Pediatric Annals

Nodular Thyroid Disease and Thyroid Carcinoma

Wellington Hung, MD, PhD

Abstract

The detection of a single or multiple nodules of the thyroid gland is an uncommon finding in pediatrics. Rallison and coworkers1 examined 5179 children and adolescents aged 11 to 18 years and detected thyroid nodules in 93 (1.8%). In 65 (1.3%), examination suggested only a single nodule and in 28 (0.5%), more than one nodule. Trowbridge et al2 examined 7785 children and adolescents aged 9 to 16 years. They detected nodules in 17 patients (0.22%).

Patients may present with either a solitary thyroid nodule or multiple discrete nodules. The implications of a solitary thyroid nodule are different than those of multiple nodules. The risk of malignancy is lower in a multinodular thyroid gland than in solitary nodules. Table 1 lists the differential diagnosis of a multinodular thyroid gland while Table 2 presents that of a solitary thyroid nodule.

CLINICAL PRESENTATION

Nodules of the thyroid gland in pediatrie patients are usually asymptomatic and are noted incidentally by parents, by friends, by the patient, or by a doctor during a routine physical examination (Figure 1). The primary challenge facing the pediatrician is to rule out the presence of a malignancy. Controversy exists regarding the appropriate evaluation of therapy of patients with solitary or multiple nodules, but particularly those with solitary nodules because the diagnostic techniques used to distinguish a benign lesion from a malignant lesion vary in reliability.

DIAGNOSIS

History and Physical Examination

The medical history is important and should include questions about external irradiation to the head, neck, and chest and whether there has been extensive diagnostic irradiation to these areas. It has been suggested that extensive diagnostic irradiation to the head and neck of infants and children may be a causative factor in inducing thyroid neoplasia.3 A history of goitrogen ingestion should also be sought. Information regarding the growth rate of the mass(es), the presence of local or systemic symptoms, hoarseness, or dysphagia should be obtained.

Rapid painless growth of a nodule suggests the presence of carcinoma, particularly anaplastic cancer. Pain or tenderness in the thyroid gland is an unusual complaint with malignancy, but may be marked in bacterial or viral thyroiditis. A rapidly enlarging nodule due to hemorrhage into a cyst may cause transient pain. The family history should be explored for the presence of Graves' disease, hypothyroidism, goiters, pheochromocytoma, or hyperparathyroidism. Medullary thyroid carcinoma can occur sporadically, can be transmitted as an autosomal dominant trait, or can be associated with multiple mucosal neuromas, pheochromocytoma, and hyperparathyroidism (multi' pie endocrine neoplasia, types Ua and lib).

Table

THYROID CARCINOMA

Etiology

Carcinoma of the thyroid gland is rare in pediatrie patients. From 1920 to 1960, radiotherapy was widely used for treating benign lesions of the head, neck, and upper chest such as tinea capitis, acne, tonsillar hypertrophy, and thymic enlargement. The carcinogenic effects of external irradiation to the thyroid gland in childhood were first recognized in 1950.14 Thereafter, radiotherapy for benign conditions gradually stopped. There is some evidence that the prevalence of thyroid cancer in pediatrie patients has decreased,7 perhaps reflecting the cessation of external low-dose irradiation for benign conditions. Investigational techniques, especially fluoroscopy, may involve exposure to radiation doses well within the range implicated in the pathogenesis of thyroid tumors, and cases of thyroid cancer have been ascribed to radiation from these sources.15

Survival rates for many pediatric malignancies have improved recently, but radiation and chemotherapy have been implicated in the development of secondary thyroid neoplasm in some patients.16 Evaluation of thyroid function and possible thyroid tumors should be a part of the follow-up in pediatrie patients surviving malignancies.

There is some evidence that an increased serum TSH level may…

The detection of a single or multiple nodules of the thyroid gland is an uncommon finding in pediatrics. Rallison and coworkers1 examined 5179 children and adolescents aged 11 to 18 years and detected thyroid nodules in 93 (1.8%). In 65 (1.3%), examination suggested only a single nodule and in 28 (0.5%), more than one nodule. Trowbridge et al2 examined 7785 children and adolescents aged 9 to 16 years. They detected nodules in 17 patients (0.22%).

Patients may present with either a solitary thyroid nodule or multiple discrete nodules. The implications of a solitary thyroid nodule are different than those of multiple nodules. The risk of malignancy is lower in a multinodular thyroid gland than in solitary nodules. Table 1 lists the differential diagnosis of a multinodular thyroid gland while Table 2 presents that of a solitary thyroid nodule.

