Seminars in Surgical Oncology 7:64-66 (1991)
Evaluation of Thyroid Nodules THOMAS R. DORSCH, M D From the University of Illinois College of Medicine at Peoria
The first consideration in evaluating the thyroid nodule is whether it is functioning and causing hyperthyroidism. Autonomous nodules should be treated with either surgery or 1-31, with surgery favored due to the possibility, although small, of malignancy. Thyroid scans are no longer recommended during the initial evaluation of the thyroid nodule. Ultrasound is useful in determining the size of the nodule and whether it is multinodular thyroid disease, but it cannot detect thyroid cancer. Fine needle aspiration biopsy is currently the procedure of choice for evaluating all thyroid nodules. For accuracy of the cytological analysis, it is important that adequate tissue samples be obtained. False negative findings are of most concern to the clinician and occur in 2-10% of reported fine needle aspiration biopsy series. Nodules thought to be benign will need continued follow-up. KEY WORDS:lymphocytic thyroiditis, etiology, metastatic cancer, hyperthyroidism, ultrasound, fine needle aspiration biopsy, hormonal suppression
Busy clinicians will encounter nodular thyroid disease every day. In subjects between 30 and 59 years of age, the Framingham study found thyroid nodules of 1 to 3 cm in 4% of the study population [ 11. Autopsy or sonographic studies demonstrate increasing nodularity with increasing age. Sixty percent of subjects over the age of 70 have thyroid nodules discovered by these techniques [2]. Although many glands are found to have multiple nodules or to harbor diffuse disease, it is usually one dominant nodule which prompts investigation. Efficient management of this problem has been debated in the past; however, consensus is now occurring on proper evaluation [ 2 4 . Most thyroid nodules are benign. In a review of 23 papers, reporting on 22,782 patients, Molitch et al. found that 89% of nodules removed surgically were benign [ 5 ] . In the United States, an estimated 11,300 new thyroid cancers will be discovered in 1989, and there will be about 1,025 deaths from thyroid cancer [6]. Death from thyroid cancer occurs primarily from aggressive anaplastic tumors; however, differentiated thyroid cancers-papillary and follicular-are fatal in 6% of patients [7]. For the patient with a thyroid nodule, the physician must decide on a cost-effective evaluation [8], do no harm with diagnostic procedures [9],and choose appropriate therapy for the thyroid disorder under study. 0 1991 Wiley-Liss, Inc.
The thyroid gland can be affected by a variety of pathologic conditions, and many of these can present as a nodular enlargement. Lymphocytic thyroiditis affects 2% of the population and can present as a dominant thyroid nodule. There is evidence that nodules arising in a Hashimoto’s gland are more likely to be malignant [lo]. Other forms of thyroiditis usually affect the gland diffusely, and a clinical diagnosis can often be made without tissue [ 111. The etiology of the various types of thyroiditis is unknown. Autoimmune attack is involved in lymphocytic thyroiditis. Follicular adenomas occur commonly in the thyroid, and their etiology is also unknown. Multinodular thyroid disease probably has a variety of causes. The work of Studer et al. suggests that there is a heterogeneity of thyroid cells and some may enlarge through a selective growth advantage [ 121. Cancer can metastasize to the thyroid and present as a thyroid nodule. The etiology of most primary thyroid cancers is unclear. Ionizing irradiation is known to induce thyroid malignancy [ 131, and familial forms of medullary and papillary cancer are recognized [ 141. The role of TSH in causing thyroid nodules is unclear. A damaged thyroid gland which cannot produce adequate amounts of T4 will Address reprint requests to Thomas R. Dorsch, M.D., 515 N.E. Glen
Oak,Suite 301, Peoria, IL 61603.
