EDITOR'S C O L U M N
Thyroid nodules in childhood and their management
DR. HOPWOOD and colleagues, in the present issue of TUE JOURNAL, present six interesting cases, four with autonomously functioning thyroid nodules and two with lobar thyroid aplasia simulating unilaterally functioning nodules. All six patients were operated upon, and one of the nodules was diagnosed as papillary carcinoma. Because of this experience t h e authors suggest that surgical excision of such nodules is the treatment of choice. This experience differs somewhat from that of others, perhaps because of the small size of the patient sample. Most authors report that the incidence of carcinoma in functioning nodules is extremely low. Dr. Hopwood and colleagues quoted the study of Bauer' who found no malignancies in a series of 2,000 cases of either solitary or rnultiple functioning nodules in adults. In addition, Beahrs and associates-~ reported an incidence of carcinoma of 1.2% in 2,229 cases of adenomatous goiter associated with hyperthyroidism in adults; Perlmntter and colleaguesa observed no malignancies in 24 patients with functioning nodules; Johnson and Beierwaltes ~ reported one case of carcinoma among 12 adults with warm or hot thyroid nodules; and Meadows ~ reported one case of thyroid carcinoma in a group of 15 adults with warm or hot nodules. Collating these cases gives an incidence of carcinoma of 0.7% in a total of 4,280 cases of hyperfunctioning (single or multiple) thyroid nodules. Functioning thyroid carcinoma is unusual enough that a number of individual cases have been reported. Several were quote d by Hopwood and associates. Of these, the patient of Sussman and colleagues '~ was unusual with a hyperfuncti0ning right thyroid lobe and a nonfunctioning carcinomatous left lobe. Molnar and associates v reported a patient with an occult carcinoma embedded in the body of one thyroid lobe. In commenting about the patient the authors said: "We have no evidence to suggest that the occult sclerosing c a r c i n o m a . . , was hyperfunctioning or that it accounted for the patient's symptoms. In itself it is of doubtful clinical significance." The patient of Bccker and colleagues~ presented a discrete hot nodule. These authors stated that: "owing to the inordinate firmness of 866
The Journal of P E D I A T R I C S VoL 89, No. 5, pp. 866-868
the nodule to palpation, surgery was recommended." The patient of Meir and Hamburger was of interest because the patient had a history of irradiation to the head and neck. All of these patients were operated upon because the thyroid was unusual and/or there were criteria suggesting malignancy. See related article, p. 710. Individualization of evaluation and approach to therapy of thyroid nodules seem to this author to be essential. Most frequently the patient presents with an asymptomatic unilateral thyroid mass thought to be of recent origin. Tire differential diagnosis in childhood includes Hashimoto's thyroiditis, subacute nonsuppurative (presumably viral) thyroiditis, thyroid abscess, thyroid dysgenesis with residual perhaps ectopic functioning tissue, benign adenoma, thyroid cyst, follicular cell (papillary-follicular) carcinoma, and medullary carcinoma. In evaluation, the history obviously i s important and should include information regarding family history of thyroid or endocrine disease, previous radiation treatment to the head and neck, rate Of growth of the mass, local or systemic manifestations, the presence of mucosal neuromas and Marfanoid habitus, etc, The physical examination should emphasize clinical thyroid status and include careful examination of the thyroid gland and surrounding lymph nodes. The thyroid tissue surrounding the mass is especially important. Painfu ! thyroid enlargement with prominent local manifestations and marked thyroid tenderness with or without mild systemic manifestations suggest acute-subactue nonsuppurative thyroiditis. A moderate-sized nontender goiter which is firm and bosselated in the presence of a characteristic moth-eaten scan, circulating antithyroid antibodies, and/or a positive perchlorate discharge test suggests Hashimoto's thyroiditis. NoduleS, even discrete ones, in such glands are likely to be benign. Laboratory examination should include routine tests of thyroid function and radiologic examination of the chest and the neck. A measurement of serum thyroxine concen-
Volume 89 Number 5
867
Editor's column
Table 1. Characteristics of thyroid follicular cell carcinoma (follicular-papillary) in childhood and adolescence*
Cervical lymph node metastases History of irradiation to head and neck Invasion of local structures Dysphagia, hoarseness, or cough Distant metastases
Tawes and De Lorimier ~" (60 patients)
Cri le' (18 patients)
20 14 14 10 8
14 11 --4
Nismyama et al?:' (36 patients)
32 17 -9
Fraction of total patients
Percent of patients
66/114 42/110 14/60 10/60 21/114
58 38 23 17 18
*References 14-16.
