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Medical Progress

P APILLARY AND F OLLICULAR T HYROID C ARCINOMA

MARTIN JEAN SCHLUMBERGER, M.D.

APILLARY and follicular (differentiated) thyroid carcinomas are among the most curable cancers. However, some patients are at high risk for recurrent disease or even death. Most of these patients can be identified at the time of diagnosis by using well-established prognostic indicators. The extent of the initial treatment and follow-up care should therefore be tailored to the level of risk. Although treatment guidelines have been published,1,2 clinical procedures vary considerably among clinicians.3
EPIDEMIOLOGY

found in some papillary carcinomas.6 RET rearrangements are found in 3 to 33 percent of papillary carcinomas unassociated with irradiation7-9 and in 60 to 80 percent of those occurring after irradiation, diagnosed either in children in Belarus exposed to radiation after the nuclear accident in Chernobyl10-12 or in patients who received external radiation treatment in childhood.13 The frequency of TRK rearrangements is much lower.8 Activating point mutations of the RAS genes are found with a similarly high frequency in thyroid adenomas and follicular carcinomas, suggesting that RAS mutations represent an early event in thyroid tumorigenesis.5,14 Activating mutations of the genes encoding the thyrotropin receptor and the a subunit of the stimulatory G (Gs) protein have been reported in some follicular carcinomas.14,15 Inactivating point mutations of the p53 tumor-suppressor gene are rare in patients with differentiated thyroid carcinomas but common in those with undifferentiated (anaplastic) thyroid carcinomas.16,17
Thyroid Irradiation

Although thyroid nodules are common, differentiated thyroid carcinomas are relatively rare. Clinically detectable thyroid carcinomas constitute less than 1 percent of all human cancers. The annual incidence rate in various parts of the world ranges from 0.5 to 10 cases per 100,000 population.4 Papillary and follicular cancers are rare in children and adolescents, and their incidence increases with age in adults. The median age at diagnosis is 45 to 50 years. Thyroid carcinomas are two to four times as frequent in women as in men. Thyroid microcarcinomas (diameter, 1 cm) are found in 5 to 36 percent of adults at autopsy but are rare in children. The reported increase in the incidence of these small carcinomas in recent years can be attributed to an improvement in pathological techniques.
PATHOGENESIS
Oncogenes

Recent advances in molecular biology have improved our understanding of the pathogenesis of thyroid carcinomas.5 Rearrangements of the tyrosine kinase domains of the RET and TRK genes with the amino-terminal sequence of an unlinked gene are

From the University of Paris XI, Institut Gustave-Roussy, Rue CamilleDesmoulins, 94805 Villejuif CEDEX, France, where reprint requests should be addressed to Dr. Schlumberger. 1998, Massachusetts Medical Society.

External irradiation to the neck during childhood increases the risk of papillary thyroid carcinoma.18-20 The latency period between exposure and diagnosis is at least five years. The risk is maximal at about 20 years, remains high for about 20 years, and then decreases gradually. The risk is increased after a mean dose to the thyroid as low as 10 cGy. At higher doses (up to 1500 cGy), there is a linear relation between the dose and the risk of carcinoma. At doses higher than 1500 cGy, the risk per gray decreases, probably because of cell killing. A major risk factor is a young age at the time of irradiation; after the age of 15 or 20 years, the risk is not increased. In children exposed to a dose of 1 Gy to the thyroid, the excess risk of thyroid carcinoma is 7.7.19 The risk of thyroid carcinoma is not increased in patients given iodine-131 for diagnostic or therapeutic purposes.18,20 However, iodine-131 given for the treatment of hyperthyroidism induces cell killing. Furthermore, the number of patients exposed to iodine-131 for medical reasons during childhood is too small to rule out a carcinogenic effect at a young age. However, the increased incidence of papillary thyroid carcinomas in children in the Marshall Islands after atomic-bomb testing and, more recently, in Belarus and Ukraine after the Chernobyl nuclear accident suggests that radioactive isotopes of iodine, both iodine-131 and short-lived isotopes, have a direct tumorigenic effect on the thyroid.21,22 In Belarus and Ukraine, the incidence of thyroid cancer started to inVo l u m e 3 3 8 Nu m b e r 5