Evaluation of Thyroid Nodules
be stimulated by TSH and will diffusely enlarge. Other factors which stimulate thyroid growth have been found; these may be important in stimulating the production of a thyroid nodule. The clinician responsible for evaluating a thyroid nodule must first consider whether the nodule is functioning and causing hyperthyroidism. Autonomous nodules causing hyperthyroidism are usually over 3.0 cm in size. The hyperthyroidism can be due to T3 or T4, although T3-toxicosis is common. The course of the autonomous nodule has been well described by Hamburger [ 151. With newer assays of TSH, it may be possible to diagnose hyperthyroidism by finding a suppressed value of TSH. If sensitive TSH determinations are not available, serum T4 and T3 should be measured to evaluate possible hyperthyroidism. Treatment of an autonomous nodule will be with either surgery or 1-31. The chance of malignancy in such nodules, although small, may favor surgical treatment [ 161. If hyperthyroidism is not present by clinical evaluation and laboratory testing, the clinician will proceed with an anatomical evaluation of the gland. Traditionally, thyroid scans have been done to evaluate whether a nodule is functioning (hot), non-functioning (cold), or intermediate (warm). A thyroid scan can no longer be recommended during the initial evaluation of a thyroid nodule [3,17]. The characteristics of a nodule on thyroid scan do not accurately predict the histology of the nodule. Ashcraft and Van Herle carefully reviewed many published series of thyroid nodules and found that 16% of patients operated on for cold nodules were found to have thyroid cancer; however, 9% of warm nodules were malignant, as were 4% of hot nodules [17]. Malignant hot nodules have been clearly described by others [ 181. Ultrasound of the thyroid is often used to better demonstrate the anatomy of the gland. It is a safe and simple procedure, which will define thyroid size and can detect multinodular thyroid disease. Traditionally, sonography has been used to evaluate solid as opposed to cystic thyroid nodules, The assumption has been that thyroid cysts are benign. In fact, 7% of thyroid cysts are malignant [19] and cystic thyroid cancers are well defined [20]. The sonogram is an extremely accurate tool for following thyroid nodules [21], but it is not helpful in detecting thyroid cancer. Suppression of thyroid nodules by giving thyroid hormone (T3 or T4) has been used for many years. The theoretical basis of this practice is that the thyroid nodule depends on TSH to stimulate its growth, and if TSH is suppressed, the nodule will decrease in size. Thyroid cancers are known to be TSH-sensitive, and their growth can be inhibited by suppressing TSH [22]. Careful observation of thyroid nodules has suggested that ‘‘colloid’’ nodules do decrease in size [23]. Using thy-
65
roid hormone to suppress nodule growth may be useful in managing thyroid nodules [5]; it does not establish a diagnosis, and thyroid cancers have been observed to apparently decrease in size with thyroid hormone [ 171. In addition to TSH, there are other factors which can stimulate thyroid growth. Receptors for epidermal growth factor have been found in thyroid malignancies [24], and growth-promoting antibodies have been observed in autoimmune thyroid disease [25]. The effect of exogenous thyroid hormone on these factors is not known. Needle biopsy of the thyroid has been practiced for many years with various sizes and types of needles. Fine needle aspiration biopsy (FNAB) is currently the procedure of choice for evaluating all thyroid nodules. The technique involves aspirating thyroid cells with a 22- to 25-gauge needle and preparing a smear of the aspirate for cytologic evaluation [26]. Complications from the technique are minimal. Bleeding can occur but is usually not a major problem. Spread of cancer cells along the needle path has been a concern, but has not been reported in primary tumors of the thyroid using a fine needle technique [17]. Reporting of FNAB should first indicate whether the sample is adequate for interpretation. If there is an adequate sample, then the report will indicate benign, malignant, or suspicious. Some specific conditions can be diagnosed based on the cytologic findings. These include lymphocytic thyroiditis and papillary carcinoma. Differentiating follicular adenoma from follicular carcinoma is a difficult problem, and, therefore, all follicular neoplasms should be considered for open surgical biopsy. Sources of error in the FNAB procedure are of critical concern to the clinician. An inadequate sample is a common source of error. Inadequate tissue was reported in 16% of one series [27]. Because only small areas of a nodule will be biopsied, the needle may miss the malignant part of a nodule. Sampling errors are more cornmon in nodules larger than 4 cm. Finally, the cytologist may make a mistake in interpreting the findings. The incidence of incorrect diagnoses has been evaluated in a number of series. Of most concern to the clinician will be false negative results, which may cause thyroid cancer to go undetected. False negative results occur in 2-10% of reported FNAB series [4,17,28]. A thyroid nodule thought to be benign will need continued follow-up. Thyroid hormone can be used to suppress the nodule and the biopsy repeated [29]. Thyroid nodules will continue to be common problems. Newer techniques for diagnosing thyroid malignancies seem unlikely. Short of removing all thyroid nodules, the clinician will attempt to select patients with a high likelihood of cancer for thyroidectomy. Fine needle biopsy with or without thyroid hormone suppression and close observation of nodules offers the best method of evaluating thyroid nodules at present.