tration (corrected for TBG variation), a serum T3 level by radioimmunoassay, and a serum TSH level are helpful. Hypothyroidism or decreased thyroid reserve (elevated TSH with normal T4 and/or T3) favors a diagnosis of Hashimoto's thyroiditis. Elevated T4 and suppressed TSH levels are observed early in the course of subacute (viral) thyroiditis. An occasional (functional) thyroid tumor will secrete T4 and/or T3. Medullary carcinoma of the thyroid may be associated with calcifications in the neck, either in the thyroid or lymph nodes. '~ Follicular cell cai'cinoma tends to metastasize to the lungs. 1~ The thyroid scan is very important as suggested by Hopwood and associates. Function in a nodule largely excludes a malignant diagnosis. Many "functioning nodules" are in fact pseudonodules in an otherwise diseased gland. Three to 4% of patients with Hashimoto's thyroiditis present such nodules, v-' Ten to 15% of patients with Hashimoto's thyroiditis will present with nonfunctioning "cold" nodules."-' These usually represent lymphoid follicles but may be follicular cysts. And since Hashimoto's thyroiditis is a relatively common disorder in childhood,"-' it is an importan t differential diagnostic consideration in a patient with a thyroid nodule or nodules. Embryonic defects in thyroid stiucture (thyroid dysgenesis) also are important i n the differential diagnosis, as Case 5 of Hopwood and colleagues emphasizes. The most difficult patients are those with discrete "cold" nodules in an otherwise normal thyroid gland. The likelihood of thyroid carcinoma in such a child Or adolescent approaches 40%.11 A serum calcitonin measurement by radioimmunoassay should be conducted to detect patients with medullary carcinoma. The incidence of medullary carcinoma among malignant tumors of the thyroid probably approximates 4%? ~ The clinical characteristics of follicular cell carcinoma (follicular-papillary) in three series totaling 114 patients are summarized in Table I. ~.... Cervical lymph node metastases were present in nearly two thirds of the patients. In the report of Tawes and DeLorimier ~" all of the 20 patients with lymph node enlargement were shown
to have metastases. In their series 62% of the patients eventually developed lymph node metastases. A history of radiation treatment to the head and neck area was obtained in 38% of the total patients. Local manifestations also were common. Lung metastases were present by chest roentgenograms in 18% of these patients. These and other studies have delineated several clinical criteria which are suggestive of thyroid carcinoma. Thus carcinoma is more likely if there is a history of prior radiation, if the nodule is hard, if adjacent lymph nodes are enlarged, if there is evidence of tracheal invasion or vocal cord paralysis, if growth of the mass has been rapid, or if there are distant metastases." In such patients surgery is indicated. If none of the malignancy criteria is present, thyroid suppression should be attempted with 0.2 to 0.3 mg of Na- 1-thyroxine daily. If over a period of four to six months the nodule grows, or if over a period of 12 months the nodule' does not reduce 50% in size, surgery is indicated. It is important to remember that follicular cell carcinoma in a young patient is a very indolent neoplasm and does not require urgent treatment, T M 1, 1~ Functional nodules usually do not produce clinical thyrotoxicosis; as noted by Dr. Hopwood and colleagues large nodules (in excess of 3 cm diameter) are more likely to do this. Autonomous nodules, however, will suppress normal thryoid tissue if they secrete significant amounts of hormone. Autonomy can be defined by stimulating the suppressed tissue (scan) by TSH or TRH or by showing nonsuppressibility of the functioning area. The latter is accomplished by scanning or by measuring radioiodine uptake after seven to ten days of 75 to 100 /~g of T3 (Cytomel) daily. Pseudonodules which are TSH dependent will show suppression (>50%) of function. Functioning nodules producing clinical and chemical thyrotoxicosis require treatment as pointed out by Drs. Hopwood and colleagues. Radioiodine treatment, now tends to be reserved for older patients (those over 40 years of age). 1~Antithyroid drug therapy is considered only for short-term management, lr Surgery is the most frequently employed therapeutic modality, and in the absence of
868
Editor's column
signs of malignancy simple enucteation can be carried out. If malignancy is a consideration "incisional biopsy or enucleation of the nodule is to be condemned. There is a danger of tumor dissemination as well as the possibility of providing the pathologist with an inadequate specimen. Complete lobectomy with removal of pericapsular lymph nodes and preservation of the recurrent laryngeal nerve is the most desirable procedure, ''~' The natural history of autonomously functioning nodules in patients with normal serum T4 and T3 concentrations has been discussed by Dr. H o p w o o d and coauthors. Most likely, such patients will remain euthyroid or the nodule will degenerate. ~-'-" Follow-up is desirable, however, because, rarely, thyrotoxicosis may develop?V.._,1 Delbert A. Fisher, M,D. Department of Pediatrics UCLA-Harbor General Hospital 1000 W. Carson St. Torrance, CA 90509 REFERENCES
l. 2.