CLINICAL PRESENTATION

Nodules of the thyroid gland in pediatrie patients are usually asymptomatic and are noted incidentally by parents, by friends, by the patient, or by a doctor during a routine physical examination (Figure 1). The primary challenge facing the pediatrician is to rule out the presence of a malignancy. Controversy exists regarding the appropriate evaluation of therapy of patients with solitary or multiple nodules, but particularly those with solitary nodules because the diagnostic techniques used to distinguish a benign lesion from a malignant lesion vary in reliability.

DIAGNOSIS

History and Physical Examination

The medical history is important and should include questions about external irradiation to the head, neck, and chest and whether there has been extensive diagnostic irradiation to these areas. It has been suggested that extensive diagnostic irradiation to the head and neck of infants and children may be a causative factor in inducing thyroid neoplasia.3 A history of goitrogen ingestion should also be sought. Information regarding the growth rate of the mass(es), the presence of local or systemic symptoms, hoarseness, or dysphagia should be obtained.

Rapid painless growth of a nodule suggests the presence of carcinoma, particularly anaplastic cancer. Pain or tenderness in the thyroid gland is an unusual complaint with malignancy, but may be marked in bacterial or viral thyroiditis. A rapidly enlarging nodule due to hemorrhage into a cyst may cause transient pain. The family history should be explored for the presence of Graves' disease, hypothyroidism, goiters, pheochromocytoma, or hyperparathyroidism. Medullary thyroid carcinoma can occur sporadically, can be transmitted as an autosomal dominant trait, or can be associated with multiple mucosal neuromas, pheochromocytoma, and hyperparathyroidism (multi' pie endocrine neoplasia, types Ua and lib).

Table

TABLE 1Differential Diagnosis of M u It I nod u Ia r Thyroid Disease

TABLE 1

Differential Diagnosis of M u It I nod u Ia r Thyroid Disease

Figure 1. Patient with a solitary nodule of the thyroid gland.

Figure 1. Patient with a solitary nodule of the thyroid gland.

Careful palpation of a thyroid nodule may help define its nature. A soft compressible round nodule is not likely to be malignant - such a node is more likely to be an adenomatous or colloid cyst. However, a cyst on occasion may be fimi to palpation. Tenderness in the nodule suggests hemorrhage into it, a cyst, or an inflammatory process. Thyroid malignancy should be suspected if the nodule is hard, if there is fixation to surrounding structures, or if there is vocal cord paralysis. Lymphadenopathy, particularly low in the neck, increases the likelihood of a thyroid nodule being malignant. In most patients with a malignant nodule, the surrounding thyroid tissue feels normal and the gland is of normal size. In some patients with chronic lymphocytic thyroiditis, diffuse thyroid enlargement with multiple nodules may be present. A medullary carcinoma should be suspected in a patient who presents with multiple mucosal neuromas, appearing as whitish nodules on the tongue, the palpebrai conjunctiva, and the commissures of the lips; these patients may also have a marfanoid body build and a variety of skeletal defects.

Laboratory Evaluations

Blood Studies, Serum T4, T,, and thyroidstimulating hormone (TSH) determinations are helpfui in determining the functional status of the thyroid gland. It should be stressed that the degree of hyperthyroidism due to a toxic nodule may not be sufficiently severe to allow diagnosis on clinical grounds. Serum antithyroid antibody studies may be helpful if chronic lymphocytic thyroiditis is suspected. It is important to exclude hypothyroidism, which, if secondary to chronic lymphocytic thyroiditis, may be associated with a solitary nodule or multiple nodules. Serum concentrations of thyroglobulin may be elevated in patients with differentiated thyroid carcinoma, but are also elevated in benign thyroid disorders. Therefore, the measurement of serum thyroglobulin is not helpful in the initial work -up.

Radionuc/ide Imaging. The traditional approach to evaluating patients with nodular thyroid disease has been by radioisotope scanning, with the aim being to classify nodules as either "cold" (Figure 2) or "hot" depending on their ability to concentrate isotope. Repeat scanning after TSH stimulation or thyroid hormone suppression may be helpful, depending on the functional status of the nodule. Theoretically, malignant tissue does not incorporate iodine, therefore scanning with either technetium-99m pertechnetate (99TC) or '"-iodide (123I) should indicate the likelihood of malignancy. However, the value of isotope scans is limited by poor differentiation of benign disease from malignant disease. The thyroid scan is helpful in detecting multiple nodules when a solitary nodule is found on physical examination (Figure 3). The most common cause of a cold thyroid nodule is a folHcular adenoma.

