Management of Thyroid Nodules in the Elderly Orlo H. Clark, MD, San Francisco, California Robert Demling, MD, San Francisco, California
The appropriate treatment of thyroid nodules in elderly patients is controversial, concern having been expressed that the operative mortality or morbidity may be especially high in this group. To investigate this issue the present study was designed to answer three questions regarding thyroid nodules in patients more than sixty years old: what parameters are useful in selecting patients for operation; what is the incidence and what types of thyroid malignancy occur in the elderly; and what is the morbidity and mortality of thyroid operations in these patients? Clinical Materlal The records were analyzed of 100 consecutive patients more than sixty years old, who had operations for thyroid nodules at the University of California Medical Center, San Francisco, from 1967 to 1973. Based on preoperative findings, two discrete groups could be identified with different probabilities of having thyroid cancer identified. Patients in the high risk group had one or more of the following characteristics: a discrete nonfunctional “cold” thyroid nodule by radioiodine scan, hoarseness, dysphagia, an enlarging thyroid mass, or palpable ipsilateral cervical adenopathy. Patients in the low risk group had multinodular glands, diffusely enlarged glands, high antibody titers, or a family history of benign goiter. Using these criteria, sixty-six patients were placed in the high risk group and thirty-four in the low risk group. Eleven of the sixty-six high risk patients (17 per cent) had malignant thyroid tumors, six of which were poorly differentiated histologically. Fifty-five patients had cold thyroid nodules by radioiodine scan, twenty-one patients had hoarseness or dysphagia, three patients had enlarging thyroid lesions, and one patient had palpable nodes adjacent to the thyroid nodule. As shown in Table I, all eleven patients, or 20 per cent of those with cold thyroid nodules, had malignant thyroid tumors; two patients were hoarse; three patients (all of whom had poorly differentiated malignant neoplasms) noted recent thyroid enlargement; and one patient had palpable ipsilateral cervical adenopathy. In three of the six patients with poorly differentiated thyroid neo-
From the Surgical Service, Veterans Administration Hospital, and Department of Surgery, University of California Hospital, San Francisco, California. Reprint requests should be addressed to Orlo H. Clark, MD, Department of Surgery (112). Veterans Administration Hospital, 4150 Clement Street, San Francisco. California 94121.
Volume 132, November 1979
plasms a thyroid nodule had been present for fifteen, twenty, and forty years before ope.ration. The technic and extent of the 100 operations varied, since the procedures were performed by numerous surgeons including resident house staff. Of the eleven patiehts with malignant thyroid neoplasms, three were treated by total lobectomy and isthmusectomy, four by near total thyroidectomy leaving a small remnant of posterior capsule on the side opposite the gross tumor, and four by total thyroidectomy. Modified radical neck dissection was performed in two patients. Ten of the eleven patients with thyroid malignancy received an ablative dose of radioiodine after operation. The histologic findings are presented in Table II. The most common gross and histologic finding in both groups was multinodular goiter. In fact, except for the malignant tumors in the high risk group, the spectrum of other pathologic entities was similar in both groups. There were no postoperative deaths and the only significant complication was injury to the right recurrent laryngeal nerve in a patient with thyroid carcinoma involving the right lobe. The mean period of hospitalization was five days (range, 4 to 8 days). Four of the five patients with differentiated thyroid cancers are alive and free of disease two to four years after operation. The fifth patient died of atherosclerotic cardiovascular disease one year after operation, (Table III.) All of these patients were given full replacement doses of L-sodium thyroxine (0.2 to 0.4 mg per day). Patients with poorly differentiated neoplasms were also treated with suppressive doses of L-sodium thyroxine and in addition received from 3,000 to 6,500 of x-ray therapy to the thyroid over a three to seven vveek period. Two of these patients also received chemotherapy and one received testosterone. As shown in Table IV, three of the six patients with poorly differentiated thyroid neoplasms lived at least three years after operation and one patient was apparently free of disease. In one patient with Hurthle and squamous cell carcinoma the disease progressed rapidly, unaffected by treatment. In two patients the response to treatment is unknown. The low risk group, which contained no patient with cancer, was characterized by the absence of the criteria found in the high risk group. Fifteen patients had multinodular glands, four patients had diffuse induration of the thyroid or high titers of thyroid antibodies suggestive of Hashimoto’s thyroiditis, and three patients had a family history of goiter. None of these patients had dysphagia, recent hoarseness, or enlargement of the nodule, and none had been exposed to external radiation.
