papillary n foliccular thyroid carcinoma

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MEDICAL PROGRESS

Vol ume 338 Nu mber 5 297

Review Articles

Medical Progress

P

APILLARY

AND

F

OLLICULAR

T

HYROID

C

ARCINOMA

M

ARTIN

J

EAN

S

CHLUMBERGER

, M.D.

From the University of Paris XI, Institut Gustave-Roussy, Rue Camille-Desmoulins, 94805 Villejuif CEDEX, France, where reprint requestsshould be addressed to Dr. Schlumberger.

©1998, Massachusetts Medical Society.

APILLARY and follicular (differentiated) thy-roid carcinomas are among the most curablecancers. However, some patients are at high risk

for recurrent disease or even death. Most of these pa-tients can be identified at the time of diagnosis by us-ing well-established prognostic indicators. The extentof the initial treatment and follow-up care shouldtherefore be tailored to the level of risk. Althoughtreatment guidelines have been published,

1,2

clinicalprocedures vary considerably among clinicians.

3

EPIDEMIOLOGY

Although thyroid nodules are common, differen-tiated thyroid carcinomas are relatively rare. Clinical-ly detectable thyroid carcinomas constitute less than1 percent of all human cancers. The annual inci-dence 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 adoles-cents, and their incidence increases with age in adults.The median age at diagnosis is 45 to 50 years. Thy-roid carcinomas are two to four times as frequent in

women as in men.Thyroid microcarcinomas (diameter, р

1 cm) arefound in 5 to 36 percent of adults at autopsy but arerare in children. The reported increase in the incidenceof these small carcinomas in recent years can be attrib-uted to an improvement in pathological techniques.

PATHOGENESIS

Oncogenes

Recent advances in molecular biology have im-proved our understanding of the pathogenesis of thyroid carcinomas.

5

Rearrangements of the tyrosinekinase domains of the RET

and TRK

genes with theamino-terminal sequence of an unlinked gene are

P

found in some papillary carcinomas.

6

RET

rearrange-

ments are found in 3 to 33 percent of papillary car-cinomas unassociated with irradiation

7-9

and in 60 to80 percent of those occurring after irradiation, diag-nosed either in children in Belarus exposed to radi-ation after the nuclear accident in Chernobyl

10-12

orin patients who received external radiation treatmentin childhood.

13

The frequency of TRK

rearrange-ments is much lower.

8

Activating point mutations of the RAS

genes arefound with a similarly high frequency in thyroid ad-enomas and follicular carcinomas, suggesting that

RAS

mutations represent an early event in thyroidtumorigenesis.

5,14

Activating mutations of the genesencoding the thyrotropin receptor and the a

subunit

of the stimulatory G (G

s

) protein have been reportedin some follicular carcinomas.

14,15

Inactivating pointmutations of the p53 tumor-suppressor gene are rarein patients with differentiated thyroid carcinomas butcommon in those with undifferentiated (anaplastic)thyroid carcinomas.

16,17

Thyroid Irradiation

External irradiation to the neck during childhoodincreases the risk of papillary thyroid carcinoma.

18-20

The latency period between exposure and diagnosisis at least five years. The risk is maximal at about 20

years, remains high for about 20 years, and then de-creases gradually. The risk is increased after a meandose to the thyroid as low as 10 cGy. At higher dos-es (up to 1500 cGy), there is a linear relation be-tween the dose and the risk of carcinoma. At doseshigher than 1500 cGy, the risk per gray decreases,probably because of cell killing. A major risk factoris a young age at the time of irradiation; after theage of 15 or 20 years, the risk is not increased. Inchildren 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 inpatients given iodine-131 for diagnostic or therapeu-tic purposes.

18,20

However, iodine-131 given for thetreatment of hyperthyroidism induces cell killing.Furthermore, the number of patients exposed to io-dine-131 for medical reasons during childhood is toosmall to rule out a carcinogenic effect at a young age.However, the increased incidence of papillary thyroidcarcinomas in children in the Marshall Islands afteratomic-bomb testing and, more recently, in Belarusand Ukraine after the Chernobyl nuclear accidentsuggests that radioactive isotopes of iodine, both io-dine-131 and short-lived isotopes, have a direct tu-morigenic effect on the thyroid.

