLE 70D.6. In our practice, patients with tumors of different stages are treated differently after having been fully informed of the potential risks and benefits. Dosimetry is often used in patients with distant metastases.




Clinical Stage

Thyroid Surgery

131I Dosage (mCi)

T4Therapy (Target Serum TSH and Tg Values)




Near-total thyroidectomya (preferred if carcinoma identified at or before surgery, follicular thyroid carcinoma, age over 45, men, prior head and neck ERT, family history of thyroid carcinoma)

< 30b to 100 (preferred)

TSH < 0.5 µU/mL Tg < 1 ng/mLc


Lobectomy or subtotal thyroidectomya (if a single nonmetastatic tumor < 1.5 cm without aggressive histology detected in a resected specimen from a young person; it is not necessary to complete thyroidectomy other than to facilitate follow-up at patient request)


TSH < 0.5 µU/mL Tg < 10 ng/mLd(after T4withdrawal)


Tg < 5 ng/mLd(after rhTSH)


Near-total or total thyroidectomy, compartmental lymph node dissections as needede


TSH < 0.5 µU/mL Tg < 1 ng/mLc


Near-total or total thyroidectomy, compartmental lymph node dissections as needede


TSH < 0.5 µU/mL Tg < 1 ng/mLc


Near-total or total thyroidectomy, compartmental lymph node dissections as needede

200 or more

TSH < 0.1 µU/mL Tg < 1 ng/mLc



Near-total thyroidectomy defined as an attempt to remove all thyroid tissue without damage to recurrent laryngeal nerves or parathyroid tissue, usually leaving portions of the posterior thyroid behind on the contralateral side.

aSubtotal thyroidectomy defined as lobectomy plus contralateral subtotal lobectomy.

b < 30 mCi (1110 MBq) for patients without postoperative residual tumor; consider larger doses for patients with cervical or mediastinal nodes, or incompletely resected tumor. Serum TSH is maintained at low normal values over the long-term if serum Tg is < 1 ng/mL during T4 suppression of TSH and after TSH stimulation by T4 withdrawal or rhTSH.

cSerum Tg measured during T4 therapy and after TSH-stimulation (T4 withdrawal or rhTSH stimulation)

dSerum Tg after T4 withdrawal or rhTSH stimulation. This is an arbitrary estimate not supported by studies.

eCentral neck dissection (level VI, sparing the parathyroid glands and laryngeal nerves), lateral neck dissection (levels II–V, sparing spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle).

ERT, external radiation therapy; rhTSH, recombinant human thyrotropin; T4, thyroxine; Tg, thyroglobulin; TSH, thyrotropin.

Stage 1 Tumors

Patients with small tumors [≤1.5 cm (many use a 1.0-cm cutoff)] that are single papillary carcinomas clearly confined to one lobe or follicular tumors with minimal capsular invasion may be adequately treated with lobectomy and T4 alone (TABLE 70D.6). When discovered postoperatively after lobectomy, we do not advise 131I therapy for stage 1 tumors because a large thyroid remnant often requires multiple or large doses for ablation and may cause severe radiation thyroiditis (136). Although one study reported minimal morbidity after 30 mCi 131I ablation of lobar remnants in patients with minimally invasive follicular carcinoma (137), this strategy is not widely used. Instead, we advise completion thyroidectomy and 131I ablation for anyone with a small tumor that is metastatic or that invades the thyroid capsule, or for patients with a history of head and neck radiation or a family history of differentiated thyroid cancer or whose tumor is multifocal or has histology that suggests a more aggressive tumor, such as tall cell papillary carcinoma, tumor necrosis, marked nuclear atypia, or vascular invasion. If none of these features are present, the patient is advised that the only merit for performing completion thyroidectomy and 131I ablation is to facilitate follow-up with sensitive tests, which is not ordinarily possible after subtotal thyroidectomy (138).

However, when the diagnosis of carcinoma is known preoperatively, we advise near-total thyroidectomy because tumor stage is not completely apparent until after the specimen has been studied by the pathologist and 131I scanning has been done. If a small amount (< 2 g) of thyroid is detected by thyroid ultrasonography (US) after near-total or completion thyroidectomy, we advise 131I ablation. In this group, we maintain serum TSH in the low-normal range if the Tg level is undetectable during T4 therapy. If the TSH-stimulated serum Tg is less than 2 ng/mL 1 year later, a second ablation is unlikely to be of further benefit (139,140).

Stage 2 Tumors

For tumors that are 1.5 to 4.4 cm in diameter that are not locally invasive, with or without regional lymph node metastases, we advise total or near-total thyroidectomy with compartmental lymph node dissections for metastases recognized at surgery followed by 131I therapy (Table 70.D6). Small ablative doses of about 30 mCi (1,110 MBq) are used for tumors confined to the thyroid, whereas higher doses are given for the more aggressive tumors. Repeat 131I therapy may be necessary 1 year later if the serum Tg concentration during T4 withdrawal is greater than 10 ng/mL or Tg is over 2 ng/mL after rhTSH stimulation and resectable disease cannot be identified by neck US. T4 is given at dosages sufficient to maintain the serum TSH concentrations just below normal for several years. Over the long-term, if rhTSH-stimulated Tg remains undetectable (< 1 ng/mL), sufficient T4 is given to keep serum TSH concentrations in the low-normal range.