615
Clark and Demling
TABLE I Clinical Manifestations in 66 High Risk Patients and 11 Patients with Thyroid Malignancy High Risk Thyroid
Discrete cold nodule Hoarseness or dysphagia Recent enlargement Palpable cervical
No. of Patients
Percentage with Clinical Findings
of Pa-
Percentage with Clinical
tients
Findings
55 21 3 1
83 32 5 1
11 2 3 1
20 10 100 100
Nlalignancy
No.
TABLE II
Histologic Diagnosis in High and Low Risk Patients
No. of High Risk Patients
No. of Low Risk Patients
Benign Nodular goiter Adenoma Thyroiditis Involutionary nodule
21 15 9 6 4
cyst Malignant Differentiated Undifferentiated Total
(32%) (23%) (13%) (9%) (6%)
5 (8%) 6 (9%) 66 (100%)
15 (44%) 10 4 3 2
(29%) (12%) (9%) (6%)
0 0 34 (100%)
adenopathy
was
Comments
Choosing appropriate treatment for elderly patients with nontoxic nodular goiter may be difficult because an accurate diagnosis of the histology of the nodule cannot be made on clinical findings alone. Separation of these patients into those at high risk and those with negligible risk for cancer should eliminate some unnecessary diagnostic operations and increase the yield of the remainder. Shimaoka et al [I] found that skilled physicians could fairly accurately estimate the risk of thyroid cancer in nontoxic goiter. They found that only 2 per cent of 202 patients classified as “benign” on clinical evaluation proved to have thyroid cancer, whereas 28 per cent of those classified as “suspected of cancer” and 53 per cent of those classified as “probable cancer” had malignant goiters. In their patients malignancy
suspected if the nodules grew progressively, caused compression of neighboring structures, and were hard and fixed or if ipsilateral cervical nodes or vocal cord paralysis were present. Conversely, patients with benign lesions had asymptomatic nodules, unchanged in size for years. Some benign nodules enlarged rapidly. Greenspan [Z] found a 30 per cent incidence of thyroid cancer if any one or more of the following were present: irradiation to the neck, recent growth of the thyroid nodule, a large (more than 2 cm) firm solitary nodule clearly different from the rest of the gland, vocal cord paralysis, hoarseness, palpable regional lymph nodes, distant metastatic lesions, or failure to regress after full replacement doses of TABLE
IV
6 Patients with Poorly Differentiated Thyroid Neoplasms
Histology TABLE III
5 Patients with Differentiated Thyroid Carcinoma
Histology
Duration
of Nodule
Follow-up Alive, free of disease 3 yr postoperatively Alive, free of disease 2 yr postoperatively Dead of atherosclerotic cardiovascular disease 1 yr postoperatively
Papillary
1 mo
Papillary-follicular
Unknown
Papillary-follicular
6 wk
Papillary-follicular
Less than 1 yr
Alive, free of disease 4 yr postoperatively
Follicular
10 yr
Alive, free of disease 3 yr postoperatively
616
Duration of Nodule
Follow-Up
Poorly differentiated papillary carcinoma with squamous metaplasia Poorly differentiated carcinoma
40 yr (recent growth)
Unknown
Unknown
Anaplastic
Unknown
Died of carcinoma of thyroid 3 yr after operation Alive and free of disease 3 yr after operation Severe pain and inability to swallow 4 mo after operation Died 6 yr after operation of atherosclerotic cardiovascular disease Unknown
small cell
Hiirthle and squamous cell carcinoma
20 yr (recent growth
Reticulum cell sarcoma of thyroid
15 yr (recent growth
Poorly differentiated carcinoma
3 wk
The American Journal of Surgery
Thyroid Nodules in Elderly
thyroxine. Patients with a family history of goiter suggesting Hashimoto’s thyroiditis or dyshormonogenesis, patients with soft nodules or a multinodular goiter or a hot nodule on radioiodine scan, patients with significant regression of the nodule while receiving thyroxine therapy, and patients with high antithyroid antibody titers most often had benign thyroid neoplasms. Marchetta and Sako [3] reviewed thyroid lesions in patients sixty years of age and older and concluded that thyroid nodules in the elderly should be viewed with the same suspicion as thyroid nodules in younger individuals. In their patients, as in ours, half the malignant thyroid tumors were histologically anaplastic carcinoma. Our finding of a 17 per cent incidence of cancer in high risk patients and no cancer in the low risk patients indicates that separating elderly patients into these two groups would be valuable in determining who will benefit from operation. Thus, since elderly patients with soft nodules, high antibody titers, and