66
Dorsch
REFERENCES 1. Vander JB, Gaston EA, Dawber TR: The significance of nontoxic
thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 69537-540, 1968. 2. Griffin JE: Southwestern Internal Medicine Conference: Management of thyroid nodules. Am J Med Sci 296:336347, 1988. 3. Gharib H, Goellner JR: Evaluation of nodular thyroid disease. Endocrinol Metab Clin North Am 1751 1-526. 1988. 4. Mazzafem EL, De Los Santos ET. Rofagha-Keyhani S: Solitary thyroid nodule: Diagnosis and management. Med Clin North Am 72: I 177-121 I . 1988. 5. Molitch ME, Beck JR, Dreisman M, et al.: The cold thyroid nodule: An analysis of diagnostic and therapeutic options. Endocr Rev 5:185-199, 1984. 6. Silverberg E, Lubera JA: Cancer statistics. CA 39:3-20, 1989. 7. Ruegemer JJ, Hay ID, Berg Stralh W ,et al.: Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 67501-508. 1988. 8. Solomon DH: Cost-effective analysis of the evaluation of thyroid nodule. Ann Intern Med 96:227-231, 1982. 9. Foster RS: Morbidity and mortality after thyroidectomy . Surg Gynecol Obstet 146:423-429, 1978. 10. Ott RA, Calandra DB, McCall A, et al.: The incidence of thyroid carcinoma in patients with Hashimoto’s thyroiditis and solitary cold nodules. Surgery 98:1202-1206, 1985. 11 Hay ID: Thyroiditis: A clinical update. Mayo Clin Proc 60:836 843, 1985. 12. Studer H, Peter HS, Gerber H: Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth. Endocr Rev 10:125-135, 1989. 13 Schneider AB, Shore-Freedman E, Ryo UY. et al.: Radiation induced tumors of the head and neck following childhood irradiation. Medicine (Baltimore) 64:l-15, 1985. 14 Stoffer SS. VanDyke DL, Vaden Bach J , et al.: Familial papillary carcinoma of the thyroid. Am J Med Genet 25:775-782, 1986. 15 Hamburger JI: Evaluation of toxicity in solitary nontoxic autonomously functioning thyroid nodules. J Clin Endocrinol Metab 50: 1089-1093, 1980. 16. Smith M, McHenry C, Jarosz H, et al.: Carcinoma of the thyroid
in patients with autonomous nodules. Am Surg 5 4 : 4 4 8 4 9 , 1988. 17. Ashcraft MW, Van Herle AJ: Management of thyroid nodules 11: Scanning techniques, thyroid suppressive therapy, and fine needle aspiration. Head Neck Surg 3:297-322, 1981. 18. Sandler MP, Fellmeth B, Salhany KE, et al.: Thyroid carcinoma masquerading as a solitary benign hyperfunctioning nodule. Clin Nucl Med 13:41@415, 1988. 19. Ashcraft MW, Van Herle AJ: Management of thyroid nodules. I: History and physical examination, blood tests, x-ray tests and ultrasonography. Head Neck Surg 3:216-230, 1981. 20. Rosen IB, Provias SP, Walfish PG: Pathologic nature of cystic thyroid nodules selected for surgery by needle aspiration biopsy. Surgery 100:606413, 1986. 21. Gharib H, James EM, Charboneau JW, et al.: Suppressive therapy with levothyroxine for solitary thyroid nodules. A doubleblind controlled clinical study. N Engl J Med 317:70-75, 1987. 22. Clark OH: TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 5:3%47, 1981. 23. Morita T, Tamai H, Ohshima A, et al.: Changes in serum thyroid hormone, thyrotropin and thyroglobulin concentrations during thyroxine therapy in patients with solitary thyroid nodules. J Clin Endocrinol Metab 69:227-230, 1989. 24. Masuda H, Sugenoya A, Kobayashi S , et al.: Epidermal growth factor receptor on human thyroid neoplasms. World J Surg 12:616-622, 1988. 