21,22

In Belarus andUkraine, the incidence of thyroid cancer started to in-

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298

January 29, 1998

The New England Journal of Medicine

crease as early as four years after the accident. To date,about 1000 cases have been reported, mostly in chil-dren who were younger than 10 years old at the timeof the accident, which corresponds to an incidence100 times that in nonirradiated children.

Other Factors

In countries where iodine intake is adequate, dif-ferentiated cancers account for more than 80 per-cent of all thyroid carcinomas, with the papillary his-tologic type being the more frequent (accountingfor 60 to 80 percent of cases). There is no increasein the incidence of thyroid carcinomas in countries

where iodine intake is low, but there is a relative in-crease in follicular and anaplastic carcinomas.

20,23

A high incidence of papillary carcinomas has beenreported in patients with adenomatous polyposiscoli and Cowden’s disease (the multiple hamartomasyndrome).

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 charac-terized by overlapping cell nuclei that have a ground-glass appearance and longitudinal grooves, with in-

vaginations of cytoplasm into the nuclei (Fig. 1).

25,26

Encapsulated, follicular, tall-cell, columnar-cell, clear-cell, and diffuse sclerosing carcinomas are recognizedhistologic variants; they are classified as papillary car-cinomas because of their characteristic nuclear fea-tures. The tumor is multicentric in 20 to 80 percentof patients (with the wide range attributable to vari-ations in the care used to examine the thyroid) andbilateral in about one third. It spreads through thelymphatics within the thyroid to the regional lymphnodes and, less frequently, to the lungs.

Follicular Carcinoma

Follicular carcinoma is characterized by folliculardifferentiation but without the nuclear changescharacteristic of papillary carcinoma (Fig. 1).

25,26

Fol-licular carcinomas are encapsulated, and invasion of the capsule and vessels is the key feature distinguish-ing follicular carcinomas from follicular adenomas.Two forms are recognized according to the patternof invasion: minimally invasive and widely invasivecarcinomas. The growth pattern may also vary, rang-ing from a well-differentiated pattern with macrofol-licular structures to a poorly differentiated pattern

with areas of solid growth and a high degree of atyp-ia. Hürthle-cell (oxyphilic follicular or oncocytic)carcinoma is a cytologic variant of follicular carcino-ma. Multicentricity and lymph-node involvementare less frequent than in papillary carcinoma, andmetastases to the lungs and bones stem from hema-tologic spread.

DIAGNOSIS

Most differentiated thyroid carcinomas present asasymptomatic thyroid nodules, but the first sign of thedisease is occasionally lymph-node metastases or inrare cases lung or bone metastases. Hoarseness, dys-phagia, cough, and dyspnea suggest advanced disease.

On physical examination, the carcinoma, usually single, is firm, moves freely during swallowing, and isnot distinguishable from a benign nodule. Amongpatients with thyroid nodules, the nodule is morelikely to be a carcinoma in children and adolescents,patients older than 60 years, and men than in women20 to 60 years old. Carcinoma should be suspected if a hard, irregular thyroid nodule is found, ipsilaterallymph nodes are enlarged or compressive symptomsare present, and there is a history of a progressive in-crease in the size of the nodule. Virtually all patients

with thyroid carcinoma are clinically euthyroid andhave normal serum thyrotropin concentrations.

Whatever the presentation, fine-needle aspirationcytology is the best test for distinguishing betweenbenign and malignant thyroid nodules.

1,27

Providedan adequate specimen is obtained, three cytologic re-sults are possible: benign, malignant, or indeterminate(or suspicious). False negative results, usually fromsampling or interpretive errors, and false positive re-sults are rare. Only about 20 percent of patients withindeterminate findings have malignant nodules, re-flecting the difficulty of differentiating benign follic-ular adenomas from their malignant counterparts.Thyroid ultrasonography is useful for assessing thesize of the nodule, detecting other nodules, and guid-ing fine-needle biopsy in the case of a nodule that issmall or difficult to palpate.

PROGNOSTIC FACTORS

The overall survival rate at 10 years for middle-agedadults with thyroid carcinomas is about 80 to 95 per-cent (Fig. 2).