Ultrasonography. Ultrasound examination of the thyroid provides an accurate means of assessing thyroid size and the presence and size of thyroid nodules. It is valuable in allowing differentiation of solid from cystic lesions. A solid nodule has the greatest likelihood of being malignant, although most solid lesions are benign, and the presence of a cystic lesion does not exclude malignancy.

Figure 2. "mTC scan showing a cold nodule in the left lobe. At surgery, a papillary carcinoma was present.

Figure 2. "mTC scan showing a cold nodule in the left lobe. At surgery, a papillary carcinoma was present.

Table

TABLE 2Differentfal Diagnosis of Solitary Thyroid Nodules

TABLE 2

Differentfal Diagnosis of Solitary Thyroid Nodules

Roentgenography. Roentgenography of the neck may be of value in suspected cases of cancer. Medullary thyroid carcinoma may be associated with calcification in the thyroid gland or cervical lymph nodes. Pulmonary métastases of thyroid cancer may be detected on chest x-ray.

Thyroid Hormone Suppression. Attempts have been made to distinguish benign from malignant nodules according to their dependency on TSH for growth, in most studies, thyroxine has been administered for several months in an attempt to define any change in the size of the nodule. The criteria for suppression have differed between studies, but substantial shrinkage (greater than 50%) of thyroid nodules during therapy reduces concern about cancer. Suppressive therapy remains controversial. A recent double-blind, randomized clinical study of suppressive therapy of thyroid nodular disease in adults concluded that such therapy had no significant effect on nodule size during a 6-month trial.4 Thus, thyroxine suppressive therapy is not recommended.

Biopsy. Fine-needle aspiration biopsy of thyroid nodules has been routinely used in the evaluation of nodules in adults. This requires an experienced aspirationist and cytopathologist. Fine-needle aspiration has not been used extensively in pediatrie patients but will probably be used with increased frequency in older children and adolescents. Currently, open surgical biopsy is used more frequently for diagnostic purposes in pediatrie patients.

MANAGEMENT

The primary challenge in the management of a solitary nodule of the thyroid or of a multinodular thyroid gland is to rule out malignancy. Some clinicians recommend excision of all thyroid nodules in pediatrie patients.5

A warm or isofunctional nodule is one in which the radioisotope concentration is similar to the concentration in the remainder of the gland. Some clinicians believe that patients with warm solitary thyroid nodules can be treated first with suppressive doses of thyroid hormones.6

A hot nodule may represent a follicular adenoma, adenomatous goiter, hyperplasia, chronic lymphocytic thyroiditis, a colloid goiter, and, rarely, a carcinoma.7 A variant of the hot nodule is seen in patients with agenesis of the contralateral lobe of the thyroid. This anomaly must be differentiated from the typical hot nodule because excision is not indicated. Repeat thyroid scanning following TSH stimulation or ultrasonography will exclude the functioning tissue as being the only thyroid tissue present. A solitary hot nodule may be toxic or nontoxic and may be autonomously functioning. A hot toxic nodule should be removed surgically after proper preparation with antithyroid drugs.

Hot nodules that do not produce thyrotoxicosis initially may increase their secretion of thyroid hormones gradually and insidiously until the patient becomes thyrotoxic. In pediatrie patients, there is a more rapid progression to thyrotoxicosis and there is also a higher incidence of thyroid carcinoma compared to adults.8 All hot solitary thyroid nodules should be removed surgically in children and adolescents.5·8 Thyrotoxicosis due to a multinodular goiter is rare in pediatrics,9 and a thyroidectomy should be performed after preoperative preparation with antithyroid drugs.

Table

TABLE 3Histologie Classification of Epithelial Thyroid Tumors According to the World Health Organization*

TABLE 3

Histologie Classification of Epithelial Thyroid Tumors According to the World Health Organization*

Patients with coíd nodules present the greatest clinical problem in differentiating malignant lesions from benign lesions. Cold nodules may be found in chronic lymphocytic thyroiditis or may represent cysts, follicular adenomas, abscesses, carcinomas, and embryonic defects such as intrathyroidal thyroglossal duct cysts. The highest incidence of carcinoma occurs in patients with cold, solid solitary nodules.10 Most cysts result from necrosis and degeneration of nodules, and cystic lesions are considered to be benign. How' ever, in one study of 12 pediatrics patients with thyroid carcinoma, nearly half had cystic lesions.11 All solitary thyroid nodules should therefore be removed surgically.

