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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

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.

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

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

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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

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

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.
298 

DIAGNOSIS

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

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

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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Survival (%)

100
80
60
20 yr
20 39 yr
40 59 yr
60 yr

40
20
0
0

10

15

20

25

30

Years after Initial Therapy

A
PATIENTS AT RISK
20 yr
20 39 yr
40 59 yr
60 yr

142
659
672
228

110
391
471
101

92
232
304
51

73
133
199
27

55
84
128
14

30
45
81
11

15
29
43
9

Survival (%)

100
80
60

Iodine-131 Therapy

Papillary
Follicular, well
differentiated
Follicular, poorly
differentiated

40
20
0
0

10

15

20

25

30

Years after Initial Therapy

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

802
64

518
36

339
21

221
11

130
7

74
4

207

125

72

49

30

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).

300 

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

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

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 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

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

TABLE 1. TUMORNODEMETASTASIS (TNM)

STAGING SYSTEM FOR PAPILLARY
AND FOLLICULAR THYROID CARCINOMAS.*
STAGE

AGE
45

I
II
III
IV

45

YR

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

YR

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

*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

Chest Radiography

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

OF

DISEASE

TOTAL ABLATION

TOTAL THYROIDECTOMY

DURING

AFTER WITHDRAWAL

DURING

AFTER WITHDRAWAL

TREATMENT

OF TREATMENT

TREATMENT

OF TREATMENT

% of patients with detectable serum thyroglobulin

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

2
80
95

10
90
100

20

100

100

*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 

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

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

Positive scan

Serum thyroglobulin
concentration
(with patient not
receiving thyroxine)

Iodine-131 TBS
(100 mCi)

1 ng/ml

1 10 ng/ml

10 ng/ml

Yearly follow-up
during thyroxine
therapy

Iodine-131 TBS
(2 5 mCi)
every 2 5 yr

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

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
304 

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

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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