asymptomatic multinodular goiter that have not changed in size almost certainly have benign lesions, observation rather than operation is indicated. It is of interest that dysphagia and hoarseness were such poor indicators of malignancy in this series. Only two (10 per cent) of twenty-one patients with hoarseness or dysphagia had malignant thyroid tumors. In fact, the accuracy in diagnosing thyroid malignancy was higher if the presence of cold nodules alone was used as the discriminator of malignancy (20 per cent) rather than including dysphagia and hoarseness as well (17 per cent). A possible explanation is that dysphagia or hoarseness unrelated to thyroid disease brought the patient’s or physician’s attention to the thyroid nodule. General experience has shown that dysphagia and hoarseness are usually more reliable in predicting thyroid malignancy than our figures would suggest, especially if there is an associated vocal cord palsy. In some patients the principal indication for operation may be relief of dysphagia (by removing the isthmus of the gland). Most clinicians would agree that if a thyroid nodule is enlarging, if it is associated with adjacent adenopathy or vocal cord paralysis, or if the patient has previously had x-ray treatment to the head and neck, operation is unequivocally indicated. A more difficult decision is what to recommend for the patient with a solitary nontender, smooth, firm, and mobile nodule. Such a lesion is usually benign, but it might be follicular or papillary carcinoma. The first step in such a patient should be to obtain a radioiodine scan. If the nodule is functional, or a “hot” nodule, it is rarely malignant, whereas 5 to 20 per cent of patients
Volume132, November 1976
with “cold” nodules harbor malignant tumors [z], as did 20 per cent of patients with cold nodules in our series. Malignant thyroid tumors rarely take up iodine because of a defect in iodide trapping [4,5]. When a cold nodule is discovered, thyroid echography will differentiate solid from cystic lesions [6]. Cysts less than 4 cm in diameter can be successfully treated by aspiration since they are rarely malignant [7]. Four (6 per cent) of the patients with cold solitary thyroid nodules in this series, could have been successfully treated by aspiration rather than operation. At present, other scanning agents such as technetium 99m, selenomethionine 75, cesium 131, gallium 67, and indium 111 bleomycin are being investigated, but as yet they are of little clinical value in differentiating benign from malignant lesion. In young adults with asymptomatic thyroid nodules, suppression of the nodule with full replacement doses of thyroxine may be tried as long as the patient is closely followed. The nodule should be considered benign only if it totally disappears, since both normal thyroid tissue and thyroid tumors may regress to some extent after suppression of thyrotropin (TSH) by exogenous thyroxine [8,9]. However, in the elderly, suppressive therapy is usually not recommended because of possible cardiovascular complications. Older patients are known to have a higher incidence of multinodular goiter than the young, but the incidence of malignant thyroid neoplasms is similar [IO]. Many patients who clinically are thought to have solitary nodules are found to have multinodular goiter at operation [II]. The higher incidence of multinodular goiter in patients more than sixty years old probably accounts for the lower incidence of cancer found at operation in the elderly. In this series, the 20 per cent incidence of thyroid malignancy in cold solitary thyroid nodules is only slightly lower than the 26 per cent incidence of thyroid malignancy found in cold solitary thyroid nodules in patients less than sixty years old treated at the University of California, Medical Center, San Francisco, during the same period as the present study [12]. A higher diagnostic yield could be obtained in the high risk group by using more restrictive criteria. The four patients with thyroid cysts could now be diagnosed by ultrasound and successfully treated by aspiration. Some of the nine patients with thyroiditis could probably also be eliminated from the high risk group, because of the more diffuse involvement of the gland and high antithyroid antibodies. It must be emphasized, however, that the presence of thyroiditis does not exclude the possibility of thyroid cancer so if other features of the high risk category are present, operation should not be delayed.