As with solitary nodules of the thyroid, there is no complete agreement regarding multiple nodules, except in patients with toxic multinodular goiters who require therapy for thyrotoxicosis. Some authorities suggest that an open biopsy should be obtained, even though the risk of cancer is low.12 Others have recommended therapy with full suppressive doses of thyroid hormone unless one or more of the nodules is hard or there is continued enlargement of the nodule(s), despite adequate thyroid therapy.13

In the few reports concerning the histopathology of solitary thyroid nodules in children and adolescents, the incidence of carcinomas has ranged from 14% to 40%.s The most common cause of a solitary thyroid nodule is follicular adenoma.

Figure 3. ""1TC scan showing a nodule in the left lobe (right of photo) of the thyroid corresponding to the palpable solitary nodule. The two nodules in the right lobe (left of photo) were not detected clinically.

Figure 3. ""1TC scan showing a nodule in the left lobe (right of photo) of the thyroid corresponding to the palpable solitary nodule. The two nodules in the right lobe (left of photo) were not detected clinically.

THYROID CARCINOMA

Etiology

Carcinoma of the thyroid gland is rare in pediatrie patients. From 1920 to 1960, radiotherapy was widely used for treating benign lesions of the head, neck, and upper chest such as tinea capitis, acne, tonsillar hypertrophy, and thymic enlargement. The carcinogenic effects of external irradiation to the thyroid gland in childhood were first recognized in 1950.14 Thereafter, radiotherapy for benign conditions gradually stopped. There is some evidence that the prevalence of thyroid cancer in pediatrie patients has decreased,7 perhaps reflecting the cessation of external low-dose irradiation for benign conditions. Investigational techniques, especially fluoroscopy, may involve exposure to radiation doses well within the range implicated in the pathogenesis of thyroid tumors, and cases of thyroid cancer have been ascribed to radiation from these sources.15

Survival rates for many pediatric malignancies have improved recently, but radiation and chemotherapy have been implicated in the development of secondary thyroid neoplasm in some patients.16 Evaluation of thyroid function and possible thyroid tumors should be a part of the follow-up in pediatrie patients surviving malignancies.

There is some evidence that an increased serum TSH level may be implicated as a cause of thyroid cancer. Several retrospective studies18'20 have indicated that the recurrence of cancer can be minimized and survival improved with thyroid hormone therapy.

Classification and Pathology

The histologie classification of thyroid tumors as suggested by the World Health Organization is presented in Table 3.17 All of the histologie types of thyroid cancer that occur in adults are found in children and adolescents, but fortunately with a slightly higher proportion of differentiated carcinomas. Papillary carcinoma is the most common histologie type. Papillary cancers often contain follicular elements and may be designated mixed papillary and follicular carcinomas. Papillary carcinomas spread to the surrounding normal thyroid parenchyma and regional lymph nodes. These carcinomas characteristically grow slowly.18

Follicular carcinomas have a marked tendency for vascular invasion and spread to bone and lung. Medullary thyroid cancer arises from the C cells of the thyroid and secretes calcitonin and other substances. Anaptastic carcinoma is rare in children and causes early death because of extensive local and disseminated disease.

Clinical Findings

Thyroid cancer is two to three times as common in females as in males. It usually presents as one or more firm, painless nodules in the neck. These nodules may be metastatic lesions of the cervical lymph nodes without any detectable thyroid nodule; in such instances, the primary thyroid tumor is occult. Usually, these lymph nodes are movable, smooth, nontendec and discrete. Carcinoma localized only to the thyroid gland is unusual.

Diagnosis

The diagnostic investigation for suspected thyroid cancer is identical with that discussed for evaluation of thyroid nodules. Almost all patients with thyroid cancer are euthyroid. A definitive diagnosis of cancer can be made only by histopathologic examination.

Treatment

The therapy for thyroid cancer is primarily surgical. There is controversy regarding the extent of surgery, the role of adjuvant radioiodine and thyroid hormone therapy, and external irradiation in treatment because of the protracted course of most thyroid malignancies, differing biological characteristics of the several types, low incidence, differing methods of therapy, and absence of controlled clinical trials. There is seldom an indication for radical surgery in children.19

Thyroid hormone and radioactive iodine therapy to suppress TSH release should be prescribed after surgery. Thyroid hormone therapy seems to be more effective in papillary and mixed papillary-follicular carcinomas than in follicular carcinomas.