28-38

Five to 20 percent of patients havelocal or regional recurrences, and 10 to 15 percenthave distant metastases. The prognostic indicators of recurrent disease and of death are the patient’s ageat diagnosis and the histologic subtype and extent of the tumor.

28-42

There are many staging systems for thyroid carci-noma,

28-35,38

among which the tumor–node–metasta-sis (TNM) system is the most widely used (Table1).

33,34

On the basis of these systems, 80 to 85 per-cent of patients are classified as being at low risk fordeath from thyroid carcinoma. Some patients have ahigher risk of recurrence, even if their risk of death islow. This group includes younger patients (

Ͻ

16 years old)

39,40

and older patients (

Ͼ

45 years old),those with certain histologic subtypes (among papil-lary carcinomas, the tall-cell, columnar-cell, and dif-fuse sclerosing variants, and among follicular carcino-mas, the widely invasive and poorly differentiatedsubtypes

38,41

and Hürthle-cell carcinomas), and those





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Vol ume 338 Nu mber 5

299

with large tumors, tumors that extend beyond thethyroid capsule, or lymph-node metastases. The ex-tent of initial treatment and follow-up should be de-termined according to these prognostic indicators.

INITIAL TREATMENT

Surgery

The goal of surgery is to remove all tumor tissuein the neck. Therefore, the thyroid gland and affect-ed cervical lymph nodes should be resected.

43

Although there is still some controversy about theextent of thyroid surgery, there are strong argumentsin favor of a total or near-total thyroidectomy (leavingno more than 2 to 3 g of thyroid tissue) in all pa-tients.

30-32,35-38

Total or near-total thyroidectomy re-sults in a lower recurrence rate than more limited thy-

roidectomy because many papillary carcinomas aremultifocal and bilateral.

44,45

Furthermore, removal of most, if not all, of the thyroid gland facilitates totalablation with iodine-131. The argument against totalthyroidectomy is that it increases the risk of surgicalcomplications such as recurrent laryngeal-nerve inju-ries and hypoparathyroidism. Even with total thy-roidectomy, often some thyroid tissue remains, as de-tected by postoperative scanning with iodine-131.

In low-risk patients (those with papillary carcino-mas less than 1.5 cm in diameter, if unifocal andintralobar), a lobectomy may be appropriate. In pa-tients who have undergone a lobectomy for a suppos-edly benign tumor that proves to be a follicular car-cinoma, a completion thyroidectomy is advisable,because it will facilitate follow-up.

Figure 1.

Histologic Appearance of Papillary and Follicular Carcinoma of the Thyroid (Hematoxylin and Eosin).

Panel A shows papillary carcinoma under low magnification (

ϫ

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 (

ϫ

1000). Characteristic nuclearchanges include a large size, a ground-glass appearance, longitudinal grooves (arrow), and marked overlapping (arrowhead). PanelC shows well-differentiated follicular carcinoma (

ϫ

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 (

ϫ

500). Photographs were provid-

ed by B. Caillou, Institut Gustave-Roussy, Villejuif, France.

A B

C D





300

January 29, 1998


In patients with papillary carcinoma, lymph nodesin the central compartment (paratracheal and trache-oesophageal areas) and the ipsilateral supraclaviculararea and lower third of the jugulocarotid chain shouldbe dissected. A modified neck dissection is performedif there are palpable lymph-node metastases in the

jugulocarotid chain. Dissection of lymph nodes ispreferable to sampling. Although this type of lymph-node dissection has not been shown to improve recur-rence and survival rates, its routine use in patients withpapillary carcinomas is warranted for several reasons.

About two thirds of the patients have lymph-nodemetastases, and in more than 80 percent of patients

with lymph-node metastases the central compartmentis involved.

46

In addition, metastases are difficult todetect in lymph nodes located behind the vessels or inthe paratracheal groove. Among patients with follicu-lar carcinomas, a small proportion (about 35 percent)have lymph-node metastases. In these patients, alymph-node dissection is performed only if the diag-

nosis of follicular carcinoma is established during sur-gery or lymph nodes are palpable at surgery.