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crease as early as four years after the accident. To date, about 1000 cases have been reported, mostly in children who were younger than 10 years old at the time of the accident, which corresponds to an incidence 100 times that in nonirradiated children.
Other Factors

DIAGNOSIS

In countries where iodine intake is adequate, differentiated cancers account for more than 80 percent of all thyroid carcinomas, with the papillary histologic type being the more frequent (accounting for 60 to 80 percent of cases). There is no increase in the incidence of thyroid carcinomas in countries where iodine intake is low, but there is a relative increase in follicular and anaplastic carcinomas.20,23 A high incidence of papillary carcinomas has been reported in patients with adenomatous polyposis coli and Cowdens disease (the multiple hamartoma syndrome).20 About 3 percent of cases of papillary carcinoma are familial.24
PATHOLOGICAL FEATURES
Papillary Carcinoma

Papillary carcinoma is an unencapsulated tumor with papillary and follicular structures that is characterized by overlapping cell nuclei that have a groundglass appearance and longitudinal grooves, with invaginations of cytoplasm into the nuclei (Fig. 1).25,26 Encapsulated, follicular, tall-cell, columnar-cell, clearcell, and diffuse sclerosing carcinomas are recognized histologic variants; they are classified as papillary carcinomas because of their characteristic nuclear features. The tumor is multicentric in 20 to 80 percent of patients (with the wide range attributable to variations in the care used to examine the thyroid) and bilateral in about one third. It spreads through the lymphatics within the thyroid to the regional lymph nodes and, less frequently, to the lungs.
Follicular Carcinoma

Most differentiated thyroid carcinomas present as asymptomatic thyroid nodules, but the first sign of the disease is occasionally lymph-node metastases or in rare cases lung or bone metastases. Hoarseness, dysphagia, cough, and dyspnea suggest advanced disease. On physical examination, the carcinoma, usually single, is firm, moves freely during swallowing, and is not distinguishable from a benign nodule. Among patients with thyroid nodules, the nodule is more likely to be a carcinoma in children and adolescents, patients older than 60 years, and men than in women 20 to 60 years old. Carcinoma should be suspected if a hard, irregular thyroid nodule is found, ipsilateral lymph nodes are enlarged or compressive symptoms are present, and there is a history of a progressive increase in the size of the nodule. Virtually all patients with thyroid carcinoma are clinically euthyroid and have normal serum thyrotropin concentrations. Whatever the presentation, fine-needle aspiration cytology is the best test for distinguishing between benign and malignant thyroid nodules.1,27 Provided an adequate specimen is obtained, three cytologic results are possible: benign, malignant, or indeterminate (or suspicious). False negative results, usually from sampling or interpretive errors, and false positive results are rare. Only about 20 percent of patients with indeterminate findings have malignant nodules, reflecting the difficulty of differentiating benign follicular adenomas from their malignant counterparts. Thyroid ultrasonography is useful for assessing the size of the nodule, detecting other nodules, and guiding fine-needle biopsy in the case of a nodule that is small or difficult to palpate.
PROGNOSTIC FACTORS

Follicular carcinoma is characterized by follicular differentiation but without the nuclear changes characteristic of papillary carcinoma (Fig. 1).25,26 Follicular carcinomas are encapsulated, and invasion of the capsule and vessels is the key feature distinguishing follicular carcinomas from follicular adenomas. Two forms are recognized according to the pattern of invasion: minimally invasive and widely invasive carcinomas. The growth pattern may also vary, ranging from a well-differentiated pattern with macrofollicular structures to a poorly differentiated pattern with areas of solid growth and a high degree of atypia. Hrthle-cell (oxyphilic follicular or oncocytic) carcinoma is a cytologic variant of follicular carcinoma. Multicentricity and lymph-node involvement are less frequent than in papillary carcinoma, and metastases to the lungs and bones stem from hematologic spread.
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The overall survival rate at 10 years for middle-aged adults with thyroid carcinomas is about 80 to 95 percent (Fig. 2).28-38 Five to 20 percent of patients have local or regional recurrences, and 10 to 15 percent have distant metastases. The prognostic indicators of recurrent disease and of death are the patients age at diagnosis and the histologic subtype and extent of the tumor.28-42 There are many staging systems for thyroid carcinoma,28-35,38 among which the tumornodemetastasis (TNM) system is the most widely used (Table 1).33,34 On the basis of these systems, 80 to 85 percent of patients are classified as being at low risk for death from thyroid carcinoma. Some patients have a higher risk of recurrence, even if their risk of death is low. This group includes younger patients (16 years old)39,40 and older patients (45 years old), those with certain histologic subtypes (among papillary carcinomas, the tall-cell, columnar-cell, and diffuse sclerosing variants, and among follicular carcinomas, the widely invasive and poorly differentiated subtypes38,41 and Hrthle-cell carcinomas), and those