25. Valente WA, Vitti P, Rotella CM, et al.: Antibodies that promote thyroid growth. A distinct population of thyroid-stimulating autoantibodies. N Engl J Med 309:1028-1034, 1983. 26. L Jung B: Fine-needle aspiration of the thyroid nodule. Ann Intern Med 96:223-226, 1982. 27. Hall TL. Layfield LJ, Philippe A. et al.: Sources of diagnostic error in fine needle aspiration of the thyroid. Cancer 63:718-725, 1989. 28. Boey J. Hsu C, Collins RJ: False-negative errors in fine-needle aspiration biopsy of dominant thyroid nodules: A prospective follow-up study. World J Surg 10:623-630, 1986. 29. Hamburger 11: Consistency of sequential needle biopsy findings for thvroid nodules. Management imolications. Arch Intern Med .. 1479-99, 1987.
Evaluation of Thyroid Nodules THOMAS R. DORSCH, M D From the University of Illinois College of Medicine at Peoria
The first consideration in evaluating the thyroid nodule is whether it is functioning and causing hyperthyroidism. Autonomous nodules should be treated with either surgery or 1-31, with surgery favored due to the possibility, although small, of malignancy. Thyroid scans are no longer recommended during the initial evaluation of the thyroid nodule. Ultrasound is useful in determining the size of the nodule and whether it is multinodular thyroid disease, but it cannot detect thyroid cancer. Fine needle aspiration biopsy is currently the procedure of choice for evaluating all thyroid nodules. For accuracy of the cytological analysis, it is important that adequate tissue samples be obtained. False negative findings are of most concern to the clinician and occur in 2-10% of reported fine needle aspiration biopsy series. Nodules thought to be benign will need continued follow-up. KEY WORDS:lymphocytic thyroiditis, etiology, metastatic cancer, hyperthyroidism, ultrasound, fine needle aspiration biopsy, hormonal suppression
Busy clinicians will encounter nodular thyroid disease every day. In subjects between 30 and 59 years of age, the Framingham study found thyroid nodules of 1 to 3 cm in 4% of the study population [ 11. Autopsy or sonographic studies demonstrate increasing nodularity with increasing age. Sixty percent of subjects over the age of 70 have thyroid nodules discovered by these techniques [2]. Although many glands are found to have multiple nodules or to harbor diffuse disease, it is usually one dominant nodule which prompts investigation. Efficient management of this problem has been debated in the past; however, consensus is now occurring on proper evaluation [ 2 4 . Most thyroid nodules are benign. In a review of 23 papers, reporting on 22,782 patients, Molitch et al. found that 89% of nodules removed surgically were benign [ 5 ] . In the United States, an estimated 11,300 new thyroid cancers will be discovered in 1989, and there will be about 1,025 deaths from thyroid cancer [6]. Death from thyroid cancer occurs primarily from aggressive anaplastic tumors; however, differentiated thyroid cancers-papillary and follicular-are fatal in 6% of patients [7]. For the patient with a thyroid nodule, the physician must decide on a cost-effective evaluation [8], do no harm with diagnostic procedures [9],and choose appropriate therapy for the thyroid disorder under study. 0 1991 Wiley-Liss, Inc.