3.
4,
5. 6.
Bauer FK: Scanning in thyroid cancer, in Medical radioisotope scanning, Vienna, 1959, LAEA, p 225. Beahrs OH, Pemberton JJ, and Black BM: Nodular goiter and malignant lesions of the thyroid gland, J Clin Endocrinol Metab 11:1157, 1951. Perlmutter M, Slater SL, and Attie J: Method for preoperative differentiation between benign and possibly malignant nontoxic thyroid nodules, J Clin Endocrinol Metab 14:672, 1954. Johnson PC, and Beierwaltes WH: Reliability ofscintiscanning modular gliters in ,judging presence or absence of carcinoma, J Clin Endocrinol Metab 15:865, 1955. Meadows PM: Scintillation scanning in the management of clinically autonomous nodules, JAMA 177:229, 1961. Sussman L, Librik L, and Clayton GW: Hyperthyroidism attributable to a hyperfunctioning thyroid carcinoma, J PEDIATR 72:208, 1968.
The Journal of Pediatrics November 1976
7. Molnar'GD, Child DS, and Woolner LB: Histologic evidence of malignancy &the thyroid gland bearing a "hot" nodule, J Clin Endocrinol Metab 181:1132, 1958. 8. Becker FO, Economou PG, and Schwartz TB: The occurrence of carcinoma in "hot" thyroid nodules, Ann Intern Med 58:877, 1963. 9. Meier DA, and Hamburger JI: An autonomously functioning thyroid nodule, cancer and prior radiation, Arch Surg 103:759, 1971. 10. Wallace S, Hill CS, Paulus DD Jr, lbanez ML, and Clark RL: The radiologic aspects of medullary (solid) thyroid carcinoma, Radiol Clin North Am 8:463, 1970. 11, Thomas CG Jr: Thyroid cancer: clinical aspects and treatment, in Werner SC, and Ingbar SH, editors: The thyroid, New York, 1971, Harper & Row, Publishers, pp 442-467. 12. Fisher DA, Oddie TH, Johnson DE, and Nelson JC: The diagnosis of Hashimoto's thyroiditis, J Clin Endocrinol Metab 40:795, 1975. 13. Weiler J, Lacour J, Gerard-Marchant R, Tubiana M, Parmentier C, Milhaud G, and Bock J: Les epithelimos medullaires a stroma amyloide du corps thyro~'de, Pathol Biol 17:995, 1969. 14. Crile G Jr: Carcinoma of the thyroid in children, Ann Surg 150:959, 1959. 15. Nishiyama RH, Schmidt RW, and Batsakis JG: Carcinorna of the thyroid gland in children and adolescents, JAMA 181:1034, 1962. 16. Tawes RL, and DeLorimier AA: Thyroid carcinoma during youth, J Pediatr Surg 3:210, 1968.. 17. Burman KD: Solitary autonomous thyroid nodules, Postgrad Med 56:70, 1974. 18. Silvcrstein GE, Burke EG, and Cogan R: The natural history of the autonomous hyperfunctioning thyroid nodule, Ann Intern Med 67:539, 1967. 19. Landgarten S, and Spencer RP: A study of the natural history of "hot" thyroid nodules, Yale J Biol Med 46:259, 1973, 20. Burman KD, Warkel RL, and Wartofsky L: Hyperfunctioning thyroid .nodules that become "cold," Med Ann DC 42:541, 1973. 21, Blum M, Shenkman L, and Hollander CS: The autonomous nodule of the thyroid: correlation of patient age, nodule size and functional status, Am J Med Sci 269:43, 1975.