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Figure 1. Histologic Appearance of Papillary and Follicular Carcinoma of the Thyroid (Hematoxylin and Eosin). Panel A shows papillary carcinoma under low magnification (500). The papillae have a fibrovascular core (arrows) covered by a single layer of neoplastic cells. Panel B shows papillary-carcinoma cells under high magnification (1000). Characteristic nuclear changes include a large size, a ground-glass appearance, longitudinal grooves (arrow), and marked overlapping (arrowhead). Panel C shows well-differentiated follicular carcinoma (250). There is minimal invasion of neoplastic cells into the thick fibrous capsule (arrow). Panel D shows poorly differentiated follicular carcinoma with a solid, trabecular pattern (500). Photographs were provided by B. Caillou, Institut Gustave-Roussy, Villejuif, France.

with large tumors, tumors that extend beyond the thyroid capsule, or lymph-node metastases. The extent of initial treatment and follow-up should be determined according to these prognostic indicators.
INITIAL TREATMENT
Surgery

The goal of surgery is to remove all tumor tissue in the neck. Therefore, the thyroid gland and affected cervical lymph nodes should be resected.43 Although there is still some controversy about the extent of thyroid surgery, there are strong arguments in favor of a total or near-total thyroidectomy (leaving no more than 2 to 3 g of thyroid tissue) in all patients.30-32,35-38 Total or near-total thyroidectomy results in a lower recurrence rate than more limited thy-

roidectomy because many papillary carcinomas are multifocal and bilateral.44,45 Furthermore, removal of most, if not all, of the thyroid gland facilitates total ablation with iodine-131. The argument against total thyroidectomy is that it increases the risk of surgical complications such as recurrent laryngeal-nerve injuries and hypoparathyroidism. Even with total thyroidectomy, often some thyroid tissue remains, as detected by postoperative scanning with iodine-131. In low-risk patients (those with papillary carcinomas less than 1.5 cm in diameter, if unifocal and intralobar), a lobectomy may be appropriate. In patients who have undergone a lobectomy for a supposedly benign tumor that proves to be a follicular carcinoma, a completion thyroidectomy is advisable, because it will facilitate follow-up.
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100

Survival (%)

80 60 40 20 0 0 5 10 15 20 25 30
20 yr 20 39 yr 40 59 yr 60 yr

A
PATIENTS AT RISK 20 yr 20 39 yr 40 59 yr 60 yr 142 659 672 228

Years after Initial Therapy

110 391 471 101 92 232 304 51 73 133 199 27 55 84 128 14 30 45 81 11 15 29 43 9

100

Survival (%)

80 60 40 20 0 0 5 10 15 20 25 30
Papillary Follicular, well differentiated Follicular, poorly differentiated

In patients with papillary carcinoma, lymph nodes in the central compartment (paratracheal and tracheoesophageal areas) and the ipsilateral supraclavicular area and lower third of the jugulocarotid chain should be dissected. A modified neck dissection is performed if there are palpable lymph-node metastases in the jugulocarotid chain. Dissection of lymph nodes is preferable to sampling. Although this type of lymphnode dissection has not been shown to improve recurrence and survival rates, its routine use in patients with papillary carcinomas is warranted for several reasons. About two thirds of the patients have lymph-node metastases, and in more than 80 percent of patients with lymph-node metastases the central compartment is involved.46 In addition, metastases are difficult to detect in lymph nodes located behind the vessels or in the paratracheal groove. Among patients with follicular carcinomas, a small proportion (about 35 percent) have lymph-node metastases. In these patients, a lymph-node dissection is performed only if the diagnosis of follicular carcinoma is established during surgery or lymph nodes are palpable at surgery.
Iodine-131 Therapy