The thyroid gland can be affected by a variety of pathologic conditions, and many of these can present as a nodular enlargement. Lymphocytic thyroiditis affects 2% of the population and can present as a dominant thyroid nodule. There is evidence that nodules arising in a Hashimoto’s gland are more likely to be malignant [lo]. Other forms of thyroiditis usually affect the gland diffusely, and a clinical diagnosis can often be made without tissue [ 111. The etiology of the various types of thyroiditis is unknown. Autoimmune attack is involved in lymphocytic thyroiditis. Follicular adenomas occur commonly in the thyroid, and their etiology is also unknown. Multinodular thyroid disease probably has a variety of causes. The work of Studer et al. suggests that there is a heterogeneity of thyroid cells and some may enlarge through a selective growth advantage [ 121. Cancer can metastasize to the thyroid and present as a thyroid nodule. The etiology of most primary thyroid cancers is unclear. Ionizing irradiation is known to induce thyroid malignancy [ 131, and familial forms of medullary and papillary cancer are recognized [ 141. The role of TSH in causing thyroid nodules is unclear. A damaged thyroid gland which cannot produce adequate amounts of T4 will Address reprint requests to Thomas R. Dorsch, M.D., 515 N.E. Glen
Oak,Suite 301, Peoria, IL 61603.
Evaluation of Thyroid Nodules
be stimulated by TSH and will diffusely enlarge. Other factors which stimulate thyroid growth have been found; these may be important in stimulating the production of a thyroid nodule. The clinician responsible for evaluating a thyroid nodule must first consider whether the nodule is functioning and causing hyperthyroidism. Autonomous nodules causing hyperthyroidism are usually over 3.0 cm in size. The hyperthyroidism can be due to T3 or T4, although T3-toxicosis is common. The course of the autonomous nodule has been well described by Hamburger [ 151. With newer assays of TSH, it may be possible to diagnose hyperthyroidism by finding a suppressed value of TSH. If sensitive TSH determinations are not available, serum T4 and T3 should be measured to evaluate possible hyperthyroidism. Treatment of an autonomous nodule will be with either surgery or 1-31. The chance of malignancy in such nodules, although small, may favor surgical treatment [ 161. If hyperthyroidism is not present by clinical evaluation and laboratory testing, the clinician will proceed with an anatomical evaluation of the gland. Traditionally, thyroid scans have been done to evaluate whether a nodule is functioning (hot), non-functioning (cold), or intermediate (warm). A thyroid scan can no longer be recommended during the initial evaluation of a thyroid nodule [3,17]. The characteristics of a nodule on thyroid scan do not accurately predict the histology of the nodule. Ashcraft and Van Herle carefully reviewed many published series of thyroid nodules and found that 16% of patients operated on for cold nodules were found to have thyroid cancer; however, 9% of warm nodules were malignant, as were 4% of hot nodules [17]. Malignant hot nodules have been clearly described by others [ 181. Ultrasound of the thyroid is often used to better demonstrate the anatomy of the gland. It is a safe and simple procedure, which will define thyroid size and can detect multinodular thyroid disease. Traditionally, sonography has been used to evaluate solid as opposed to cystic thyroid nodules, The assumption has been that thyroid cysts are benign. In fact, 7% of thyroid cysts are malignant [19] and cystic