617
Clark and Demling
If one waited for more obvious disease, such as progressively enlarging or fixed painful lesions, hoarseness due to infiltration of the recurrent laryngeal nerve, the development of cervical lymph nodes, or distant metastasis, diagnostic accuracy could approach 100 per cent, but of course these are features of more advanced, incurable cancer and such a policy would sacrifice curability for the sake of diagnosis. None of our patients had had previous radiotherapy to the neck, but this markedly increases the possibility that a goiter contains cancer. For example, Winship and Rosvoll [13] found that 80 per cent of children less than fifteen years old who had carcinoma of the thyroid gland had received x-ray therapy to the thymus, tonsils, skin, or cervical lymph nodes. Frohman et al [14] reported that 36 per cent of patients with thyroid nodules who received x-ray therapy as children had thyroid cancer. Current estimates are that thyroid neoplasms will develop in between 4 and 7 per cent of all patients who have received x-ray treatment to the head and neck during childhood [15,16]. It is worrisome that the incidence of malignancy seems to increase for at least the first three decades after radiation exposure [17]. Eventually, a history of radiation exposure will be present in some patients more than sixty years old with thyroid nodules and should be regarded as an absolute indication for surgery. With further refinements, diagnostic technics such as ultrasound [18,19], thermography [20], xerography [21], fluorescent scanning [22], calcitonin [23], and thyroglobulin radioimmunoassays [24] will probably’ be of help in determining whether a thyroid nodule is malignant. Percutaneous needle biopsy has been found to be too unrepresentative of the pathology to be reliable [25]. Undifferentiated cancers are more common in the elderly and have a very poor prognosis [26]. Sloan [27] in 1954 was the first to suggest that the aggressiveness of thyroid cancer depends on the patient’s age at the time of diagnosis, a supposition that has been confirmed by McDermott et al [28], Woolner et al [29], and Halnan [30]. This is reflected by an especially high mortality rate in patients more than sixty years old [31] even when patients with undifferentiated thyroid tumors are excluded. The reason for the increased mortality in this group is not known, although some evidence suggests that thyroid tumors are less sensitive to thyrotropin in the elderly [32]. Altered hormonal balance and immunologic resistance may also be important factors. Winship and Rosvoll[33] in 1961 reported that the mortality from thyroid cancer in children less than seven years old
616
was 61.4 per cent, whereas it was 12.8 per cent for children from seven to fifteen years old. Nathanson et al [34] in 1941 had previously documented a slight but significant increase in urinary estrogen and 17-ketosteroids between ages seven and eight years in healthy children, supporting the thesis that an indolent growth pattern for thyroid cancer is associated with adequate levels of sex steroids. Pincus et al [35] observed decreased urinary estrogens in women and decreased urinary estradiol and estrone in men with advancing age. Alteration of immune mechanisms with aging may also underlie age-related variations in behavior of thyroid cancer. Ram [36] ‘noted that the increased mortality due to thyroid cancer in early childhood and with senescence corresponds with a decreased natural immunity at these times. These factors may account for the more aggressive behavior of differentiated thyroid carcinomas in the elderly and for the greater frequency of undifferentiated thyroid tumors in this group. Three of the six patients with undifferentiated thyroid tumors had a history of preexisting goiter for at least fifteen years. Spindle and giant cell thyroid cancer, probably the most malignant tumor in humans, has been shown to arise from preexisting