B
PATIENTS AT RISK Papillary 1261 Follicular, well 97 differentiated Follicular, poorly 343 differentiated

Years after Initial Therapy

802 64 207 518 36 125 339 21 72 221 11 49 130 7 30 74 4 18

Figure 2. Survival Rate among 1701 Patients with Papillary or Follicular Carcinoma and No Distant Metastases at the Time of Diagnosis. The patients were treated at Institut Gustave-Roussy, Villejuif, France, during the period from 1950 through 1991. The overall survival rate was 82 percent at 10 years, 72 percent at 20 years, and 60 percent at 30 years. The standardized mortality ratio (the ratio of the number of deaths among the patients to the number of expected deaths, based on the rate in the general population) was 2.6 (P0.001). Panel A shows the corrected survival rate according to the age at diagnosis. The rate was adjusted by taking into account the mortality rate for the French population of the same age and sex. Panel B shows the corrected survival rate according to histologic subtype (papillary carcinoma, well-differentiated follicular carcinoma, or poorly differentiated follicular carcinoma).

Iodine-131 therapy is given postoperatively for three reasons. First, it destroys any remaining normal thyroid tissue, thereby increasing the sensitivity of subsequent iodine-131 total-body scanning and the specificity of measurements of serum thyroglobulin for the detection of persistent or recurrent disease. Second, iodine-131 therapy may destroy occult microscopic carcinoma, thereby decreasing the longterm risk of recurrent disease.30,35-38 Third, the use of a large amount of iodine-131 for therapy permits postablative iodine-131 total-body scanning, a sensitive test for detecting persistent carcinoma.47,48 Postoperative iodine-131 therapy should be used selectively (Table 2). In low-risk patients, the longterm prognosis after surgery alone is so favorable that iodine-131 ablation is not usually recommended. However, all patients who are at high risk for recurrent disease should be treated with iodine-131, because it decreases both recurrence and death rates.30,35-38 Iodine-131 scanning is performed four to six weeks after surgery, with no thyroid hormone treatment given in the interim. At our center, we use a dose of 2 mCi (74 MBq) of iodine-131 and obtain a total-body scan three days later. If any iodine-131 uptake is detected in the thyroid bed or elsewhere, a treatment dose is given. Another total-body scan is obtained four to seven days later, and thyroxine therapy is initiated. Total ablation is verified by performing iodine-131 total-body scanning 6 to 12 months later with 2 mCi. Total ablation (no visible uptake) is achieved after the administration of either 100 mCi (3700 MBq) or 30 mCi (1110 MBq) in more than 80 percent of patients who have undergone a total or near-total

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thyroidectomy.49 After less extensive surgery, ablation with 30 mCi of iodine-131 is achieved in only two thirds of patients. Therefore, total or near-total thyroidectomy should be performed in all patients who are to be treated with iodine-131. Total ablation requires that a dose of at least 300 Gy be delivered to the thyroid remnant; a dosimetric study may allow a more precise estimate of the dose of iodine-131 to be given.50
External Radiotherapy

TABLE 1. TUMORNODEMETASTASIS (TNM) STAGING SYSTEM FOR PAPILLARY AND FOLLICULAR THYROID CARCINOMAS.*
STAGE 45
YR

AGE 45
YR

I II III IV

Any T, any N, M0 Any T, any N, M1

T1, N0, M0 T2 or T3, N0, M0 T4 or N1, M0 Any T, any N, M1

External radiotherapy to the neck and mediastinum is indicated only in patients in whom surgical excision is incomplete or impossible and the tumor tissue does not take up iodine-131.51
FOLLOW-UP

The goals of follow-up after initial therapy are to maintain adequate thyroxine therapy and to detect persistent or recurrent thyroid carcinoma. Recurrences are usually detected during the early years of follow-up, but may be detected later. Therefore, follow-up is necessary throughout the patients life.
Thyroxine Treatment

*The size of the primary tumor (T) is classified as T1, 1 cm; T2, 1 cm and 4 cm; T3, 4 cm; or T4, extending beyond the thyroid capsule. Lymph nodes (N) are classified as N0, no lymph-node metastasis, or N1, lymph-node metastases. Distant metastases (M) are classified as M0, no distant metastases, or M1, distant metastases. Data are from Hermanek and Sobin.33