Stage 3 Tumors

For tumors that are large (>4.5 cm) or invading local structures, we advise total thyroidectomy and compartmental neck dissection for lymph node metastases recognized at surgery followed by 131I therapy (TABLE 70D.6). If there is any question that residual tumor remains after surgery, as with microscopic locally invasive tumors, at least 150 mCi (5,550 MBq) 131I should be given (assuming normal renal function) followed by doses of T4 sufficient to maintain the serum TSH just below normal. If there is gross local tumor invasion, external beam radiotherapy (EBRT) is recommended in patients over age 45 following 131I therapy. Long-term, serum TSH concentrations are maintained in the low normal range if serum Tg remains below 1 ng/mL on T4 therapy and after TSH stimulation.

Stage 4 Tumors (Distant Metastases)

Treatment includes total thyroidectomy and compartmental neck dissections as required, followed by 131I (TABLE 70D.6). T4 is given in doses sufficient to maintain the serum TSH below normal, often less than 0.1 µU/mL. Over the long term, however, if serum Tg measured by a sensitive assay is maintained below the detection limit (≤1 ng/mL), and there is no clinical evidence of tumor, serum TSH is kept in the low normal range.

When tumor deposits are unresectable, treatment with 131I is repeated at 6- to 12-month intervals until the tumor no longer concentrates it or there is no benefit from the previous therapy, large cumulative doses are reached, or there are serious adverse effects. We try to wait a full year between treatments and try to keep the cumulative dose under 500 mCi (18,500 MBq) in children and under 700 mCi (25,900 MBq) in adults. However, there is no specific limit to the cumulative dose that can be administered safely, although the frequency of complications does increase.

Treatment of Patients with Negative Diagnostic Iodine 131 Scans (DxWBS) and High Serum Thyroglobulin Levels

After total thyroidectomy and thyroid remnant 131I ablation, a detectable serum Tg during T4 suppression of TSH or a Tg level greater than 2 ng/mL after rhTSH stimulation is sometimes associated with negative DxWBS 131I scans. This may be caused by at least five different situations (141): (a) TSH is too low to stimulate tumor 131I uptake; (b) iodine contamination, usually from radiographic contrast material; (c) tumor dedifferentiation with a reduction in or an absence of sodium iodine symporter function; (d) metastases too small to see on the body scans; or (e) heterophile antibody interference with Tg assays (142).

Patients with both negative 131I DxWBS and neck US often are treated with 131I to locate and treat persistent tumor (143). However, whether this benefits patients has sparked controversy (144,145,146) because of a lack of randomized prospective studies and the considerable differences in patient cohorts and end points among studies. Nonetheless, there is one consistent observation: serum Tg levels almost invariably decline when  131I uptake is seen on the RxWBS, particularly in patients with lung metastases (144,146). Follow-up is so short in most studies that only a few find enhanced survival after empirically treating a high serum Tg level when the DxWBS is negative. Schlumberger (57) reported complete remission and 10-year survival rates, respectively, of 96% and 100% in 19 patients with tumor found only on a positive RxWBS, compared with 83% and 91% in 55 patients with metastases seen on DxWBS and RxWBS, and 53% and 63% in 64 patients with micronodules seen on chest x-ray, and with 14% and 11% in 77 patients with macronodules seen on chest x-ray.

A more recent study (147) of 56 patients with DTC who were treated with 150 mCi 131I because of an elevated serum Tg level after T4 withdrawal, despite having a negative 10 mCi 131I DxWBS, found that half had 131I uptake on the RxWBS and half did not. After a median of 4.2 years (range 0.5–13.5 years) and treatment with a median cumulative 131I dose of 150 mCi (range 50–650 mCi), 64% of the 28 patients with positive RxWBS achieved complete remission (negative RxWBS and undetectable Tg), compared with only 36% of the 28 patients with a negative RxWBS. None of those with a positive RxWBS died of thyroid cancer, whereas 9 without uptake did so, producing 5-year survival rate of 100% in the former and 76% in the latter ( < .001).p

The best responses to 131I therapy occur in children and younger adults with diffuse pulmonary metastases not seen on any imaging studies except on the RxWBS (117,148). This is not uncommon. One study (149) reported that 15% of 45 children had lung metastases identified by a serum Tg greater than 10 ng/mL. We found that 13% of 89 consecutive paired DxWBS and RxWBS studies in 79 patients (15) with high serum Tg levels (usually > 15 ng/mL after T4withdrawal) and a negative DxWBS had 131I uptake in the lung on the RxWBS (2). Among 23 patients treated with 131I for diffuse pulmonary metastases detected only by 131I imaging, 87% had no lung uptake on subsequent scans (150). After 131I therapy, serum Tg became undetectable and lung computed tomography (CT) scans showed disappearance of the micronodules in almost half the patients, whereas lung biopsy showed no evidence of disease in two. Others also report a substantial decrease in serum Tg levels after 131I treatment of such patients (144). Others report a reduction of metastatic disease in most patients whose lung metastases concentrate 131I, but find that a complete remission is uncommon (56,133). Still, a partial response with reduction of metastatic disease is usually possible, and patients generally have a good quality of life with no further disease progression.

