tratamiento de nodulos

7/30/2019 Tratamiento de Nodulos

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TREATMENT OF BENIGN NODULARTHYROID DISEASE

NODULAR

thyroid disease is common. Palpable thyroid nodules were detected in 0.8 percent of

adult men and 5.3 percent of adult women in Whickham, northeast England,1 and in 1.5 percent of

men and 6.4 percent of women between 30 and 59 years of age in Framingham, Massachusetts. In

the latter population, new nodules appeared in 0.1 percent per year during a 15- year follow-up

period. Thyroid nodules are even more commonly detected when the thyroid is examined by

ultrasonography. The overwhelming majority of these nodules are benign. Several reviews

describe diagnostic strategies to distinguish between benign and malignant nodules 5-9 or address

the treatment of thyroid cancer. Here, we focus on the treatment of patients with benign nodular

thyroid disease.

CLINICALLY SOLITARY THYROID NODULES

A clinically solitary thyroid nodule is a discrete swelling within an otherwise palpably normal thyroid

gland. With time, solitary thyroid nodules may enlarge, shrink, or even disappear

spontaneously,13,14 but most do not change appreciably.3 Most of these nodules are benign

colloid nodules composed of ir- regularly enlarged follicles containing abundant colloid. Most are

actually the largest of multiple colloid nodules in small, clinically unrecognized multinodular

goiters.15 Other causes of benign solitary nodules are thyroid adenomas, cysts, and thyroiditis.

Ap- proximately 5 percent of all solitary thyroid nodules are thyroid carcinomas.5-9

A strong clinical suspicion of carcinoma (e.g., when there is a firm, fixed nodule, enlarged cervical

lymph nodes, or hoarseness) is in itself an indication for surgical treatment. Fine-needle aspiration

biopsy is indicated in all patients with solitary thyroid nodules and is especially helpful in patients

in whom there are no obvious symptoms or signs of carcinoma. When this technique is used,

approximately 70 percent of nodules are found to be cytologically benign (with a false negative

rate of 1 to 2 percent) and approximately 4 percent to be malignant.8,16 In the remaining patients,

either the distinction cannot be made on the basis of cytologic findings (indeterminate cytologic

findings) or the aspirate con- tains an insufficient number of follicular cells for a reliable diagnosis

(inadequate cytologic findings). Surgery is advised for patients with indeterminate or repeatedly

inadequate cytologic findings. An ex- ception can be made for patients with low serum thyrotropin

concentrations, in whom thyroid scintigraphy with iodine-123 (or iodine-131) should demonstrate

hyperfunctioning of the nodule and little or no uptake in the extranodular tissue. These

autonomously functioning nodules are rarely malignant.6

Given the imprecision of palpation, ultrasonography is critical for evaluating changes in nodule or


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goiter volume in studies of therapy, but it is not indicated for routine clinical management. Ultraso-

nography is of value when cystic nodules do not disappear completely or when they recur after as-

piration. In these cases, ultrasonographic guidance can be used to obtain adequate cytologic

findings from the solid components. Patients with cystic le- sions that disappear permanently after

aspiration need no further diagnostic evaluation, even when the cytologic findings in the aspiratedfluid are inadequate.17

MULTINODULAR GOITER

A multinodular goiter may be defined as a struc- turally and functionally heterogeneous thyroid en-

largement. Worldwide, such goiters are most often caused by iodine deficiency. In the early phase

of goitrogenesis, the thyroid may be diffusely enlarged, but with time diffuse goiters tend to grow

and become more nodular. Thyroid function often becomes more autonomous with increasing

age,18,19 and euthyroidism may gradually change to subclinical hyperthyroidism (defined as a

low serum thyrotropin concentration and normal serum free thyroxine and triiodothyronine

concentrations) and eventually into overt hyperthyroidism.

In patients with multinodular goiter, serum thyrotropin and free thyroxine should be measured to

identify those with subclinical or overt hyperthyroidism. Thyroid scintigraphy and ultrasonography

are not routinely indicated. Fine-needle aspiration biopsy may be helpful when carcinoma is

suspected: cytologic examination should focus on the domi- nant nodule or nodules or those that

have a different consistency from other nodules within the gland.20 In surgical series of patients

with multinodular goiter, the reported incidence of carcinoma was as high as 10 percent.21

However, the patients were highly selected, and most of the carcinomas were tiny pap- illary

carcinomas. In less highly selected groups of patients with multinodular goiter, such as those pre-

senting to a thyroid clinic, the incidence of carcinoma was 1 to 4 percent.22,23 In unselected

patients with multinodular goiter, the prevalence of clinically important carcinoma must be less than

1 percent, given the high prevalence of multinodular goiter and the very low incidence of clinically

evident thyroid carcinoma.