TABLE 2. INDICATIONS FOR ABLATIVE TREATMENT WITH IODINE-131 AFTER SURGERY IN PATIENTS WITH THYROID CARCINOMA.
No indication Low risk of cancer-specific mortality and low risk of relapse Indication Distant metastases Incomplete excision of tumor Complete excision of tumor but high risk of mortality associated with thyroid carcinoma Complete excision of tumor but high risk of relapse due to age (16 or 45 yr), histologic subtype (tall-cell, columnar-cell, or diffuse sclerosing papillary variants; widely invasive or poorly differentiated follicular subtypes; Hrthle-cell carcinomas), or extent of tumor (large tumor mass, extension beyond the thyroid capsule, or lymph-node metastases) Elevated serum thyroglobulin concentration more than three months after surgery

The growth of thyroid-tumor cells is controlled by thyrotropin, and the inhibition of thyrotropin secretion with thyroxine improves the recurrence and survival rates.35 Therefore, thyroxine, in the form of levothyroxine sodium, should be given to all patients with thyroid carcinoma, whatever the extent of thyroid surgery and other treatment. The effective dose in adults is between 2.2 and 2.8 mg per kilogram of body weight; children require higher doses.52 The adequacy of therapy is monitored by measuring serum thyrotropin three months after treatment is begun, the initial goal being a serum thyrotropin concentration of 0.1 mU per milliliter or less and a serum free triiodothyronine concentration within the normal range. When these guidelines are followed, thyroxine therapy does not have deleterious effects on the heart or bone.52,53
Clinical and Ultrasonographic Examinations

Chest Radiography

Palpation of the thyroid bed and lymph-node areas should be performed routinely. Ultrasonography is performed in patients at high risk for recurrent disease and in any patient with suspicious clinical findings. Palpable lymph nodes that are small, thin, or oval or that are reduced in size after an interval of three months are considered benign. Serum thyroglobulin concentrations are undetectable in 20 percent of patients receiving thyroxine treatment who have isolated lymph-node metastases, and therefore, undetectable values do not rule out metastatic lymph-node disease. If there is a question of metastasis, an ultrasonographically guided lymph-node biopsy may be performed.54

Chest radiography is no longer routinely performed in patients with undetectable serum thyroglobulin concentrations. The reason is that virtually all patients with abnormal radiographs have detectable serum thyroglobulin concentrations.55
Serum Thyroglobulin Measurements

Thyroglobulin is a glycoprotein that is produced only by normal or neoplastic thyroid follicular cells. It should not be detectable in patients who have undergone total thyroid ablation, and its detection in such patients signifies the presence of persistent or recurrent disease.56 Good thyroglobulin assays can detect concentrations as low as 1 ng per milliliter or even lower.57 The results, however, can be artifactually altered by the presence of serum antithyroglobulin antibodies,
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TABLE 3. PATIENTS WITH DETECTABLE SERUM THYROGLOBULIN CONCENTRATIONS DURING THYROXINE TREATMENT AND AFTER ITS WITHDRAWAL, ACCORDING TO THE PRESENCE OR ABSENCE OF NORMAL THYROID TISSUE.*
EXTENT DISEASE TOTAL ABLATION
DURING TREATMENT AFTER WITHDRAWAL OF TREATMENT

OF

TOTAL THYROIDECTOMY
DURING TREATMENT AFTER WITHDRAWAL OF TREATMENT

% of patients with detectable serum thyroglobulin

Complete remission Lymph-node metastases Distant metastases with normal radiographs Large distant metastases

2 80 95 100

10 90 100 100

20

*Detectable serum thyroglobulin concentrations were defined as values equal to or higher than 1 ng per milliliter. Serum thyroglobulin values are highly dependent on the assay used. In this study, an immunoradiometric assay that can detect values as low as 1 ng per milliliter was used. Data are from Schlumberger et al.55 and Schlumberger.57 In most patients, detectable serum thyroglobulin concentrations were lower than 5 ng per milliliter. In most patients, serum thyroglobulin concentrations were higher than 10 ng per milliliter.