Benefit from 131I therapy is inversely related to tumor mass. When a large tumor is not visualized on a DxWBS, the implication is that its 131I-concentrating ability is low and a poor response to 131I therapy is anticipated. Patients with a high serum Tg and negative DxWBS should not be treated with 131I when (a) there is no 131I uptake on a previous RxWBS, (b) the Tg did not decrease despite optimal conditions of a high serum TSH level without iodine contamination, (c) 18FDG-PET scanning shows intense uptake in metastases, or (d) anatomic imaging, such as US, shows tumor deposits amenable to surgery.

Treatment of Children and Adolescents

Treatment of children and adolescents is even more controversial than it is in adults because experience is more limited and there are no randomized studies. However, cohort studies provide some guidance about management. Hung and Sarlis (12) conceptually separated young patients with DTC into two groups: children under 10 years of age and teenagers and adolescents between 10 and 18 years of age, because DTC developing in the two groups have different clinical behaviors with regard to recurrence and mortality rates. They made treatment recommendations that were especially pertinent for younger children, because after midpuberty patients have generally fully matured and their optimal treatment is addressed in the literature on adults with this malignancy (2).

Although younger children commonly present with more advanced clinical disease stage, perhaps due to late diagnosis (2), their prognosis for survival over several decades is usually excellent, even when distant metastases are present (151,152). Overall survival rates at 20 to 30 years in most series published since 1997 are over 95% (12). However, this gives an incomplete picture of the long-term prognosis of children. For example, in a study of 72 children under age 16 years, 42% developed distant metastases, mostly to lung, but 70% had a complete remission; nonetheless, their long-term mortality rate was eightfold that of healthy children (153).

Children under 10 years of age may have an even less favorable outcome. In a long-term study from London, the risk for recurrence in children 10 years of age or younger was almost 3.5-fold that of older children (154). In another study from England and Wales, 5 of 122 children died of DTC within 17 years of diagnosis: 25% of children ages 9 or younger died, compared with three deaths among 28 older children (14). Moreover, persistent disease is common in children, affecting 20% or more of all children with DTC and 50% or more with tumors of advanced stage at the time of diagnosis (133,155). Although lung metastases in children usually concentrate 131I, almost one third (63,133) are not seen on x-ray or DxWBS and may be overlooked unless they are treated with near-total thyroidectomy and 131I remnant ablation followed by Tg measurements and RxWBS scanning.

Surgery is the treatment of choice, but there is no clear consensus concerning the optimal procedure (152,156). Surgical complications occur more frequently in children than in adults, even at large centers (157). Because the risk for cancer death is low in children, the risk for complications thus constitutes the major reservation about performing more extensive surgery.

Strong arguments for an aggressive approach to the treatment of children include the high incidence of primary tumor multicentricity and metastases in children, the high recurrence rate, and the fact that life expectancy exceeds 60 years (12). For the majority of children, total or near-total thyroidectomy is recommended as the standard initial therapy, followed by 131I to destroy the thyroid remnant (12). Because in adults with DTC completion thyroidectomy may result in lower mortality rates (31) and the same may be true for children and adolescents with radiation-induced DTC (63), completion thyroidectomy when less than near-total thyroidectomy has been performed is advised (12). Others propose a similarly aggressive approach to initial therapy (155,158,159). This is especially important for children with multifocal or invasive tumors, cervical lymph node metastases, or very high serum Tg levels after hemithyroidectomy. Although the indications for postoperative 131I are controversial, 131I ablation of the thyroid remnant with 30 mCi (1,110 MBq) (63,160) is safe. TSH should be maintained in the low normal range with T4 therapy.

Persistent tumor not amenable to surgical resection should be treated with 131I in doses adjusted for body surface area or total body weight (12,161). Some routinely treat distant metastases in children with 1 mCi/kg body weight (132), whereas others recommend dosimetry (162). About half the children become free of disease after 131I treatment, usually after one or two additional therapies, although some may require more (12). The use of rhTSH has not been approved in children; if it is administered, however, the dose may be adjusted in proportion to the child's total body weight or body surface area (12).

Posttreatment Iodine 131 Scans

When 131I therapy is given, RxWBS should always be performed to document 131I uptake by the tumor. Up to 25% of RxWBS studies show lesions not detected by the DxWBS (117). Posttreatment 131I scans are likely to yield the most important information when pretreatment scans are negative and serum Tg concentrations are very high.