Thyroid nodules in childhood and their management
DR. HOPWOOD and colleagues, in the present issue of TUE JOURNAL, present six interesting cases, four with autonomously functioning thyroid nodules and two with lobar thyroid aplasia simulating unilaterally functioning nodules. All six patients were operated upon, and one of the nodules was diagnosed as papillary carcinoma. Because of this experience t h e authors suggest that surgical excision of such nodules is the treatment of choice. This experience differs somewhat from that of others, perhaps because of the small size of the patient sample. Most authors report that the incidence of carcinoma in functioning nodules is extremely low. Dr. Hopwood and colleagues quoted the study of Bauer' who found no malignancies in a series of 2,000 cases of either solitary or rnultiple functioning nodules in adults. In addition, Beahrs and associates-~ reported an incidence of carcinoma of 1.2% in 2,229 cases of adenomatous goiter associated with hyperthyroidism in adults; Perlmntter and colleaguesa observed no malignancies in 24 patients with functioning nodules; Johnson and Beierwaltes ~ reported one case of carcinoma among 12 adults with warm or hot thyroid nodules; and Meadows ~ reported one case of thyroid carcinoma in a group of 15 adults with warm or hot nodules. Collating these cases gives an incidence of carcinoma of 0.7% in a total of 4,280 cases of hyperfunctioning (single or multiple) thyroid nodules. Functioning thyroid carcinoma is unusual enough that a number of individual cases have been reported. Several were quote d by Hopwood and associates. Of these, the patient of Sussman and colleagues '~ was unusual with a hyperfuncti0ning right thyroid lobe and a nonfunctioning carcinomatous left lobe. Molnar and associates v reported a patient with an occult carcinoma embedded in the body of one thyroid lobe. In commenting about the patient the authors said: "We have no evidence to suggest that the occult sclerosing c a r c i n o m a . . , was hyperfunctioning or that it accounted for the patient's symptoms. In itself it is of doubtful clinical significance." The patient of Bccker and colleagues~ presented a discrete hot nodule. These authors stated that: "owing to the inordinate firmness of 866
The Journal of P E D I A T R I C S VoL 89, No. 5, pp. 866-868
the nodule to palpation, surgery was recommended." The patient of Meir and Hamburger was of interest because the patient had a history of irradiation to the head and neck. All of these patients were operated upon because the thyroid was unusual and/or there were criteria suggesting malignancy. See related article, p. 710. Individualization of evaluation and approach to therapy of thyroid nodules seem to this author to be essential. Most frequently the patient presents with an asymptomatic unilateral thyroid mass thought to be of recent origin. Tire differential diagnosis in childhood includes Hashimoto's thyroiditis, subacute nonsuppurative (presumably viral) thyroiditis, thyroid abscess, thyroid dysgenesis with residual perhaps ectopic functioning tissue, benign adenoma, thyroid cyst, follicular cell (papillary-follicular) carcinoma, and medullary carcinoma. In evaluation, the history obviously i s important and should include information regarding family history of thyroid or endocrine disease, previous radiation treatment to the head and neck, rate Of growth of the mass, local or systemic manifestations, the presence of mucosal neuromas and Marfanoid habitus, etc, The physical examination should emphasize clinical thyroid status and include careful examination of the thyroid gland and surrounding lymph nodes. The thyroid tissue surrounding the mass is especially important. Painfu ! thyroid enlargement with prominent local manifestations and marked thyroid tenderness with or without mild systemic manifestations suggest acute-subactue nonsuppurative thyroiditis. A moderate-sized nontender goiter which is firm and bosselated in the presence of a characteristic moth-eaten scan, circulating antithyroid antibodies, and/or a positive perchlorate discharge test suggests Hashimoto's thyroiditis. NoduleS, even discrete ones, in such glands are likely to be benign. Laboratory examination should include routine tests of thyroid function and radiologic examination of the chest and the neck. A measurement of serum thyroxine concen-
Volume 89 Number 5
867
Editor's column
Table 1. Characteristics of thyroid follicular cell carcinoma (follicular-papillary) in childhood and adolescence*
Cervical lymph node metastases History of irradiation to head and neck Invasion of local structures Dysphagia, hoarseness, or cough Distant metastases
Tawes and De Lorimier ~" (60 patients)
Cri le' (18 patients)
20 14 14 10 8
14 11 --4
Nismyama et al?:' (36 patients)
32 17 -9
Fraction of total patients
Percent of patients
66/114 42/110 14/60 10/60 21/114
58 38 23 17 18
*References 14-16.