TREATMENT OF NONTOXIC UNINODULAR THYROID DISEASE

The main indications for treatment of a euthyroid patient with a benign thyroid nodule that is not hy-

perfunctioning are compression of the trachea or esophagus, growth of the nodule, and recurrence

of a cystic nodule after aspiration. Other indications for treatment are neck discomfort, cosmetic

con- cern, and the patients anxiety about the nodule. The main therapeutic options are surgery and

thyroxine treatment.

Surgery


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Unilateral thyroid lobectomy is the preferred therapy for patients with benign solitary thyroid nod-

ules. The operative risk is lower than that of subtotal thyroidectomy for multinodular goiter, because

the resection is less extensive. As an alternative, patients with recurrent cystic nodules can be

treated by injection of a sclerosing agent, such as tetracycline24 or ethanol,25,26 into the nodule.

Thyroxine Therapy

Thyroxine is the most widely used treatment for patients with benign solitary thyroid nodules. It is

given to suppress the secretion of thyrotropin. The assumption underlying this treatment is that the

growth of thyroid nodules, like that of normal thyroid tissue, is dependent on thyrotropin, and

therefore that suppression of thyrotropin secretion will result in a decrease in nodule size.

Nonrandomized studies suggested that thyroxine treatment induced a decrease of 50 percent or

more in nodule diameter in approximately 30 percent of patients.27 However, these studies lacked

adequate control groups, nodule volumes were often not measured objectively, and patients with

subclinical hypothyroidism were not always excluded.

There have been four randomized, prospective tri- als in euthyroid patients with benign, clinically

solitary nodules that compared the effect of thyroxine given at thyrotropin-suppressive doses for 6

to 12 months with the effect of placebo or no treatment on nodule size as determined by

ultrasonography (Table 1). Three studies were limited to patients with colloid nodules,28-30 but the

fourth study in- cluded patients with degenerative, hyperplastic, and fibrotic nodules.31 Thyroxine

therapy was of no ben- efit in two studies.28,29 In the third study,30 more patients receiving

thyroxine than patients receiving placebo had a decrease in nodule volume (45 percent vs. 26

percent), but the percentages of patients with a greater than 50 percent decrease in nodule volume

did not differ significantly between the groups. In the fourth study,31 nodule volume decreased by

50 percent or more in 39 percent of the thyroxine-treated patients and in no untreated patients, but

only nodules with a volume of 10 ml or less at base line decreased by 50 percent or more. In this

study the cytologic characteristics of the nodule predicted the effect of thyroxine therapy, the

chance of shrinkage being highest in patients with colloid or degenerative nodules.32

Given the at best modest short-term results of thyrotropin-suppression therapy, the absence of data

on its long-term efficacy, and the possible adverse effects (see below), the value of thyroxine

treatment in patients with benign solitary thyroid nodules is controversial. Some have completely

abandoned this therapy, and others restrict it to men and premenopausal women, with

postmenopausal women being treated only when growth of the nodule is demonstrated.33

Another controversial issue is the appropriate level of thyrotropin suppression; we do not know

whether marked suppression of thyrotropin secretion is more effective than mild suppression.


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Management of Autonomously Functioning Thyroid Nodules

Because of the risk of inducing hyperthyroidism, thyrotropin-suppression therapy is not indicated in

euthyroid patients with autonomously functioning thyroid nodules. Most of these nodules do not

sub- stantially change in size with time; in one study, 86 percent of nodules remained stable during

a follow- up period of 1 to 15 years.34 Approximately 5 percent of the patients become

hyperthyroid each year34,35; the risk is highest when the nodule is 3 cm or more in diameter at the

time of diagnosis.34 Ra- dioiodine therapy or surgery may be indicated in case of local effects of

the nodule. Because of the risk of hyperthyroidism, therapy should also be con- sidered in

asymptomatic patients with nodules 3 cm or more in diameter, especially in elderly patients.

TREATMENT OF NONTOXIC MULTINODULAR GOITER

The main indications for the treatment of patients with nontoxic multinodular goiter are compression

of the trachea or esophagus and venous-outflow ob- struction. Another indication is growth of the

goiter, especially where there is intrathoracic extension. Such goiters are inaccessible to palpation

and fine- needle aspiration biopsy, and they may cause acute airway symptoms. Sometimes

treatment is sought because of neck discomfort or cosmetic issues.