Iodine-131 Therapy

Iodine-131 therapy is given postoperatively forthree reasons. First, it destroys any remaining normalthyroid tissue, thereby increasing the sensitivity of subsequent iodine-131 total-body scanning and thespecificity of measurements of serum thyroglobulinfor the detection of persistent or recurrent disease.Second, iodine-131 therapy may destroy occult mi-croscopic carcinoma, thereby decreasing the long-term 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 sen-sitive test for detecting persistent carcinoma.

47,48

Postoperative iodine-131 therapy should be usedselectively (Table 2). In low-risk patients, the long-term prognosis after surgery alone is so favorable thatiodine-131 ablation is not usually recommended.However, all patients who are at high risk for recurrentdisease should be treated with iodine-131, becauseit decreases both recurrence and death rates.

30,35-38

Iodine-131 scanning is performed four to six weeks after surgery, with no thyroid hormone treat-ment given in the interim. At our center, we use adose of 2 mCi (74 MBq) of iodine-131 and obtaina total-body scan three days later. If any iodine-131uptake is detected in the thyroid bed or elsewhere, atreatment dose is given. Another total-body scan isobtained four to seven days later, and thyroxine ther-apy is initiated. Total ablation is verified by perform-ing iodine-131 total-body scanning 6 to 12 monthslater with 2 mCi.

Total ablation (no visible uptake) is achieved afterthe 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

Figure 2.

Survival Rate among 1701 Patients with Papillary orFollicular 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 generalpopulation) was 2.6 (P

Ͻ

0.001). Panel A shows the correctedsurvival rate according to the age at diagnosis. The rate wasadjusted by taking into account the mortality rate for the

French population of the same age and sex. Panel B shows thecorrected survival rate according to histologic subtype (papil-lary carcinoma, well-differentiated follicular carcinoma, or

poorly differentiated follicular carcinoma).

0

100

80

60

40

20

0 5 10 15 20 25 30

15

29

43

9

142

659

672

228

110

391

471

101

92

232

304

51

73

133

199

27

55

84

128

14

30

45

81

11

Ͻ20 yr

20 – 39 yr

40– 59 yr

у60 yr

Ͻ20 yr

20–

39 yr40– 59 yr

у60 yr

Years after Initial Therapy

PATIENTS AT RISK

S u

r v i v a l ( % )

0

100

80

60

40

20

0 5 10 15 20 25 30

74

4

18

1261

97

343

802

64

207

518

36

125

339

21

72

221

11

49

130

7

30

Papillary

Follicular, well

differentiated

Follicular, poorly

differentiated

Papillary

Follicular, well

differentiated

Follicular, poorly

differentiated

Years after Initial Therapy

PATIENTS AT RISK

S u r v i v a l ( % )

A

B





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301

thyroidectomy.

49

After less extensive surgery, ablation with 30 mCi of iodine-131 is achieved in only twothirds of patients. Therefore, total or near-total thy-roidectomy should be performed in all patients whoare to be treated with iodine-131. Total ablation re-quires that a dose of at least 300 Gy be delivered to

the thyroid remnant; a dosimetric study may allow amore precise estimate of the dose of iodine-131 tobe given.

50

External Radiotherapy

External radiotherapy to the neck and mediasti-num is indicated only in patients in whom surgicalexcision is incomplete or impossible and the tumortissue does not take up iodine-131.

51

FOLLOW-UP

The goals of follow-up after initial therapy are tomaintain adequate thyroxine therapy and to detectpersistent or recurrent thyroid carcinoma. Recur-

rences are usually detected during the early years of follow-up, but may be detected later. Therefore, fol-low-up is necessary throughout the patient’s life.

Thyroxine Treatment

The growth of thyroid-tumor cells is controlledby thyrotropin, and the inhibition of thyrotropin se-cretion with thyroxine improves the recurrence andsurvival rates.

35

Therefore, thyroxine, in the form of levothyroxine sodium, should be given to all pa-tients with thyroid carcinoma, whatever the extentof thyroid surgery and other treatment. The effec-tive dose in adults is between 2.2 and 2.8 m

g perkilogram of body weight; children require higher

doses.