Acute Complications of Iodine 131 Therapy

Radiation thyroiditis occurs in about 20% of patients, most often in those with large thyroid remnants given doses of 131I that deliver about 50,000 rad (500 Gy) (136), although this may occur less often when 30 mCi doses of 131I are given (137). It usually appears within the first week after 131I administration and is recognized by neck and ear pain, painful swallowing, thyroid swelling and tenderness, and transient mild thyrotoxicosis. Rarely, the thyroid remnant may swell enough to cause airway obstruction. Mild pain can be treated with analgesics, but severe pain or swelling requires prednisone at a dose of 30 mg daily for several days and then tapered over a week to 10 days.

Painless neck edema within 48 hours after 131I administration is a rare and much different problem than radiation thyroiditis (163). It occurs after high radiation doses, sometimes rather rapidly, and may be accompanied by stridor, regardless of remnant size, and usually responds to corticosteroids.

Radiation sialadenitis involving either the parotid or submandibular glands may occur after 131I therapy in up to 33% of patients, and may be either acute or chronic (126). Acute symptoms may occur within 24 hours and are more likely when large amounts of 131I have been given to a patient with a small thyroid remnant (126). Chewing gum, lemon candies, and hydration may prevent the sialadenitis and xerostomia; however, most patients with sialadenitis experience intermittent painless salivary gland swelling that starts after several months and lasts a few hours, reminiscent of a salivary duct stone. There is a salty taste when the salivary pressure is reduced spontaneously or by manual pressure. Often misdiagnosed as infectious parotitis, it requires no therapy and improves spontaneously within about a year, but it may be associated with a chronic dry mouth or xerostomia (126). About two thirds of patients given 200 mCi or more develop mild radiation sickness characterized by headache, nausea, and occasional vomiting, which begins about 4 hours after 131I administration and resolves in about 24 hours, but rarely occurs with smaller doses (124). Some patients have transient tongue pain, whereas most have reduced taste for several weeks (126). Ocular dryness, conjunctivitis, and nasolacrimal drainage system obstruction may occur 3 to 16 months after 131I treatment (164).

The most important acute complication is tumor edema or hemorrhage, which may result from 131I effects or TSH stimulation. Serious symptoms can occur rapidly from tumor in a critical location such as the central nervous system, spinal cord, or airway (165). Similarly, pain may occur in bone metastases. Pretreatment with corticosteroids may minimize these hazards, but surgery for spinal lesions and isolated brain metastases should be considered before TSH stimulation or 131I therapy (59). Vocal cord paralysis is reported in patients with a large amount of functioning thyroid tissue in close proximity to the vocal cords (124). Transient peripheral facial nerve palsy also occurs rarely after high-dose 131I therapy (166).

Acute hematologic changes, especially a slight reduction in platelets and white blood cell counts, may follow 131I therapy but are typically transient and asymptomatic (167). Severe pancytopenia can follow very large doses of 131I, which may require transfusions, but this is typically reversible (129,167).

Late Complications of Iodine 131 Therapy

The main long-term complications of 131I are damage to the gonads, bone marrow, and lungs, and the induction of other carcinomas. During the first year after 131I therapy, middle-aged women may developed transient amenorrhea and elevated serum gonadotropin concentrations (168) and women of all ages have a higher than expected rate of spontaneous miscarriage (169), yet there are no measurable effects of 131I on fertility, birth defect, birth weight, and prematurity rates (170). Also, 131I therapy is associated with early menopause (171).

In men, the problem may be more severe (172), with permanent testicular damage or transiently reduced sperm counts roughly proportional to the 131I dose administered (173). In 37% of 103 patients treated with 131I for residual disease, the serum follicle-stimulating hormone (FSH) concentration was almost threefold higher than normal (174). In a longitudinal analysis of 21 men, 6 had no change or only a slight increase in serum FSH after 131I therapy, whereas 11 others had a transient increase above normal 6 to 12 months after treatment. Four men treated with several doses of 131I had a progressive increase in serum FSH, which eventually became permanent. Semen analysis performed in a small subgroup of men showed a consistent reduction in sperm motility. The serum testosterone concentrations in the treated and normal men were similar. A survey of 59 men treated with 131I found they had fathered 106 children, none of whom was reported to have had major malformations (175). In 33 children treated at an average age of 14.6 years with a mean dose of 196 mCi (7,252 MBq) of 131I, the frequency of infertility (12%), miscarriage (1.4%), prematurity (8%), and major congenital anomalies (1.4%) after an average of almost 19 years of follow-up was not significantly different from that in the general population (176). In another study, fertility was normal in 30 patients who were no more than 30 years of age when treated; they had 44 live births (177). Two men who had received a total of 972 and 1,432 mCi (35,964 and 52,984 MBq) between ages 10 and 19 years had fathered two and three children, respectively, up to 13 and 24 years later. Another treated at age 24 with 680 mCi had oligospermia with an elevated serum FSH. Thus, 131I therapy occasionally impairs testicular germinal cell function, posing a significant risk for infertility. Young men should consider banking sperm specimens before therapy, particularly if larger cumulative doses of 131I are to be given (172).