Patients who have symptoms and signs of tracheal compression (inspiratory stridor and dyspnea)

should undergo radiography, computed tomography (CT), or magnetic resonance imaging (MRI) of

the neck and upper thorax and pulmonary-function tests, especially flow-volume loop studies. The

sensitivity of both CT and MRI for the detection of intrathoracic extension of a goiter is 100

percent. When CT is used, iodinated contrast agents should not be given, because of the risk of

inducing hyperthyroidism.

The available treatment options are surgery, thyroxine, and radioiodine (Table 2). Even when

iodine deficiency is the cause of the goiter, iodine supple- mentation is not advisable in patients with

nontoxic multinodular goiter, because it may induce hyperthyroidism.

Surgery

Bilateral subtotal thyroidectomy is standard therapy for patients with nontoxic multinodular goi-

ter.36,37 It leads to rapid decompression of vital structures. If only one thyroid lobe is enlarged,

treatment may consist of unilateral lobectomy and isthmecto- my. Nearly all such goiters can be

removed through a collar incision, even those that extend well into the thorax, and therefore

thoracotomy is rarely needed. However, isolated intrathoracic goiters, which are extremely rare,

must be removed by a thoracic ap- proach.36


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The surgical mortality rate associated with bilateral thyroid operations in patients with nontoxic

multinodular goiter is less than 1 percent.36,37 Surgical morbidity includes postoperative tracheal

ob- struction due to hemorrhage or tracheomalacia, in- jury to the recurrent laryngeal nerve (in 1 to

2 percent of cases when the operation is performed by an experienced thyroid surgeon),

hypoparathy- roidism (0.5 to 5 percent of cases), voice changes due to superior-laryngeal-nervedamage, and hypothyroidism.36,37 The rate of postoperative hypothyroidism depends on the

extent of surgery. Surgical morbidity is highest in patients with very large goiters and in those who

undergo reoperation because of recurrent goiter.38

The rate of goiter recurrence after surgery increases with time. With adequate surgery, the

recurrence rate should not be higher than approximately 10 percent after 10 years.39 Thyroxine is

frequently pre- scribed postoperatively to decrease the chance of goiter recurrence, but several

large, uncontrolled studies have yielded no convincing evidence that this therapy is effective, and

no randomized studies with sufficient follow-up times and objective measurements of goiter havebeen performed.40 Therefore, routine thyroxine therapy after surgery for nodular goiter cannot be

advised.

Thyroxine Therapy

Suppression therapy with thyroid hormone is effective in reducing the volume of diffuse nontoxic

goiters, as measured by ultrasonography.41,42 Several nonrandomized studies suggest that this

therapy is also effective in patients with multinodular goiters.40 However, in most of the studies,

patients with iodine deficiency or subclinical hypothyroidism were not excluded, and none had

adequate control groups and objective measurements of thyroid volume. Only one randomized,

placebo-controlled trial using objective volume measurements has been reported.43 In this study

of patients with relatively small, nontoxic, predominantly multinodular goiters (mean volume, 53

ml), a decrease in goiter size, defined as a decrease in thyroid volume of more than 13 percent,

occurred in 58 percent of the patients treated with thyroxine and in only 5 percent of those given

placebo. The mean decrease in thyroid volume in the patients with a response was 25 percent

after nine months of thyroxine treatment. Goiter size returned to base line after the discontinuation

of therapy. The effect of thyroxine treatment in patients with larger multinodular goiters is probably

smaller. Further- more, there is no evidence that long-term thyroxine therapy alters the natural

history of multinodular goiter.

Before thyroxine therapy is begun in patients with multinodular goiter, serum thyrotropin should be

measured, because many patients with large multinodular goiters have autonomous thyroid

hormone production and subclinical hyperthyroidism. In such patients, thyroxine therapy is

inadvisable because it may cause overt hyperthyroidism, and no shrinkage of the goiter can be


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expected when thyrotropin secretion is already suppressed.44

Radioiodine Therapy

Radioiodine (iodine-131) treatment is effective in reducing thyroid volume in most patients with non-

toxic multinodular goiter.45-49 In the reported studies, the average initial thyroid volumes ranged

from 73 to 269 ml. Approximately 100 mCi (3.7 MBq) of radioiodine per gram of thyroid tissue

(corrected for the percentage uptake of radioiodine in the thyroid at 24 hours) was administered.