papillary and follicular carcinoma [37]. Small foci of undifferentiated tumors are not infrequently observed within papillary, mixed, and follicular thyroid cancers and a focus of differentiated thyroid tumor is often found in undifferentiated thyroid neoplasms [38]. An ominous outlook can be predicted when a goiter that has been stationary for years begins to increase in size, causing discomfort and a sense of constriction. If poorly differentiated and undifferentiated thyroid tumors arise from preexisting differentiated thyroid cancers, then one important step towards preventing undifferentiated thyroid cancer would be to remove existing thyroid nodules that contain differentiated thyroid carcinoma. Summary
Eleven malignant thyroid tumors were found in 100 consecutive patients more than sixty years old having thyroid operations. Based on preoperative findings, these 100 patients could be separated into two groups according to high and low risk for malignancy. Clinical manifestations in the high risk group were presence of a discrete cold thyroid nodule, hoarseness, dysphagia, an enlarging mass, or palpable ipsilateral cervical adenopathy; and in the low risk group, asymptomatic multinodular goiter, diffusely enlarged glands with elevated antithyroid antibody
The American Journal 01 SW&IW
Thyroid
titers, and a family history of goiter. All eleven patients with malignant thyroid tumors were found in the sixty-six patients considered at high risk, whereas no malignant lesions were found in the low risk patients. Six of the malignant thyroid tumors were undifferentiated and in three of these a thyroid nodule had been present for more than fifteen years. There were no operative deaths and only one significant complication, a recurrent laryngeal nerve injury. Thyroidectomy is indicated for elderly patients with thyroid nodules who have features of the high risk group, whereas patients in the low risk group can be safely followed. Acknowledgment: We are greatly indebted to our colleagues in endocrinology, nuclear medicine, and surgery. Many of the patients were cared for by Doctors Francis S. Greenspan, Ralph R. Cavalieri, Malcolm Powell, Andrea Blum, Leon Goldman, J. Englebert Dunphy, Maurice Galante, and Thomas Hunt. We would also like to thank Doctor Lawrence W. Way for his helpful suggestions and James Gorring for his excellent clerical assistance. References 1. Shimaoka K, Badillo J, Sokal JE. Marchetta FC: Clinical differentiation between thyroid cancer and benign goiter. JAMA 181: 179, 1962. 2. &senspan FS: Thyroid ncdufes and thyroki cancer. West J h4sd 121: 359.1974. 3. Marchetta FC. Sako K: The enlarged thyroid in the elderly patient. Geriatrics 23: 181. 1968. 4. DeGroot LJ: Lack of iodide trapping in “cold” nodules. Acta Endocrinol Panam 1: 27. 1970. 5. Field JB, Larsen PR. Yamashita K, Mashiter K, Dekker A: Demonstration of iodide transport defect but normal iodide organification in non-functioning nodules of human thyroid glands. J C/in invest 51: 1109. 1972. 6. Clark DH. Greenspan FS, Ccggs GC. Goldman L: Evaluation of solitary cold thyroid nodules by echography and thermography. Am J Surg 130: 206, 1975. 7. Blum A, Goldman AB. Herskovic A, Hernberg J: Clinical ap plications of thyroid echography. N Engl J Med 287: 1184, 1972. 8. Astwood CB, Casskfy CE. Aubach GD Treaant of goiter and thyroid nodules with thyroid. JAMA 174: 459, 1980. 9. Crile G Jr: Endocrine dependency of papillary carcinomas of the thyroid. JAMA 195: 721, 1966. 10. Taylor S: Carcinoma of the thyroid gland. JR Co// Surg Edinb 14: 183, 1969. 11. Beales JSM, Nundy S. Taylor S: Thyroid lymphography. Br J Surg58: 168. 1971. 12. Clark OH, Goldman L: Thyroid and parathyroid disease, p 254. Current Surgical Diagnosis and Treatment (Dunphy JE. Way LW. ed). Los Altos, California. Lange Medical, 1975. 13. Winship T. Rosvoll RV: Cancer of the thyroid in children. p 75. Thyroid Cancer (Hedinger CE, ed). Berlin, Springer-Verlag.