thyroid cancers are well defined [20]. The sonogram is an extremely accurate tool for following thyroid nodules [21], but it is not helpful in detecting thyroid cancer. Suppression of thyroid nodules by giving thyroid hormone (T3 or T4) has been used for many years. The theoretical basis of this practice is that the thyroid nodule depends on TSH to stimulate its growth, and if TSH is suppressed, the nodule will decrease in size. Thyroid cancers are known to be TSH-sensitive, and their growth can be inhibited by suppressing TSH [22]. Careful observation of thyroid nodules has suggested that ‘‘colloid’’ nodules do decrease in size [23]. Using thy-
65
roid hormone to suppress nodule growth may be useful in managing thyroid nodules [5]; it does not establish a diagnosis, and thyroid cancers have been observed to apparently decrease in size with thyroid hormone [ 171. In addition to TSH, there are other factors which can stimulate thyroid growth. Receptors for epidermal growth factor have been found in thyroid malignancies [24], and growth-promoting antibodies have been observed in autoimmune thyroid disease [25]. The effect of exogenous thyroid hormone on these factors is not known. Needle biopsy of the thyroid has been practiced for many years with various sizes and types of needles. Fine needle aspiration biopsy (FNAB) is currently the procedure of choice for evaluating all thyroid nodules. The technique involves aspirating thyroid cells with a 22- to 25-gauge needle and preparing a smear of the aspirate for cytologic evaluation [26]. Complications from the technique are minimal. Bleeding can occur but is usually not a major problem. Spread of cancer cells along the needle path has been a concern, but has not been reported in primary tumors of the thyroid using a fine needle technique [17]. Reporting of FNAB should first indicate whether the sample is adequate for interpretation. If there is an adequate sample, then the report will indicate benign, malignant, or suspicious. Some specific conditions can be diagnosed based on the cytologic findings. These include lymphocytic thyroiditis and papillary carcinoma. Differentiating follicular adenoma from follicular carcinoma is a difficult problem, and, therefore, all follicular neoplasms should be considered for open surgical biopsy. Sources of error in the FNAB procedure are of critical concern to the clinician. An inadequate sample is a common source of error. Inadequate tissue was reported in 16% of one series [27]. Because only small areas of a nodule will be biopsied, the needle may miss the malignant part of a nodule. Sampling errors are more cornmon in nodules larger than 4 cm. Finally, the cytologist may make a mistake in interpreting the findings. The incidence of incorrect diagnoses has been evaluated in a number of series. Of most concern to the clinician will be false negative results, which may cause thyroid cancer to go undetected. False negative results occur in 2-10% of reported FNAB series [4,17,28]. A thyroid nodule thought to be benign will need continued follow-up. Thyroid hormone can be used to suppress the nodule and the biopsy repeated [29]. Thyroid nodules will continue to be common problems. Newer techniques for diagnosing thyroid malignancies seem unlikely. Short of removing all thyroid nodules, the clinician will attempt to select patients with a high likelihood of cancer for thyroidectomy. Fine needle biopsy with or without thyroid hormone suppression and close observation of nodules offers the best method of evaluating thyroid nodules at present.