Radioiodine treatment resulted in a mean reduction in thyroid volume of approximately 40

percent after one year45-49 and 50 to 60 percent after three to five years (Fig. 1).46,50 More

important was the finding that compressive symptoms decreased in the majority of patients. In

one study, there was significant tracheal widening as measured by MRI (Fig. 1 and 2),47 and this

widening was accompanied by improvement in respiratory function (Fig. 3).47,51

Early side effects (pain in the thyroid region, radiation thyroiditis, increase in compressive symp-

toms, and esophagitis) are rare, and when present they are usually mild and transient.47,50,52 The

devel- opment of autoimmune (Graves) hyperthyroidism, probably triggered by the radiation -

induced release of thyroid antigens, is the most important complica- tion, occurring several months

after therapy in approximately 5 percent of patients.53,54 The incidence of post-treatment

hypothyroidism is 20 to 30 percent at five years.46

No follow-up data are available on the risk of in- duction of carcinoma by the high doses of radioio-

dine needed for the treatment of patients with large multinodular goiters. The lifetime risk of

radiation- induced carcinoma depends not only on the administered dose of radioiodine but also

on the age of the patient. It has been estimated that the lifetime risk of radiation-induced carcinoma

in extrathyroidal tis- sues in people 65 years of age or older who are treated with high doses of

radioiodine is similar to the mortality rate associated with subtotal thyroidectomy.55

Adverse Effects of Suppression Therapy with Thyroid Hormone

Thyroxine therapy in doses sufficient to suppress serum thyrotropin may have adverse effects. A

meta- analysis of all controlled cross-sectional studies of the effects of thyroid hormone therapy on

bone mineral density that were published between 1982 and 1994 demonstrated substantial

decreases (5 to 9 percent) in bone mineral density at the lumbar spine, the proximal femur, and the

radius in postmenopausal women receiving long-term suppression therapy with thyroid

hormone.56 No negative effect of therapy on bone mineral density was found in premenopausal

women or in men. Estrogen-replace- ment therapy in postmenopausal women ameliorates thyroid

hormoneassociated bone loss.57


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A low serum thyrotropin concentration in persons 60 years of age or older is associated with a

tripling of the risk of atrial fibrillation in the subsequent decade.58 Therefore, it is not unreasonable

to assume that suppression therapy with thyroid hormone might have adverse cardiac effects. The

therapy increases left ventricular mass,59-61 but whether it causes cardiac dysfunction is not

clear. In one study the patients treated with thyroid hormone had a normal heart rate, no atrialarrhythmias, and normal left ventricular function,61 whereas in another study similarly treated

patients had an increased heart rate, an increased incidence of atrial arrhythmias, and decreased

left ventricular function.59

TREATMENT OF TOXIC UNINODULAR AND MULTINODULAR GOITER

In patients with nodular thyroid disease, treatment is always indicated when overt hyperthyroidism is

present. In cases of subclinical hyperthyroidism, treatment is advisable in elderly patients and in

younger ones who are at risk for cardiac disease or osteoporo- sis. The available treatment options

are antithyroid drugs, surgery, radioiodine, and, in patients with autonomously functioning thyroid

nodules, percutaneous ethanol injection (Tables 3 and 4).

Antithyroid-Drug Therapy

Hyperthyroidism caused by nodular thyroid disease is reversible by antithyroid-drug treatment.

However, for most patients this therapy is not attractive, because it must be lifelong;

hyperthyroidism nearly always recurs after the antithyroid drug is discontinued.62 Antithyroid-drug

therapy is indicated before thyroid surgery because it lowers operative risk. In addition, it is

recommended before and sometimes after radioiodine treatment in elderly patients and those with

other health problems, because euthyroidism is achieved more quickly with drug therapy and the

risk of exacerbation of hyperthyroidism after radioiodine treatment is likely to be lower. The

antithyroid drug should be discontinued for at least three days before and three days after ra-

dioiodine therapy.

Surgery

In patients with hyperthyroidism who have solitary autonomously functioning thyroid nodules, ei-

ther lobectomy or nodulectomy is simple and effective. As in euthyroid patients with solitary thyroid

nodules, the operative risk is lower than that of surgery for multinodular goiter. Recurrences after

surgery are rare.63,64 Hypothyroidism develops in 10 to 20 percent of patients.63,65

Patients with toxic multinodular goiter may be treated by bilateral subtotal thyroidectomy. Among

adequately prepared patients, the operative risk is similar to that of surgery for nontoxic

multinodular goiter. After adequate surgery, the combined incidence of persistent and recurrent