vti
152. norrmkr
1a7e
Nodules in Elderly
1969. 14. Frohman L, Arnold J, Arnold M. Colman M. Favus M, Pinsky M, Pinsky S, Ryo Y. Schneider A, Stachura M: Thyroid tumors occurring as late effects of head and neck irradiation: preliminary report. C/in Res 22: 599A. 1974. 15. Pincus RA. Reichlin S, Hempelmann LH: Thyroid abnormalities after radiation exposue in infancy. Ann /n&m Med66:1154, 1967. 16. Refetoff S, Harrison J. Karanfilski BT, Kaplan EL, DeGroot LJ, Bekerman C: Continuing occurrence of thyroid, carcinoma after irradiation to the neck in infancy and childhood. N Engl JMed292: 171, 1975. 17. DeGroot LJ: Thyroid carcinoma. h&d C/in North Am 59: 1233, 1975. 18. Rosen IB, Walfish PG. Miskin M: The use of B mode ultrasonoqaphy in changing indications fcr thyroid operations. Sug Gynecol Obstet 139: 193, 1974. 19. Thijs LG, Wiener JD: Ultrascntc examination of the thyroid gland. Am J h4ed 60: 96, 1976. 20. Samuels BE: Thermography: a valuable tool in the detection of thyroid disease. Radiology 102: 59. 1972. 21. Holinger PH. Lutterbeck EF, Bulger R: Xeroradiography of the larynx. Ann Otol Rhino1 Laryngol81: 806. 1972. 22. Patton JA, Hollifield JW, Brill AB. Lee GS, Patton DD: Differentiation between malignant and benign solitary thyroid nodules by fluorescent scanning. J Nucl Med 17: 17, 1976. 23. Melvin KEW: The paraneoplastic syndromes associated with carcinoma of the thyroid gland. Ann NY Acad Sci 230: 378, 1974. 24. Van Herle AJ, Uller RP: Elevated serum thyroglobulin. J C/in Invest 56: 272 1975. 25. Boeme CJ. Winship T, Lindsay S, Kypridakis G: An evaluation of needle biopsy of the thyroid gland. Surg Gynecol06s~ 119: 831. 1964. 26. Thomas CG. Buckwalter JA: Poorly differentiated neoplasms of the thyroid gland. Ann Surg 177: 632. 1973. 27. Sloan WL: Of origin, characteristics and behavior of thyroid cancer. J C/in EndocrinolMatab 14: 1309, 1954. 28. McDermott WV, Morgan WS, Hamlin E Jr, Cope 0: Cancer of the thyroid. J C/in Endocrinol Metab 14: 1336, 1954. 29. Woolner LB, Beahrs OH, Black BM. McConahey WM, Keating FR: Classification and prognosis of thyroid carcinoma. Am J Surg 102: 354. 1961. 30. Halnan KE: Influence of age and sex on incidence and prognosis of thyroid cancer. Cancer 19: 1534, 1966. 31. Rawson RW, Leeper R: Factors influencing benignancy vmsus malignancy of thyroid neoplasms, p 159. Thyroid Neoplasia (Young S. lnman DR. ed). London and New York, Academic Press. 1968. 32. Crile G Jr: Treatrnsnt of carcinomas of the thyroid, p 39. Thyroid Neoplasia (Young S, lnrnan DR. ed). London and New York, Academic Press, 1968. 33. Winship T. Rosvoll RV: Childhood thyroid carcinoma. Cancer 14: 734, 1961. 34. Nathanson IT, Towne LE, Aub JC: Normal excretion of sex hormones in childhood. Endocrinology28: 851. 1941. 35. Pincus G. Dorfman RI, Rornanoff L, Rubin BL. Block E, Carlo J, Freeman H: Sterobd rnetabofism in aging men and women. Recent frog l-&m Res 11: 307. 1955. 36. Ram JS: Aging and immunological phenomena-a review. J Gerontol22: 92, 1967. 37. Russell WO, lbanex ML. Clark RL. White EC: Thyroid carcinoma. Cancer 16: 1425, 1963. 38. Frazell EL. Foote FW Jr: Papillary cancer of the thyroid. Cancer 11: 895. 1958.