66
Dorsch
REFERENCES 1. Vander JB, Gaston EA, Dawber TR: The significance of nontoxic
thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 69537-540, 1968. 2. Griffin JE: Southwestern Internal Medicine Conference: Management of thyroid nodules. Am J Med Sci 296:336347, 1988. 3. Gharib H, Goellner JR: Evaluation of nodular thyroid disease. Endocrinol Metab Clin North Am 1751 1-526. 1988. 4. Mazzafem EL, De Los Santos ET. Rofagha-Keyhani S: Solitary thyroid nodule: Diagnosis and management. Med Clin North Am 72: I 177-121 I . 1988. 5. Molitch ME, Beck JR, Dreisman M, et al.: The cold thyroid nodule: An analysis of diagnostic and therapeutic options. Endocr Rev 5:185-199, 1984. 6. Silverberg E, Lubera JA: Cancer statistics. CA 39:3-20, 1989. 7. Ruegemer JJ, Hay ID, Berg Stralh W ,et al.: Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 67501-508. 1988. 8. Solomon DH: Cost-effective analysis of the evaluation of thyroid nodule. Ann Intern Med 96:227-231, 1982. 9. Foster RS: Morbidity and mortality after thyroidectomy . Surg Gynecol Obstet 146:423-429, 1978. 10. Ott RA, Calandra DB, McCall A, et al.: The incidence of thyroid carcinoma in patients with Hashimoto’s thyroiditis and solitary cold nodules. Surgery 98:1202-1206, 1985. 11 Hay ID: Thyroiditis: A clinical update. Mayo Clin Proc 60:836 843, 1985. 12. Studer H, Peter HS, Gerber H: Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth. Endocr Rev 10:125-135, 1989. 13 Schneider AB, Shore-Freedman E, Ryo UY. et al.: Radiation induced tumors of the head and neck following childhood irradiation. Medicine (Baltimore) 64:l-15, 1985. 14 Stoffer SS. VanDyke DL, Vaden Bach J , et al.: Familial papillary carcinoma of the thyroid. Am J Med Genet 25:775-782, 1986. 15 Hamburger JI: Evaluation of toxicity in solitary nontoxic autonomously functioning thyroid nodules. J Clin Endocrinol Metab 50: 1089-1093, 1980. 16. Smith M, McHenry C, Jarosz H, et al.: Carcinoma of the thyroid
in patients with autonomous nodules. Am Surg 5 4 : 4 4 8 4 9 , 1988. 17. Ashcraft MW, Van Herle AJ: Management of thyroid nodules 11: Scanning techniques, thyroid suppressive therapy, and fine needle aspiration. Head Neck Surg 3:297-322, 1981. 18. Sandler MP, Fellmeth B, Salhany KE, et al.: Thyroid carcinoma masquerading as a solitary benign hyperfunctioning nodule. Clin Nucl Med 13:41@415, 1988. 19. Ashcraft MW, Van Herle AJ: Management of thyroid nodules. I: History and physical examination, blood tests, x-ray tests and ultrasonography. Head Neck Surg 3:216-230, 1981. 20. Rosen IB, Provias SP, Walfish PG: Pathologic nature of cystic thyroid nodules selected for surgery by needle aspiration biopsy. Surgery 100:606413, 1986. 21. Gharib H, James EM, Charboneau JW, et al.: Suppressive therapy with levothyroxine for solitary thyroid nodules. A doubleblind controlled clinical study. N Engl J Med 317:70-75, 1987. 22. Clark OH: TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 5:3%47, 1981. 23. Morita T, Tamai H, Ohshima A, et al.: Changes in serum thyroid hormone, thyrotropin and thyroglobulin concentrations during thyroxine therapy in patients with solitary thyroid nodules. J Clin Endocrinol Metab 69:227-230, 1989. 24. Masuda H, Sugenoya A, Kobayashi S , et al.: Epidermal growth factor receptor on human thyroid neoplasms. World J Surg 12:616-622, 1988. 25. Valente WA, Vitti P, Rotella CM, et al.: Antibodies that promote thyroid growth. A distinct population of thyroid-stimulating autoantibodies. N Engl J Med 309:1028-1034, 1983. 26. L Jung B: Fine-needle aspiration of the thyroid nodule. Ann Intern Med 96:223-226, 1982. 27. Hall TL. Layfield LJ, Philippe A. et al.: Sources of diagnostic error in fine needle aspiration of the thyroid. Cancer 63:718-725, 1989. 28. Boey J. Hsu C, Collins RJ: False-negative errors in fine-needle aspiration biopsy of dominant thyroid nodules: A prospective follow-up study. World J Surg 10:623-630, 1986. 29. Hamburger 11: Consistency of sequential needle biopsy findings for thvroid nodules. Management imolications. Arch Intern Med .. 1479-99, 1987.