52

The adequacy of therapy is monitored by measuring serum thyrotropin three months aftertreatment is begun, the initial goal being a serumthyrotropin concentration of 0.1 m

U per milliliter orless and a serum free triiodothyronine concentration

within the normal range. When these guidelines arefollowed, thyroxine therapy does not have deleteri-ous effects on the heart or bone.

52,53

Clinical and Ultrasonographic Examinations

Palpation of the thyroid bed and lymph-node ar-eas should be performed routinely. Ultrasonography is performed in patients at high risk for recurrentdisease and in any patient with suspicious clinicalfindings. Palpable lymph nodes that are small, thin,or oval or that are reduced in size after an intervalof three months are considered benign. Serum thy-roglobulin concentrations are undetectable in 20percent of patients receiving thyroxine treatment

who have isolated lymph-node metastases, and there-fore, undetectable values do not rule out metastaticlymph-node disease. If there is a question of metas-tasis, an ultrasonographically guided lymph-node bi-opsy may be performed.

54

Chest Radiography

Chest radiography is no longer routinely per-formed in patients with undetectable serum thyro-globulin concentrations. The reason is that virtually all patients with abnormal radiographs have detect-able serum thyroglobulin concentrations.

55

Serum Thyroglobulin Measurements

Thyroglobulin is a glycoprotein that is producedonly by normal or neoplastic thyroid follicular cells.It should not be detectable in patients who have un-dergone total thyroid ablation, and its detection insuch patients signifies the presence of persistent orrecurrent disease.

56

Good thyroglobulin assays can detect concentra-tions 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,

*The size of the primary tumor (T) is classified asT1,

р

1 cm; T2, Ͼ

1 cm and р

4 cm; T3, Ͼ

4 cm; orT4, extending beyond the thyroid capsule. Lymphnodes (N) are classified as N0, no lymph-node metas-tasis, or N1, lymph-node metastases. Distant metasta-ses (M) are classified as M0, no distant metastases, orM1, distant metastases. Data are from Hermanek andSobin.

33

T

ABLE

1.

TUMOR –NODE–METASTASIS (TNM)STAGING S YSTEM FOR P APILLARY

AND FOLLICULAR THYROID C ARCINOMAS.*

STAGE AGE

Ͻ

45 YR у

45 YR

I Any T, any N, M0 T1, N0, M0

II Any T, any N, M1 T2 or T3, N0, M0

III T4 or N1, M0

IV Any T, any N, M1

TABLE 2. INDICATIONS FOR A BLATIVETREATMENT WITH IODINE-131 AFTER SURGERY IN P ATIENTS WITH THYROID C ARCINOMA .

No indication

Low risk of cancer-specific mortality and low risk of relapse

Indication

Distant metastasesIncomplete excision of tumorComplete excision of tumor but high risk of mortal-

ity associated with thyroid carcinomaComplete excision of tumor but high risk of relapse

due to age (Ͻ16 or Ͼ45 yr), histologic subtype(tall-cell, columnar-cell, or diffuse sclerosing papil-lary variants; widely invasive or poorly differentiated

follicular subtypes; Hürthle-cell carcinomas), or ex-tent of tumor (large tumor mass, extension beyondthe thyroid capsule, or lymph-node metastases)

Elevated serum thyroglobulin concentration morethan three months after surgery





302 January 29, 1998


which are found in about 15 percent of patients withthyroid carcinoma. Tests for these antibodies shouldalways be performed when serum thyroglobulin ismeasured, but the extent to which the presence of theantibodies alters the results of serum thyroglobulinassays depends on whether a radioimmunoassay or animmunoradiometric assay is performed.56-58

The production of thyroglobulin by both normaland neoplastic thyroid tissue is in part dependent onthyrotropin.57,59-64 Thus, when interpreting the se-

rum thyroglobulin value, one should take into ac-count the serum thyrotropin value, as well as thepresence or absence of thyroid remnants (Table 3).If the serum thyroglobulin concentration is detect-able during thyroxine treatment, it will increase afterthe treatment has been withdrawn.