which are found in about 15 percent of patients with thyroid carcinoma. Tests for these antibodies should always be performed when serum thyroglobulin is measured, but the extent to which the presence of the antibodies alters the results of serum thyroglobulin assays depends on whether a radioimmunoassay or an immunoradiometric assay is performed.56-58 The production of thyroglobulin by both normal and neoplastic thyroid tissue is in part dependent on thyrotropin.57,59-64 Thus, when interpreting the serum thyroglobulin value, one should take into account the serum thyrotropin value, as well as the presence or absence of thyroid remnants (Table 3). If the serum thyroglobulin concentration is detectable during thyroxine treatment, it will increase after the treatment has been withdrawn. The serum thyroglobulin concentration is an excellent prognostic indicator. Patients with undetectable serum thyroglobulin concentrations after thyroxine has been withdrawn have been free of relapse after more than 15 years of follow-up.61 Conversely, 80 percent of patients with serum thyroglobulin concentrations above 10 ng per milliliter during thyroxine treatment and higher than 40 ng per milliliter after the withdrawal of treatment have detectable foci of iodine-131 uptake in the neck or at distant sites after the administration of therapeutic doses of iodine-131.65-68
Iodine-131 Total-Body Scanning

The results of iodine-131 total-body scanning depend on the ability of thyroid-cancer tissue to take up iodine-131 in the presence of high serum thyrotropin concentrations, which are achieved by with302
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drawing thyroxine for four to six weeks. However, the resulting hypothyroidism is poorly tolerated by some patients. This problem can be attenuated by substituting the more rapidly metabolized triiodothyronine, in the form of liothyronine sodium, for thyroxine for three weeks and withdrawing it for two weeks69 or by simply reducing the dose of thyroxine by about half.70 The serum thyrotropin concentration should be higher than some arbitrary level (e.g., 30 mU per milliliter) in patients treated in this way, and if necessary, the administration of iodine-131 should be delayed until the value has exceeded that level. Intramuscular injection of recombinant human thyrotropin is a promising alternative, because thyroxine treatment does not need to be discontinued and the side effects are minimal. The results of thyroid scanning performed after the administration of thyrotropin and after the withdrawal of thyroxine are similar in most patients.71 When iodine-131 scanning is planned, patients should be instructed to avoid iodine-containing medications and iodine-rich foods, and urinary iodine should be measured in doubtful cases.72 In women of childbearing age, pregnancy must be ruled out. For routine diagnostic scans, 2 to 5 mCi (74 to 185 MBq) of iodine-131 is given; higher doses may reduce the uptake of a subsequent therapeutic dose of iodine-131.73 Scanning is performed and uptake, if any, is measured three days after the dose has been administered, with the use of a doublehead gamma camera equipped with high-energy collimators. False positive results are rare.49 Assuming equivalent fractional uptake after the administration of a diagnostic or therapeutic dose of

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iodine-131, an uptake too low to be detected with 2 to 5 mCi may be detectable after the administration of 100 mCi. This is the rationale for administering 100 mCi (or more) of iodine-131 in patients with elevated serum thyroglobulin concentrations (10 ng per milliliter after thyroxine has been withdrawn), even if the results of diagnostic scanning are negative. When this is done, total-body scanning should be performed four to seven days later.47,48,65-68 If the total-body scan obtained after the administration of iodine-131 to destroy the thyroid remnant does not show any uptake outside the thyroid bed, serum thyrotropin and thyroglobulin concentrations are measured during thyroxine treatment three months later. As noted above, a diagnostic iodine-131 total-body scan is obtained after thyroxine withdrawal 6 to 12 months after iodine-131 treatment (Fig. 3). If any uptake is detected, 100 mCi of iodine-131 is given. If no uptake is detected, subsequent follow-up in patients with either papillary or follicular carcinomas is based on prognostic indicators and on the serum thyroglobulin concentration. In low-risk patients considered cured (those with undetectable serum thyroglobulin concentrations and negative results on iodine-131 total-body scanning), the dose of thyroxine is decreased to maintain a low but detectable serum thyrotropin concentration (0.1 to 0.5 mU per milliliter). In higher-risk patients (Table 2), higher doses are continued, the goal being a serum thyrotropin concentration of 0.1 mU per milliliter or less, as noted above. Clinical and biochemical evaluations are performed annually; any other testing is unnecessary as long as the serum thyroglobulin concentration is very low. If the serum thyroglobulin concentration becomes detectable in a patient receiving thyroxine, it should be withdrawn, an iodine-131 total-body scan should be obtained, and serum thyroglobulin should be measured. If any uptake is detected or if the serum thyroglobulin concentration rises above 10 ng per milliliter, 100 mCi of iodine-131 should be given. In the absence of iodine-131 uptake, computed tomography (CT) of the neck and lungs, bone scintigraphy,74 and scintigraphy using a less specific tracer (e.g., thallium, tetrofosmin, or [18F]fluorodeoxyglucose)75-77 can be useful. In low-risk patients who have undergone a neartotal or total thyroidectomy but have not been given iodine-131 postoperatively, iodine-131 total-body scanning is performed 6 to 12 months after surgery. The follow-up protocol described above is then applied, on the basis of serum thyroglobulin concentrations. In low-risk patients who have undergone a lobectomy, follow-up should consist of a yearly neck examination and serum thyroglobulin measurement during thyroxine treatment. Ultrasonography will show abnormalities in the remaining lobe in most patients