tration (corrected for TBG variation), a serum T3 level by radioimmunoassay, and a serum TSH level are helpful. Hypothyroidism or decreased thyroid reserve (elevated TSH with normal T4 and/or T3) favors a diagnosis of Hashimoto's thyroiditis. Elevated T4 and suppressed TSH levels are observed early in the course of subacute (viral) thyroiditis. An occasional (functional) thyroid tumor will secrete T4 and/or T3. Medullary carcinoma of the thyroid may be associated with calcifications in the neck, either in the thyroid or lymph nodes. '~ Follicular cell cai'cinoma tends to metastasize to the lungs. 1~ The thyroid scan is very important as suggested by Hopwood and associates. Function in a nodule largely excludes a malignant diagnosis. Many "functioning nodules" are in fact pseudonodules in an otherwise diseased gland. Three to 4% of patients with Hashimoto's thyroiditis present such nodules, v-' Ten to 15% of patients with Hashimoto's thyroiditis will present with nonfunctioning "cold" nodules."-' These usually represent lymphoid follicles but may be follicular cysts. And since Hashimoto's thyroiditis is a relatively common disorder in childhood,"-' it is an importan t differential diagnostic consideration in a patient with a thyroid nodule or nodules. Embryonic defects in thyroid stiucture (thyroid dysgenesis) also are important i n the differential diagnosis, as Case 5 of Hopwood and colleagues emphasizes. The most difficult patients are those with discrete "cold" nodules in an otherwise normal thyroid gland. The likelihood of thyroid carcinoma in such a child Or adolescent approaches 40%.11 A serum calcitonin measurement by radioimmunoassay should be conducted to detect patients with medullary carcinoma. The incidence of medullary carcinoma among malignant tumors of the thyroid probably approximates 4%? ~ The clinical characteristics of follicular cell carcinoma (follicular-papillary) in three series totaling 114 patients are summarized in Table I. ~.... Cervical lymph node metastases were present in nearly two thirds of the patients. In the report of Tawes and DeLorimier ~" all of the 20 patients with lymph node enlargement were shown
to have metastases. In their series 62% of the patients eventually developed lymph node metastases. A history of radiation treatment to the head and neck area was obtained in 38% of the total patients. Local manifestations also were common. Lung metastases were present by chest roentgenograms in 18% of these patients. These and other studies have delineated several clinical criteria which are suggestive of thyroid carcinoma. Thus carcinoma is more likely if there is a history of prior radiation, if the nodule is hard, if adjacent lymph nodes are enlarged, if there is evidence of tracheal invasion or vocal cord paralysis, if growth of the mass has been rapid, or if there are distant metastases." In such patients surgery is indicated. If none of the malignancy criteria is present, thyroid suppression should be attempted with 0.2 to 0.3 mg of Na- 1-thyroxine daily. If over a period of four to six months the nodule grows, or if over a period of 12 months the nodule' does not reduce 50% in size, surgery is indicated. It is important to remember that follicular cell carcinoma in a young patient is a very indolent neoplasm and does not require urgent treatment, T M 1, 1~ Functional nodules usually do not produce clinical thyrotoxicosis; as noted by Dr. Hopwood and colleagues large nodules (in excess of 3 cm diameter) are more likely to do this. Autonomous nodules, however, will suppress normal thryoid tissue if they secrete significant amounts of hormone. Autonomy can be defined by stimulating the suppressed tissue (scan) by TSH or TRH or by showing nonsuppressibility of the functioning area. The latter is accomplished by scanning or by measuring radioiodine uptake after seven to ten days of 75 to 100 /~g of T3 (Cytomel) daily. Pseudonodules which are TSH dependent will show suppression (>50%) of function. Functioning nodules producing clinical and chemical thyrotoxicosis require treatment as pointed out by Drs. Hopwood and colleagues. Radioiodine treatment, now tends to be reserved for older patients (those over 40 years of age). 1~Antithyroid drug therapy is considered only for short-term management, lr Surgery is the most frequently employed therapeutic modality, and in the absence of
868
Editor's column
signs of malignancy simple enucteation can be carried out. If malignancy is a consideration "incisional biopsy or enucleation of the nodule is to be condemned. There is a danger of tumor dissemination as well as the possibility of providing the pathologist with an inadequate specimen. Complete lobectomy with removal of pericapsular lymph nodes and preservation of the recurrent laryngeal nerve is the most desirable procedure, ''~' The natural history of autonomously functioning nodules in patients with normal serum T4 and T3 concentrations has been discussed by Dr. H o p w o o d and coauthors. Most likely, such patients will remain euthyroid or the nodule will degenerate. ~-'-" Follow-up is desirable, however, because, rarely, thyrotoxicosis may develop?V.._,1 Delbert A. Fisher, M,D. Department of Pediatrics UCLA-Harbor General Hospital 1000 W. Carson St. Torrance, CA 90509 REFERENCES
l. 2.