The serum thyroglobulin concentration is an ex-cellent prognostic indicator. Patients with undetect-able serum thyroglobulin concentrations after thy-roxine has been withdrawn have been free of relapseafter more than 15 years of follow-up.61 Conversely,80 percent of patients with serum thyroglobulinconcentrations above 10 ng per milliliter duringthyroxine treatment and higher than 40 ng per mil-liliter after the withdrawal of treatment have detect-able foci of iodine-131 uptake in the neck or at dis-tant sites after the administration of therapeuticdoses of iodine-131.65-68

Iodine-131 Total-Body Scanning

The results of iodine-131 total-body scanning de-pend on the ability of thyroid-cancer tissue to takeup iodine-131 in the presence of high serum thyro-tropin concentrations, which are achieved by with-

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 triiodo-thyronine, in the form of liothyronine sodium, forthyroxine for three weeks and withdrawing it fortwo weeks69 or by simply reducing the dose of thy-roxine by about half.70 The serum thyrotropin con-centration should be higher than some arbitrary lev-el (e.g., 30 mU per milliliter) in patients treated in

this way, and if necessary, the administration of io-dine-131 should be delayed until the value has ex-ceeded that level. Intramuscular injection of recom-binant human thyrotropin is a promising alternative,because thyroxine treatment does not need to bediscontinued and the side effects are minimal. Theresults of thyroid scanning performed after the ad-ministration of thyrotropin and after the withdrawalof thyroxine are similar in most patients.71

When iodine-131 scanning is planned, patientsshould be instructed to avoid iodine-containingmedications and iodine-rich foods, and urinary io-dine should be measured in doubtful cases.72 In

women of childbearing age, pregnancy must beruled out. For routine diagnostic scans, 2 to 5 mCi(74 to 185 MBq) of iodine-131 is given; higher dos-es may reduce the uptake of a subsequent therapeu-tic dose of iodine-131.73 Scanning is performed anduptake, if any, is measured three days after the dosehas been administered, with the use of a double-head gamma camera equipped with high-energy col-limators. False positive results are rare.49

Assuming equivalent fractional uptake after theadministration of a diagnostic or therapeutic dose of

*Detectable serum thyroglobulin concentrations were defined as values equal to or higher than1 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 arefrom Schlumberger et al.55 and Schlumberger.57

†In most patients, detectable serum thyroglobulin concentrations were lower than 5 ng per milli-liter.

‡In most patients, serum thyroglobulin concentrations were higher than 10 ng per milliliter.

TABLE 3. P ATIENTS WITH DETECTABLE SERUM THYROGLOBULIN CONCENTRATIONS DURING THYROXINE TREATMENT AND AFTER ITS W ITHDRAWAL ,

A CCORDING TO THE PRESENCE OR A BSENCE OF NORMAL THYROID TISSUE.*

EXTENT OF DISEASE TOTAL ABLATION TOTAL THYROIDECTOMY

DURINGTREATMENT

AFTER WITHDRAWAL OF TREATMENT

DURINGTREATMENT

AFTER WITHDRAWAL OF TREATMENT

% of patients with detectable serum thyroglobulin

Complete remission† Ͻ2 10 7 20

Lymph-node metastases 80 ϳ90 — —

Distant metastases withnormal radiographs

95 ϳ100 — —

Large distant metastases‡ ϳ100 ϳ100 — —





MEDICAL PROGRESS


iodine-131, an uptake too low to be detected with2 to 5 mCi may be detectable after the administra-tion of 100 mCi. This is the rationale for adminis-tering 100 mCi (or more) of iodine-131 in patients

with elevated serum thyroglobulin concentrations(Ͼ10 ng per milliliter after thyroxine has been with-

drawn), even if the results of diagnostic scanning arenegative. When this is done, total-body scanningshould be performed four to seven days later.47,48,65-68

If the total-body scan obtained after the adminis-tration of iodine-131 to destroy the thyroid rem-nant does not show any uptake outside the thyroidbed, serum thyrotropin and thyroglobulin concen-trations are measured during thyroxine treatmentthree months later. As noted above, a diagnostic io-dine-131 total-body scan is obtained after thyroxine

withdrawal 6 to 12 months after iodine-131 treat-ment (Fig. 3). If any uptake is detected, 100 mCi of iodine-131 is given. If no uptake is detected, subse-quent follow-up in patients with either papillary or

follicular carcinomas is based on prognostic indica-tors and on the serum thyroglobulin concentration.