Persistent bone marrow damage and induction of other tumors are the most serious late problems of 131I therapy. Large doses of 131I (usually > 1,000 mCi, 37,000 MBq) can cause a small but significant excess of deaths from bladder carcinoma and leukemia (177). Bladder carcinoma occurs more often in those with relatively little 131I uptake in the neck or metastases. In one report, 80% of 35 patients treated with 131I had bone marrow abnormalities, including three with acute myeloid leukemia (178). Those with pancytopenia had received very high 131I doses, all greater than 1,000 mCi (37,000 MBq) (178). In 13 large series comprising a total of 2,753 patients with thyroid carcinoma, 14 cases of leukemia were detected (179). The resulting prevalence of about five leukemia cases per 1,000 patients (0.5%) is higher than expected in the general population. Acute myeloid leukemia, the type associated with 131I therapy, usually has occurred within 10 years of treatment. Leukemia was less likely when 131I was given annually rather than every few months, and when total blood doses per administration was less than 200 rad (2 Gy). Despite this report, the lifetime risk for leukemia is so small (0.33) that it does not outweigh the benefit of 131I therapy (180). The absolute risk for life lost because of recurrent thyroid carcinoma exceeds that from leukemia by 4-fold to 40-fold, depending on the age at which the patient is treated (180). When lower total cumulative 131I doses (600–800 mCi, 22,000–29,600 MBq) are given at widely spaced intervals (12 months), long-term effects on the bone marrow are minimal (167), and few cases of leukemia occur. Furthermore, one large population study did not find an increased risk for leukemia in patients with thyroid carcinoma treated with 131I (181). Pulmonary fibrosis occurs rarely in patients with diffuse pulmonary metastases treated with 131I (182). It can be avoided by using 131I doses that result in a whole body retention of less than 80 mCi 48 hours after its administration when there is diffuse 131I uptake in the lungs seen on the DxWBS, recognizing that retention of greater than 50% at 48 hours is uncommon (127).

Treatment of Persistent Disease Not Amenable to Iodine 131 Therapy

Whenever possible, surgery is the treatment of choice for recurrent or residual tumor. Before other therapies are given, surgical excision or external irradiation should be considered for focal lesions that do not concentrate 131I adequately and isolated skeletal or brain metastases (10). A few patients with tumor that does not concentrate 131I may benefit from 13-cis retinoic acid therapy, which partly redifferentiates follicular thyroid carcinoma . In an early study, when retinoic acid was given orally for at least 2 months to 12 patients with differentiated carcinoma that could not be treated with other modalities, significant in vitro131I uptake was induced in 2 patients, and a faint response was seen in 3 (183). However, subsequent studies have shown the effect is less than previously reported (184).

Octreotide inhibits the growth of DTC  (185). Although there are a few examples of patients with DTC who have responded to this therapy (186), it has not been effective in most patients (187). Those with an impending fracture should receive prompt orthopedic stabilization. They also should receive antiresorptive therapy that may improve their quality of life and has induced clinical remission in some patients (188). Patients with pain or symptoms of compression from metastases should be considered for surgery, embolization, EBRT, and in vitro131I (189).

External Beam Radiation Therapy

Selected bone metastases and postoperative macroscopic residual disease that does not concentrate 131I may respond to EBRT (104,105). It improves locoregional control and is particularly effective in the treatment of patients over age 45 years with incompletely resected gross residual cervical tumor (107,190), including tumors that invade the aerodigestive tract, or in the treatment of microscopic perithyroidal tumor that is invading muscle or fat tissues (105). Patients with microscopic residual papillary carcinoma after surgery are more commonly rendered disease free when EBRT is given (90%) than when it is not (26%) (104). This is also true for patients with microscopically invasive follicular carcinoma, more of whom are disease free when postoperative EBRT is given (53%) than when it is not (38%) (104). In another study of patients who had incomplete surgical resection of their tumors, although the irradiated tumors were larger and more extensive than those treated with surgery alone, the 15-year local recurrence rate after EBRT was about half that of patients treated with surgery alone (11% vs. 23%) (191). Two studies found that EBRT had an independent therapeutic effect on the control of locoregional tumor: in one (190) the 5-year control rates were 95% in those treated with EBRT and 68% in those not so treated, and in the other (107) EBRT reduced the risk for locoregional failure to 35% that of patients not so treated. Some have also observed improved survival rates in patients with residual disease treated with EBRT (191).

Although children and young adults may be treated with EBERT if they have macroscopically invasive neck tumor that is unresponsive to other therapy (12), its side effects are significant, and it is generally recommended mainly for those over age 45 years (10). A few children and young adults have been reported to develop neck sarcomas decades after EBRT therapy (192).