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hyperthyroidism should be less than 10 to 20 percent.66,67 Widely varying rates of post-treatment

hypothyroidism (up to 70 percent) are reported in the literature; the variation is probably due to

variation in the extent of surgery.66

Radioiodine Therapy

Traditionally, patients with toxic uninodular or multinodular goiter have been treated with relatively

high doses of radioiodine. For patients with solitary autonomously functioning nodules, doses of 200

to 400 mCi (7.4 to 14.8 MBq) per gram of nodular tissue are advised.64 For patients with toxic

multinodular goiter, the usual dose is 150 to 200 mCi (5.5 to 7.4 MBq) per gram of thyroid

tissue.68 However, we and others have found that lower doses result in similar cure rates,69,70 so

we now treat patients who have toxic multinodular goiter with doses of 80 to 100 mCi (3.0 to 3.7

MBq) per gram of thyroid tissue.

Radioiodine therapy is as effective as surgery for the treatment of patients with autonomously func-

tioning thyroid nodules and those with toxic multinodular goiters. The reversal of hyperthyroidism

after radioiodine therapy is, however, more gradual than that after surgery. For patients with

autonomously functioning thyroid nodules, radioiodine results in a one-dose cure rate of 90

percent, on average.63,65 Radioiodine therapy is effective in 80 to 100 percent of patients with

toxic multinodular goiter, although more than one treatment may be neces- sary.69 In most patients,

radioiodine treatment results not only in the reversal of hyperthyroidism but also in a substantial

reduction in thyroid (or nodule) volume.71

Hypothyroidism after radioiodine treatment is con- siderably less common in patients with toxic

nodular goiter than in those with Graves hyperthyroidism. Among patients with autonomously

functioning thyroid nodules, the cumulative incidence of subclinical and clinical hypothyroidism is

10 percent, on average, after mean follow-up ranging from 1 to 10 years.63,65 The frequency of

hypothyroidism appears to be inversely related to the degree of suppression of thyrotropin secretion

at the time of treatment and the resultant reduction in radioiodine uptake in the normal paranodular

tissue.64 Among patients with toxic multinodular goiter, hypothyroidism occurred in less than 20

percent in most studies, even after long-term follow-up. The frequency of hypothyroidism is

highest among patients who also have thyroid autoimmunity.72

Theoretically, patients treated with radioiodine have an increased risk of thyroid carcinoma,

because the paranodular tissue may receive sublethal mu- tagenic doses of radiation.73 However,

in a large follow-up study, the risk of thyroid carcinoma was not increased and the risk of

carcinoma elsewhere was not increased or only marginally increased.74

Percutaneous Injection of Ethanol


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Percutaneous injection of ethanol is a recently proposed alternative to radioiodine therapy and sur-

gery for patients with autonomously functioning thyroid nodules. The procedure involves the instilla-

tion of ethanol directly into the nodule under ultrasound guidance. Multiple injections, usually

causing mild-to-moderate pain, are required, and a few patients have transient paralysis of the

recurrent laryngeal nerve.

Of patients with overt hyperthyroidism in a large Italian multicenter study, 67 percent had normal se-

rum thyrotropin concentrations and iodine uptake in the previously suppressed extranodular tissue

12 months after the injections were completed.75 In another study from Italy, 78 percent of

patients with overt hyperthyroidism were cured after a median follow-up of 2.5 years.76 In both

studies, nodule volume decreased in the majority of patients.

CONCLUSIONS

Several medical and surgical treatment options are available for patients with benign nodular

thyroid disease. Surgery is indicated in euthyroid patients with benign solitary thyroid nodules that

cause tracheal compression. When treatment is sought by euthyroid patients with solitary

nodules that do not cause tracheal compression, we offer a 6-to-12- month trial of thyroxine

therapy, provided that the nodule is not functioning autonomously. We inform patients that the data

on the efficacy of thyroxine therapy are controversial, and we discourage postmenopausal women

who are not taking estrogen from trying thyroxine therapy.

Surgery is standard therapy for patients with nontoxic multinodular goiter, especially when rapid

decompression of vital structures is required. Thyrox- ine may be tried in young patients with small

goiters (not larger than 50 ml) who have normal serum thyrotropin concentrations. Radioiodine

treatment is an attractive alternative to surgery in elderly patients and those with cardiopulmonary

disease.

Adults with solitary hyperfunctioning thyroid nodules are usually treated with radioiodine, although

some prefer surgery. For children and adolescents with solitary hyperfunctioning thyroid nodules,

surgery is advised.77 For the treatment of patients with toxic multinodular goiters, radioiodine is

usually recommended, but surgery is more appropriate for patients with large goiters when rapid

decompression of vital structures is needed.


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