In low-risk patients considered cured (those withundetectable serum thyroglobulin concentrations andnegative results on iodine-131 total-body scanning),the dose of thyroxine is decreased to maintain a low but detectable serum thyrotropin concentration (0.1to 0.5 mU per milliliter). In higher-risk patients (Ta-ble 2), higher doses are continued, the goal being aserum thyrotropin concentration of 0.1 mU per mil-liliter or less, as noted above. Clinical and biochem-ical evaluations are performed annually; any othertesting is unnecessary as long as the serum thyro-globulin concentration is very low.

If the serum thyroglobulin concentration be-comes detectable in a patient receiving thyroxine, itshould be withdrawn, an iodine-131 total-body scanshould be obtained, and serum thyroglobulin shouldbe measured. If any uptake is detected or if the se-rum thyroglobulin concentration rises above 10 ngper milliliter, 100 mCi of iodine-131 should be given.In the absence of iodine-131 uptake, computed to-mography (CT) of the neck and lungs, bone scintig-raphy,74 and scintigraphy using a less specific tracer(e.g., thallium, tetrofosmin, or [18F]fluorodeoxyglu-cose)75-77 can be useful.

In low-risk patients who have undergone a near-total or total thyroidectomy but have not been giveniodine-131 postoperatively, iodine-131 total-body scanning is performed 6 to 12 months after surgery.The follow-up protocol described above is then ap-plied, on the basis of serum thyroglobulin concen-trations.

In low-risk patients who have undergone a lobec-tomy, follow-up should consist of a yearly neck exam-ination and serum thyroglobulin measurement dur-ing thyroxine treatment. Ultrasonography will show abnormalities in the remaining lobe in most patients

with detectable serum thyroglobulin concentrations.If the lesions are small, fine-needle biopsy may be im-possible, and surgery is frequently the only option.

LOCAL AND REGIONAL RECURRENCES

Five to 20 percent of patients with differentiatedthyroid carcinomas have local or regional recurrenc-es. Some are related to incomplete initial treatment(recurrent disease in a thyroid remnant or lymphnodes), and others indicate the presence of an aggres-sive tumor (in the thyroid bed after total thyroidecto-my or in soft tissues).

A local or regional recurrence that is palpable oreasily visualized with ultrasonography or CT scan-ning should be excised. A total-body scan obtainedfour to seven days after the administration of 100mCi of iodine-131 may identify additional tissuethat should be excised. Surgery is performed one day after scanning, preferably with the use of an intraop-erative probe.78 The completeness of resection is ver-ified one to two days after surgery by obtaining an-other total-body scan.

External radiotherapy is indicated in patients with

Figure 3. Recommended Follow-up of Patients after Total Thy-roid Ablation, on the Basis of Serum Thyroglobulin Measure-

ments and Iodine-131 Total-Body Scanning (TBS).

The decision whether to perform iodine-131 scanning dependson the assay used to measure serum thyroglobulin; with a giv-en assay, it depends on the tumor stage and the clinical likeli-

hood of recurrent or persistent disease. To convert millicuriesto megabecquerels, multiply by 37.

Thyroid ablation plus iodine-131 TBSThyroxine 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 thyroglobulinconcentration

(with patient notreceiving thyroxine)

Yearly follow-upduring thyroxine

therapy

Ͻ1 ng/ml 1–10 ng/ml Ͼ10 ng/ml

Iodine-131 TBS(2 – 5 mCi)

every 2– 5 yr

Iodine-131 TBS(100 mCi)

Iodine-131 TBS(100 mCi)

Positive scan





304 January 29, 1998


soft-tissue recurrences that cannot be completely ex-cised 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 differen-

tiated thyroid carcinomas.79 Lung metastases aremost frequent in young patients with papillary car-cinomas, and the lungs are almost the only site of distant spread in children. Bone metastases are morecommon in older patients and in those with follicu-lar carcinomas. Other, less common sites of metasta-sis are the brain, liver, and skin.55

Diagnosis

Symptoms of lung metastases are uncommon. Incontrast, pain, swelling, or fracture occurs in morethan 80 percent of patients with bone metastases. Thepattern of lung involvement may range from macro-nodular to diffuse infiltrates. The latter, when not de-tected by chest radiography, are usually diagnosed

with iodine-131 total-body scanning and may be con-firmed by CT. Enlarged mediastinal lymph nodes areoften present in patients with papillary carcinomas, es-pecially children.39,40 Bone metastases are osteolyticand are often difficult to visualize on radiographs.Bone scintigraphy may show decreased or moderately increased uptake.74 Bone involvement is better visual-ized by CT or magnetic resonance imaging. Nearly allpatients with distant metastases have high serum thy-roglobulin concentrations, and two thirds of patientshave iodine-131 uptake in the metastases.