Serum thyroglobulin concentration is a useful marker for metastatic differentiated thyroid cancer, and chemotherapy is indicated for a patient with thyroid cancer that is unresponsive to surgery, thyroid hormone therapy, or radiation therapy. The effectiveness of available chemotherapeutic agents has not been evaluated extensively in pediatrìe patients.

Patients with medullary thyroid cancer who undergo thyroidectomy should be evaluated for residual tumor or métastases by basal and provocative tests using calcium or pentagastrin to stimulate calcitonin release.

Follow-Up

Children or adolescents with differentiated thyroid cancers should be followed for the rest of their lives. The course of these tumors is extremely slow and unpredictable.20 They may remain quiescent for a long period and then produce métastases.

REFERENCES

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2. Trwwhridgc FL, Matovirwic J, McLaren GD. Nichainan MZ. Iodine and goiter in children. fcdiairici. 1975;S6:82-90.

3. Pillay R, Graham-Rile J, Miraldi F, Yulish B, Newman A. Liebman J. Diagnostic X .irradiai ion as a possible criologie agent in thyroid neoplasms of childhood. J ftdiutr. I9S2;101:566-56S.

4. Oarih H, James EM, Charboneau JW. Naessens JM, Offord KP, Gorman CA. Suppressive therapy with levothyroxlne fot solitary thyroid nodules: a double-blind controlled clinical study. N En8JJ Med. 1987;31 7:70-75.

5. Hung W. August OR Randolph JO, Schisali RM, Chandra R. Solitary thyroid nodules In children and adolescents. J IMotr Surj. 1982;! 7:225-229.

6. Fisher DA. Thyroid nodule* in childhood and their management. } Pediatr. 1976:89:866-868.

7. Scott MD, Crawtbrd JD. Solitary thyroid nodules in childhood: is the incidence of thyroid carcinoma declininjj.' Pediatrics, 1976;58:52l-525.

8. Groom RD 111, Thomas CG Jt, ReJdick RL, Tawil MT. Autonomously functioning thyroid nodules in childhood and adolescence. Surgery, 1987;1U2:I 101-1 1 OS.

9. Hahn HB, McKenney JF, Stinsoti JO Nixlular toxic iioitcr in a teenage girl. AmJ Du Child. L 982; 136:849-851.

10. Belfiore A, Giuddrida D, La Rosa GL, et al. High frequency of cancer in cold thyroid nodules occurring in young age. Acw EnJoomiii. 1989;! 2 1:197-202.

11. Desjardins JG, Bass J, Leboeuf G, el »I. A twenty-year experience wich thyroid carcinoma in children. J ftdiafrSwg, l9rlHì2Ì:709-71ì.

12. Beckers C. Thyroid nodules. Clin Endocrino! Maab. 1979:8:181-192.

13. Wright HK, BumwGN, SpauldingS, et »I. Current therapy of thyroid nodules. Surg ClinNonAAm. 1974; 5-4:2 77 -288.

14- Dufry BJ, Finyerald PJ. Thyroid cancer in childhood and adolescence. Cancer. 1950;3:1018-IOJ2.

15. Yoshtda A, Noguchi S, Fultuda K, Hirohata T. Low-dost irradiation to Ueud, neck, ut chest during infancy as a possible cause of thyroid carcinoma in teenauers: a matched case-conmilstudy.JpnJCBncrrRii. 1987:78:991-994.

16. Vane D, King RD, Boles ET Jr. Secondary thyroid neoplasms in pediatrie cancer patients: increased risk with improved survival. J PaJiatr Surg, 1 984 i19:85 S-StO.

17. Jedinser C. Histological Typing of Thyroid Turnias. 2nd cd. New York, NY: Sprintjer- Verlag; 1988.

18. Zimmcrroan D, Hay ID, Gough IR, dal. Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservnrively ireiited at one institution durinK three decades. Sargerj. 1988i104:M57-1 166.

19. La Quaglia MR Curbaliy MT. Heller G, Ext-lby PR, rVennan MF. Recurrence and morbidity in different iated thyroid carcinoma in children. Surgery. 1988;104:l H91156.

20. Schlumbereer M1 Dc Vathaire F, Travasi JP, et al. Differentiated rriyroid carcinoma in childhood: long term follow-up of 72 patients. J Clin Endocrinol Metab. 1987:65=1080.1094.

TABLE 1

Differential Diagnosis of M u It I nod u Ia r Thyroid Disease

TABLE 2

Differentfal Diagnosis of Solitary Thyroid Nodules

TABLE 3

Histologie Classification of Epithelial Thyroid Tumors According to the World Health Organization*

10.3928/0090-4481-19920101-09

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