Experience with chemotherapy in patients with DTC is limited, because most tumors grow slowly and respond well to conventional therapy (e.g., surgery, 131I therapy, or EBRT). Chemotherapy is mainly for tumors that are progressive and have failed conventional therapy. Among 49 patients with metastatic DTC treated with five chemotherapy protocols, only two (3%) patients had objective responses (193). In a review of published series, 38% of patients had a response to doxorubicin defined as a reduction in tumor mass (194). Low-dose doxorubicin has been used with EBRT as a radiation sensitizer, but usually is no better than radiotherapy alone. A recent study found that the combination of carboplatin and epirubicin with TSH stimulation to promote cell proliferation produced temporary complete or partial remission or tumor stabilization in 81% of the patients with advanced DTC, although no long-term cures were achieved and one third of the patients died after a short follow-up time (195). Interested and informed patients should be encouraged to participate in appropriate clinical trials.


Follow-up can be divided onto three stages: 4 to 6 weeks postoperatively, 6 to 12 months postoperatively, and thereafter annual long-term follow-up (Fig. 70D.8). Until recently, this was usually done with serum Tg determinations and 131I DxWBS imaging. More recently, however, follow-up has become more complex, and substantially more accurate. Older antithyroglobulin antibody (TgAb) assays did not detect low levels of TgAb, which factitiously lower serum Tg results from immunometric assays (IMAs). Also, 3 to 5 mCi 131I DxWBS, CT, and magnetic resonance imaging (MRI), the mainstays of imaging in the past, are far less capable of locating tumor than are newer more sensitive US and Doppler techniques, 131I RxWBS, and 18FDG PET imaging studies. Identifying persistent DTC late in its course was the inevitable consequence of using insensitive tests: long-term studies show that late tumor recurrences, some as long as 45 years after initial treatment, are common (Fig. 70D.1B) (196). Many were probably persistent tumors that had fallen below the detection limits of older tests. Newer follow-up paradigms identify persistent tumor 6 to 18 months after total thyroid ablation, permitting the application of earlier therapy with the hope of improving outcome.


FIGURE 70D.8. The three phases of follow-up of patients after thyroidectomy for differentiated thyroid carcinoma.  Phase 1: rhTSH is recombinant human thyrotropin (see Fig. 70D.7 and text for dosage schedules). DxWBS is diagnostic A:131I whole-body scan, which after withdrawal of thyroid hormone is performed with 2 to 3 mCi 131I (74–185 MBq) or with 4 mCi of 131I if rhTSH is given for preparation of the scan. Treatment with 30 mCi 131I (1,110–3,700 MBq), 75 to 100 mCi (2,775–3,700 MBq), or 200 mCi (2,775 MBq) 131I is given, depending on the clinical situation (see text and Figure 70D.8). *Serum TSH and antithyroglobulin antibody () levels should be performed any time serum Tg is determined. US is neck ultrasonography. †See text for criteria for completion thyroidectomy.  Phase 2 follow-up.  Phase 3 follow-up. (Reproduced from Mazzaferri EL, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma.  2003;88(4): 1433–1441, with permission.)TgAbB:C:J Clin Endocrinol Metab

Serum Thyroglobulin

The paradigm for the follow-up of patients who appear to be free of tumor after thyroid ablation has shifted to performing neck US and measuring Tg during TSH suppression and after rhTSH stimulation or T4 withdrawal, although the latter produces symptomatic hypothyroidism that many patients choose to avoid (109). Accurate serum Tg measurement is the cornerstone of this follow-up paradigm (see Chapter 20). Done accurately, serum Tg and US identifies almost all patients with residual tumor, thus preventing unnecessary additional testing in those who are cured. However, Tg measurements may be misleading. Tg is now usually measured by IMA, which may be altered by failure to use the CRM-457 international standard, poor assay functional sensitivity, a “hook” effect, or the presence of serum TgAb that falsely lowers Tg results (98), or, conversely, serum heterophile human antianimal antibodies that factitiously increase Tg levels measured in some Tg IMA systems (142). Serial Tg measurements in a patient should be made in the same laboratory using the same assay method (98) because methodologies standardized to CRM-457 may still yield different results, and the trend in Tg levels is often more important than a single Tg measurement (139). Circulating Tg messenger RNA is a potentially more sensitive marker of thyroid tissue or carcinoma than Tg by IMA, particularly during T

4 treatment or with circulating TgAb, but it is not yet ready for clinical use and remains controversial (197).

Measuring serum Tg during T4 suppression of TSH and performing DxWBS after T4 withdrawal or rhTSH administration often fail to identify persistent DTC (140,143,198,199), whereas a TSH-stimulated serum Tg level above 2 µg/L, achieved either after T4 withdrawal or rhTSH injection, is highly accurate in identifying persistent tumor (139,140,200). For example, eight studies comprising 1,029 patients showed that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually less than 1 ng/mL during T4 suppression of TSH had an rhTSH-stimulated serum Tg of greater than 2 ng/mL. When this happened, 36% of the patients were found to have metastases, including 36% to distant sites. A rhTSH-stimulated Tg level of greater than 2 ng/mL identified 91% of the patients with metastases, whereas DxWBS, after either rhTSH or T4 withdrawal, identified only 19% (200). Ten studies comprising 1,599 patients found that using a TSH-stimulated Tg cutoff of 2 ng/L, either after T4 withdrawal or 72 hours after rhTSH, is sufficiently sensitive to be used as the principal test in the follow-up of low-risk patients with DTC without routine use of DxWBS (200). Still, some patients with tumor, especially those with lymph node metastases (201,202), may have a false-negative TSH-stimulated serum Tg level, which in almost all reported cases was measured by recovery Tg assays performed on sera with TgAb (139,140,202,203), a controversial practice (98).