3.
4,
5. 6.
Bauer FK: Scanning in thyroid cancer, in Medical radioisotope scanning, Vienna, 1959, LAEA, p 225. Beahrs OH, Pemberton JJ, and Black BM: Nodular goiter and malignant lesions of the thyroid gland, J Clin Endocrinol Metab 11:1157, 1951. Perlmutter M, Slater SL, and Attie J: Method for preoperative differentiation between benign and possibly malignant nontoxic thyroid nodules, J Clin Endocrinol Metab 14:672, 1954. Johnson PC, and Beierwaltes WH: Reliability ofscintiscanning modular gliters in ,judging presence or absence of carcinoma, J Clin Endocrinol Metab 15:865, 1955. Meadows PM: Scintillation scanning in the management of clinically autonomous nodules, JAMA 177:229, 1961. Sussman L, Librik L, and Clayton GW: Hyperthyroidism attributable to a hyperfunctioning thyroid carcinoma, J PEDIATR 72:208, 1968.
The Journal of Pediatrics November 1976
7. Molnar'GD, Child DS, and Woolner LB: Histologic evidence of malignancy &the thyroid gland bearing a "hot" nodule, J Clin Endocrinol Metab 181:1132, 1958. 8. Becker FO, Economou PG, and Schwartz TB: The occurrence of carcinoma in "hot" thyroid nodules, Ann Intern Med 58:877, 1963. 9. Meier DA, and Hamburger JI: An autonomously functioning thyroid nodule, cancer and prior radiation, Arch Surg 103:759, 1971. 10. Wallace S, Hill CS, Paulus DD Jr, lbanez ML, and Clark RL: The radiologic aspects of medullary (solid) thyroid carcinoma, Radiol Clin North Am 8:463, 1970. 11, Thomas CG Jr: Thyroid cancer: clinical aspects and treatment, in Werner SC, and Ingbar SH, editors: The thyroid, New York, 1971, Harper & Row, Publishers, pp 442-467. 12. Fisher DA, Oddie TH, Johnson DE, and Nelson JC: The diagnosis of Hashimoto's thyroiditis, J Clin Endocrinol Metab 40:795, 1975. 13. Weiler J, Lacour J, Gerard-Marchant R, Tubiana M, Parmentier C, Milhaud G, and Bock J: Les epithelimos medullaires a stroma amyloide du corps thyro~'de, Pathol Biol 17:995, 1969. 14. Crile G Jr: Carcinoma of the thyroid in children, Ann Surg 150:959, 1959. 15. Nishiyama RH, Schmidt RW, and Batsakis JG: Carcinorna of the thyroid gland in children and adolescents, JAMA 181:1034, 1962. 16. Tawes RL, and DeLorimier AA: Thyroid carcinoma during youth, J Pediatr Surg 3:210, 1968.. 17. Burman KD: Solitary autonomous thyroid nodules, Postgrad Med 56:70, 1974. 18. Silvcrstein GE, Burke EG, and Cogan R: The natural history of the autonomous hyperfunctioning thyroid nodule, Ann Intern Med 67:539, 1967. 19. Landgarten S, and Spencer RP: A study of the natural history of "hot" thyroid nodules, Yale J Biol Med 46:259, 1973, 20. Burman KD, Warkel RL, and Wartofsky L: Hyperfunctioning thyroid .nodules that become "cold," Med Ann DC 42:541, 1973. 21, Blum M, Shenkman L, and Hollander CS: The autonomous nodule of the thyroid: correlation of patient age, nodule size and functional status, Am J Med Sci 269:43, 1975.