Treatment

Palliative surgery is required for bone metastases when there are neurologic or orthopedic complica-tions 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-131should be treated with 100 to 150 mCi (3700 to5550 MBq) every four to six months. The effective ra-diation dose, which depends on the ratio of total up-take to the mass of thyroid tissue, is correlated withthe outcome of iodine-131 therapy.82 For this reason,higher doses (200 mCi [7400 MBq] or more) havebeen recommended in patients with bone metastases,but their effectiveness remains to be demonstrated.

Lower doses (1 mCi [37 MBq] per kilogram) are giv-en to children. There is no limit to the cumulativedose of iodine-131 that can be given to patients

with distant metastases, although the risk of leuke-mia rises slightly when the cumulative dose is higherthan 500 mCi (18,500 MBq); furthermore, higherdoses have little benefit.55 External radiotherapy isgiven to patients who have bone metastases visibleon radiographs.51,55 Chemotherapy is not effectiveand should be reserved for patients with progressivemetastases that do not take up iodine-131.83,84

Complete responses to treatment have been ob-tained in 45 percent of patients with distant metas-tases that take up iodine-131, with a higher frequen-cy of complete responses in young patients andthose with small pulmonary metastases. Few relapseshave been reported in patients with complete re-

sponses, despite detectable serum thyroglobulin con-centrations in some patients.55

The overall survival rate 10 years after the discov-ery of distant metastases is about 40 percent. Youngpatients with well-differentiated carcinomas that takeup iodine-131 and metastases that are small whendiscovered have the most favorable outcome.55,85,86

When the size of the tumor mass is considered, thelocation of the metastases (lungs or bone) has no in-dependent prognostic influence. The poor progno-sis of patients with bone metastases is linked to thebulkiness of the lesions.55 The prognostic impor-tance of the size of metastases at the time of theirdiscovery has led to the administration of 100 mCi

of iodine-131 in patients with elevated serum thyro-globulin 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) arecommon after treatment with large doses of iodine-131, 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 afteriodine-131 therapy, causing compressive symptoms.Radiation fibrosis may develop and eventually provefatal in patients with diffuse lung metastases, if highdoses of iodine-131 (Ͼ150 mCi) are administered atshort intervals (Ͻ3 months).87

Genetic Defects and Infertility

Particular care must be taken to ensure that io-dine-131 is not given to pregnant women.

After iodine-131 treatment, men may have a tran-sient reduction in spermatogenesis,88 and women

may have transient ovarian failure.89

Genetic damageinduced by exposure to iodine-131 before concep-tion has been a major concern. However, the only anomaly reported to date is an increased frequency of miscarriages in women treated with iodine-131during the year preceding the conception.90,91 There-fore, it is recommended that conception be post-poned for one year after treatment with iodine-131.There is no evidence that pregnancy affects tumorgrowth in women receiving adequate thyroxinetherapy.





MEDICAL PROGRESS


Carcinogenesis and Leukemogenesis

Mild pancytopenia may occur after repeated io-dine-131 therapy, especially in patients with bonemetastases who have also been given external radio-therapy. The overall relative risk of secondary carci-noma or leukemia is increased only in patients givena high cumulative dose of iodine-131 (Ͼ500 mCi)and those given external radiotherapy.55,90,92,93

CONCLUSIONS

Most patients with papillary or follicular carcino-mas can be cured. However, both the initial treat-ment and follow-up should be individualized ac-cording to prognostic indicators and any subsequentevidence of disease.

Supported in part by a grant from the European Commission, Director-ate 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. Lor- na Saint-Ange for editorial assistance and Mrs. Catherine Logé for secretarial assistance.

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