Imaging Studies

Based on these observations, a follow-up guideline is proposed using Tg levels during T4 suppression and after rhTSH stimulation (200) (Fig. 70D.8). Patients who have no clinical evidence of residual tumor, negative serum TgAb, and a serum Tg of less than 1 µg/L during T4 suppression of TSH usually do not require DxWBS (139,140,200). An injection of 0.9 mg rhTSH is given on 2 consecutive days and a serum Tg level is measured 72 hours after the last injection (Fig. 70D.7). If the Tg level increases above 2 ng/mL, then further testing is advised. This can also be done with T
4 withdrawal.

Neck Ultrasonography

Study of the central and lateral cervical compartments by US usually detects malignant lymph nodes and other neck tumors. The classic criterion for differentiating benign from malignant lymph nodes is a size cutoff of about 1 cm, but this misses the majority of tumors. Benign lymph nodes tend to be elongated (oval to fusiform) with a Solbiati index (SI = ratio of largest to smallest diameter) greater than 2 and show a stringlike hyperechoic central structure (hilar sign) with a central hilar-oriented pattern of blood flow on power Doppler (204). Malignant lymph nodes have a rounded or oval appearance with an SI less than or equal to 2 in over 80% of cases and do not have a hilar sign (204). The best indicators of malignancy, however, are a heterogenous echo pattern or irregular hyperechoic small intranodal structures and the presence of irregular diffuse intranodal blood flow on power Doppler (204).

Neck US combined with TSH-stimulated Tg has the highest diagnostic accuracy for detecting persistent cervical tumor. A study of 294 patients with DTC found that three patients with a serum Tg of less than 1 ng/mL had tiny lymph node metastases identified by US (110). The sensitivity and negative predictive values were, respectively, 85% and 98% for Tg alone, 96% and 99.5% for US and rhTSH-stimulated Tg together, and 21% and 99% for rhTSH-stimulated DxWBS alone, and 93% and 99% with rhTSH-stimulated Tg and DxWBS combined.

Another study (140) of 99 patients found that US identified small lymph node metastases missed by all other tests. Six to 12 months after total thyroidectomy and 131I ablation, rhTSH-stimulated DxWBS was negative in all patients with persistent DTC (sensitivity = 0); however, neck US identified lymph node metastases in 67% with rhTSH-Tg levels of greater than 5 ng/mL, in 13% with Tg levels greater than 1 but less than 5 ng/mL, and in 3% with undetectable Tg levels. The serum Tg was measured by a recovery Tg IMA method, which might account for some of the undetectable serum Tg levels.

A third study (203) of 494 patients with DTC found that 10% had recurrent neck tumor after total thyroidectomy and 131I ablation. After T4 withdrawal, the sensitivity for detecting neck metastases was 57% for Tg greater than 2 ng/mL (measured by recovery Tg assay), 45% for 131I DxWBS, and 94% for neck US. A fourth study (149) of 45 children treated with total thyroidectomy for papillary carcinoma found that 22 had cervical lymph node metastases. After T4withdrawal, the sensitivity for detecting lymph node metastases was 68% for US, 82% for DxWBS and 77% for Tg, but the lower detection limit of the Tg assay was 3 ng/mL, and Tg was measured in sera that tested positive for TgAb. Still, either Tg or US detected 100% of the lymph node metastases.

Radioiodine (131I and 123I) Scans

Although we prefer 131I DxWBS for patients at high risk for having persistent tumor, other imaging studies may be useful. DxWBS imaging with 131I may pose the problems of stunning and undesirable beta radiation, but also requires a low-iodine diet and TSH stimulation. Although 123I and 131I DxWBS studies are comparable, even after rhTSH stimulation (205), 123I for this use is expensive and has not gained wide use. The main problem with 131I DxWBS is its low sensitivity in detecting residual tumor discussed above. Other scans may be done but also have limitations.