Thyroid ablation plus iodine-131 TBS Thyroxine therapy (2.5 mg/kg) At 3 mo (during thyroxine therapy), measure serum thyrotropin and thyroglobulin At 6 12 mo (with patient not receiving thyroxine), measure serum thyrotropin and thyroglobulin and perform iodine-131 TBS (2 5 mCi) Negative scan Serum thyroglobulin concentration (with patient not receiving thyroxine) 1 ng/ml Yearly follow-up during thyroxine therapy 1 10 ng/ml Iodine-131 TBS (2 5 mCi) every 2 5 yr Positive scan Iodine-131 TBS (100 mCi)

10 ng/ml Iodine-131 TBS (100 mCi)

Figure 3. Recommended Follow-up of Patients after Total Thyroid Ablation, on the Basis of Serum Thyroglobulin Measurements and Iodine-131 Total-Body Scanning (TBS). The decision whether to perform iodine-131 scanning depends on the assay used to measure serum thyroglobulin; with a given assay, it depends on the tumor stage and the clinical likelihood of recurrent or persistent disease. To convert millicuries to megabecquerels, multiply by 37.

with detectable serum thyroglobulin concentrations. If the lesions are small, fine-needle biopsy may be impossible, and surgery is frequently the only option.
LOCAL AND REGIONAL RECURRENCES

Five to 20 percent of patients with differentiated thyroid carcinomas have local or regional recurrences. Some are related to incomplete initial treatment (recurrent disease in a thyroid remnant or lymph nodes), and others indicate the presence of an aggressive tumor (in the thyroid bed after total thyroidectomy or in soft tissues). A local or regional recurrence that is palpable or easily visualized with ultrasonography or CT scanning should be excised. A total-body scan obtained four to seven days after the administration of 100 mCi of iodine-131 may identify additional tissue that should be excised. Surgery is performed one day after scanning, preferably with the use of an intraoperative probe.78 The completeness of resection is verified one to two days after surgery by obtaining another total-body scan. External radiotherapy is indicated in patients with
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soft-tissue recurrences that cannot be completely excised and do not take up iodine-131.51
DISTANT METASTASES

Distant metastases, usually in the lungs and bones, occur in 10 to 15 percent of patients with differentiated thyroid carcinomas.79 Lung metastases are most frequent in young patients with papillary carcinomas, and the lungs are almost the only site of distant spread in children. Bone metastases are more common in older patients and in those with follicular carcinomas. Other, less common sites of metastasis are the brain, liver, and skin.55
Diagnosis

Symptoms of lung metastases are uncommon. In contrast, pain, swelling, or fracture occurs in more than 80 percent of patients with bone metastases. The pattern of lung involvement may range from macronodular to diffuse infiltrates. The latter, when not detected by chest radiography, are usually diagnosed with iodine-131 total-body scanning and may be confirmed by CT. Enlarged mediastinal lymph nodes are often present in patients with papillary carcinomas, especially children.39,40 Bone metastases are osteolytic and are often difficult to visualize on radiographs. Bone scintigraphy may show decreased or moderately increased uptake.74 Bone involvement is better visualized by CT or magnetic resonance imaging. Nearly all patients with distant metastases have high serum thyroglobulin concentrations, and two thirds of patients have iodine-131 uptake in the metastases.
Treatment