18-Fluorodeoxyglucose Positron Emission Tomography

The most consistent data concerning 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) scanning is that it localizes foci of persistent DTC in patients with elevated serum Tg levels and a negative DxWBS (206). It is thus widely used in follow-up, specifically when the serum Tg is greater than 10 ng/mL in patients with no other clinical evidence of tumor, including both a negative neck US and a 100-mCi RxWBS (206,207,208). Although 18FDG-PET may not identify miliary lung metastases, it usually makes more sense than performing a CT at this point because 18FDG-PET provides information about both the location (208,209,210,211) and prognosis of a tumor (58). Persistent tumor identified as a hot spot on the 18FDG PET scan is typically resistant to 131I therapy but may be amenable to surgery or EBRT (207,212). A large multicenter study (213) found the sensitivity of 18FDG-PET for identifying DTC was 75% in 222 patients and 85% in a subset of 166 patients with a negative DxWBS. Although 111In DTPA-octreotide scintigraphy or conventional radiographic imaging may locate metastatic DTC, both are less sensitive than 18FDG-PET (214). The Centers for Medicare and Medicaid Services recently approved coverage for 18FDG-PET by dedicated full or partial ring scanners in patients who have an elevated or increasing serum Tg of greater than 10 µg/L and negative RxWBS, but not for other indications such as initial staging. Because of their cost, however, dedicated PET systems are not available in all institutions. Coincidence 18FDG imaging with a triple-head scintillation camera does not require a dedicated PET scanner and is much less costly than conventional 18FDG-PET. Its sensitivity was 100% in a retrospective study (215) of 10 patients with serum Tg levels ranging from less than 0.5 to 54.2 µg/L. However, it is likely not as sensitive as a dedicated PET scanner, particularly for tumors smaller than 1.5 cm. TSH stimulates 18FDG uptake by DTC (211), making 18FDG-PET more accurate in DTC after rhTSH (211) or T4 withdrawal (216) than it is when the TSH is suppressed.

99mTc-Tetrofosmin, 99mTc-MIBI, and 201TI and 111In DTPA-Octreotide Scintigraphy

These isotopes might be considered for localizing tumor in patients with an elevated serum Tg concentration and negative US, 131I RxWBS, and chest CT results, but they are less sensitive than 18FDG-PET or conventional radiographic studies (214).

Computed Tomography and Magnetic Resonance Imaging

Although chest x-rays can be useful for evaluating the response to treatment of macronodular pulmonary metastases, their sensitivity is low, and other imaging studies are generally used for follow-up. CT and MRI scans yield high-resolution cross-sectional images of the thyroid bed and neck and may be particularly helpful in evaluating the extent of local invasion of a tumor prior to surgery (217). CT scanning of the lungs does not require contrast and may reveal micronodular lesions better than MRI. Iodinated radiographic contrast agents are useful for CT of the neck, mediastinum, and abdomen but seriously interfere with 131I uptake for at least 6 to 12 weeks. MRI offers certain advantages because it can be performed in transaxial, coronal, and sagittal planes, and vascular structures are well defined without contrast material. MRI can detect cervical, mediastinal, and hepatic metastases not revealed by CT. Bone metastases usually are detected with 131I scanning or 18FDG-PET, but may be found by 99mTc-pyrophosphate scan.

Follow-up Paradigm

In our clinic we depend heavily on neck US and a sensitive Tg IMA test with a detection limit of 0.9 ng/mL, which is highly reliable unless TgAb levels are detected in the serum sample.

Phase 1 begins about 4 to 6 weeks after surgery when the completeness of thyroidectomy is evaluated by reviewing the surgery and pathology reports and by performing a serum Tg and neck US examination, which provide guidance for subsequent decisions (Fig. 70.8A). A large (>2 g) thyroid remnant usually requires larger than usual amounts of 131I for ablation. If an entire thyroid lobe is present, completion thyroidectomy should be considered.

Phase 2 begins about 9 to 12 months after surgery when patients are evaluated for completeness of 131I ablation and for residual tumor (Fig. 70.8B). Patients who had no uptake outside the thyroid bed on the phase 1 RxWBS and are now clinically free of disease undergo neck US and serum Tg and TSH measurements. If the serum Tg is undetectable (< 1 ng/mL) during thyroid hormone suppressive therapy (THST) and neck US shows no tumor, serum Tg is remeasured under TSH stimulation, usually with rhTSH. If the serum Tg increases by more than 2 ng/mL after rhTSH or more than 10 ng/mL after T4withdrawal, normal or malignant thyroid tissue is often found (2,109,132,218). When malignant lymph nodes are found on US-guided FNA, ipsilateral modified neck dissection is usually performed. If the US result is negative but the Tg is high, we usually give therapeutic 131I—usually 100 mCi (3,700 MBq)—and perform an RxWBS. Up to 15% of such patients have lung metastases (2). Others use different Tg cut-off values and different doses of 131I, but the Tg levels that trigger treatment have been gradually coming down in recent years (117). We continue 131I treatment until the RxWBS is negative. When the serum Tg is undetectable during THST and fails to increase above 2 ng/mL during rhTSH stimulation, patients undergo annual long-term follow-up.

Phase 3 occurs 18 to 24 months after initial therapy (Fig. 70D.8C). In this phase, neck US and serum Tg measurements are made during THST. If the rhTSH-stimulated serum Tg was undetectable in phase 2 and remains so during THST in phase 3, the dose of thyroid hormone is reduced to maintain the serum TSH level around 0.5 ng/mL and patients are seen thereafter at about 12-month intervals. In contrast, if during phase 2 the rhTSH-stimulated serum Tg increased after rhTSH but did not increase above 2 ng/mL and does the same during phase 2, then the TSH is maintained at around 0.3 µU/mL. If rhTSH-stimulated Tg increases above 2 ng/mL, then the phase 2 protocol is followed.


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