Complete responses to treatment have been obtained in 45 percent of patients with distant metastases that take up iodine-131, with a higher frequency of complete responses in young patients and those with small pulmonary metastases. Few relapses have been reported in patients with complete responses, despite detectable serum thyroglobulin concentrations in some patients.55 The overall survival rate 10 years after the discovery of distant metastases is about 40 percent. Young patients with well-differentiated carcinomas that take up iodine-131 and metastases that are small when discovered have the most favorable outcome.55,85,86 When the size of the tumor mass is considered, the location of the metastases (lungs or bone) has no independent prognostic influence. The poor prognosis of patients with bone metastases is linked to the bulkiness of the lesions.55 The prognostic importance of the size of metastases at the time of their discovery has led to the administration of 100 mCi of iodine-131 in patients with elevated serum thyroglobulin concentrations and no other evidence of disease, as noted above.55,65-67
Complications of Treatment with Iodine-131
Acute Side Effects

Palliative surgery is required for bone metastases when there are neurologic or orthopedic complications or a high risk of such complications. Surgery may also be useful to debulk large tumor masses.80,81 Patients with metastases that take up iodine-131 should be treated with 100 to 150 mCi (3700 to 5550 MBq) every four to six months. The effective radiation dose, which depends on the ratio of total uptake to the mass of thyroid tissue, is correlated with the outcome of iodine-131 therapy.82 For this reason, higher doses (200 mCi [7400 MBq] or more) have been recommended in patients with bone metastases, but their effectiveness remains to be demonstrated. Lower doses (1 mCi [37 MBq] per kilogram) are given to children. There is no limit to the cumulative dose of iodine-131 that can be given to patients with distant metastases, although the risk of leukemia rises slightly when the cumulative dose is higher than 500 mCi (18,500 MBq); furthermore, higher doses have little benefit.55 External radiotherapy is given to patients who have bone metastases visible on radiographs.51,55 Chemotherapy is not effective and should be reserved for patients with progressive metastases that do not take up iodine-131.83,84
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Acute side effects (nausea and sialadenitis) are common after treatment with large doses of iodine131, but they are usually mild and resolve rapidly. Radiation-associated thyroiditis is usually minimal, but if the thyroid remnant is large, the patient may have enough pain to warrant glucocorticoid therapy for a few days. Tumor in certain locations the brain, spinal cord, or paratracheal region may swell in response to thyrotropin stimulation or after iodine-131 therapy, causing compressive symptoms. Radiation fibrosis may develop and eventually prove fatal in patients with diffuse lung metastases, if high doses of iodine-131 (150 mCi) are administered at short intervals (3 months).87
Genetic Defects and Infertility

Particular care must be taken to ensure that iodine-131 is not given to pregnant women. After iodine-131 treatment, men may have a transient reduction in spermatogenesis,88 and women may have transient ovarian failure.89 Genetic damage induced by exposure to iodine-131 before conception has been a major concern. However, the only anomaly reported to date is an increased frequency of miscarriages in women treated with iodine-131 during the year preceding the conception.90,91 Therefore, it is recommended that conception be postponed for one year after treatment with iodine-131. There is no evidence that pregnancy affects tumor growth in women receiving adequate thyroxine therapy.

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M E D I CA L P RO G R E S S

Carcinogenesis and Leukemogenesis

Mild pancytopenia may occur after repeated iodine-131 therapy, especially in patients with bone metastases who have also been given external radiotherapy. The overall relative risk of secondary carcinoma or leukemia is increased only in patients given a high cumulative dose of iodine-131 (500 mCi) and those given external radiotherapy.55,90,92,93
CONCLUSIONS

Most patients with papillary or follicular carcinomas can be cured. However, both the initial treatment and follow-up should be individualized according to prognostic indicators and any subsequent evidence of disease.
Supported in part by a grant from the European Commission, Directorate General XII, Radiation Protection Research Unit.

I am indebted to my colleagues at Institut Gustave-Roussy Drs. J.P. Travagli, B. Caillou, E. Baudin, F. De Vathaire, J. Lumbroso, H.G. Suarez, C. Parmentier, and M. Tubiana and to Mrs. Lorna Saint-Ange for editorial assistance and Mrs. Catherine Log for secretarial assistance.

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