619
The appropriate treatment of thyroid nodules in elderly patients is controversial, concern having been expressed that the operative mortality or morbidity may be especially high in this group. To investigate this issue the present study was designed to answer three questions regarding thyroid nodules in patients more than sixty years old: what parameters are useful in selecting patients for operation; what is the incidence and what types of thyroid malignancy occur in the elderly; and what is the morbidity and mortality of thyroid operations in these patients? Clinical Materlal The records were analyzed of 100 consecutive patients more than sixty years old, who had operations for thyroid nodules at the University of California Medical Center, San Francisco, from 1967 to 1973. Based on preoperative findings, two discrete groups could be identified with different probabilities of having thyroid cancer identified. Patients in the high risk group had one or more of the following characteristics: a discrete nonfunctional “cold” thyroid nodule by radioiodine scan, hoarseness, dysphagia, an enlarging thyroid mass, or palpable ipsilateral cervical adenopathy. Patients in the low risk group had multinodular glands, diffusely enlarged glands, high antibody titers, or a family history of benign goiter. Using these criteria, sixty-six patients were placed in the high risk group and thirty-four in the low risk group. Eleven of the sixty-six high risk patients (17 per cent) had malignant thyroid tumors, six of which were poorly differentiated histologically. Fifty-five patients had cold thyroid nodules by radioiodine scan, twenty-one patients had hoarseness or dysphagia, three patients had enlarging thyroid lesions, and one patient had palpable nodes adjacent to the thyroid nodule. As shown in Table I, all eleven patients, or 20 per cent of those with cold thyroid nodules, had malignant thyroid tumors; two patients were hoarse; three patients (all of whom had poorly differentiated malignant neoplasms) noted recent thyroid enlargement; and one patient had palpable ipsilateral cervical adenopathy. In three of the six patients with poorly differentiated thyroid neo-
From the Surgical Service, Veterans Administration Hospital, and Department of Surgery, University of California Hospital, San Francisco, California. Reprint requests should be addressed to Orlo H. Clark, MD, Department of Surgery (112). Veterans Administration Hospital, 4150 Clement Street, San Francisco. California 94121.
Volume 132, November 1979
plasms a thyroid nodule had been present for fifteen, twenty, and forty years before ope.ration. The technic and extent of the 100 operations varied, since the procedures were performed by numerous surgeons including resident house staff. Of the eleven patiehts with malignant thyroid neoplasms, three were treated by total lobectomy and isthmusectomy, four by near total thyroidectomy leaving a small remnant of posterior capsule on the side opposite the gross tumor, and four by total thyroidectomy. Modified radical neck dissection was performed in two patients. Ten of the eleven patients with thyroid malignancy received an ablative dose of radioiodine after operation. The histologic findings are presented in Table II. The most common gross and histologic finding in both groups was multinodular goiter. In fact, except for the malignant tumors in the high risk group, the spectrum of other pathologic entities was similar in both groups. There were no postoperative deaths and the only significant complication was injury to the right recurrent laryngeal nerve in a patient with thyroid carcinoma involving the right lobe. The mean period of hospitalization was five days (range, 4 to 8 days). Four of the five patients with differentiated thyroid cancers are alive and free of disease two to four years after operation. The fifth patient died of atherosclerotic cardiovascular disease one year after operation, (Table III.) All of these patients were given full replacement doses of L-sodium thyroxine (0.2 to 0.4 mg per day). Patients with poorly differentiated neoplasms were also treated with suppressive doses of L-sodium thyroxine and in addition received from 3,000 to 6,500 of x-ray therapy to the thyroid over a three to seven vveek period. Two of these patients also received chemotherapy and one received testosterone. As shown in Table IV, three of the six patients with poorly differentiated thyroid neoplasms lived at least three years after operation and one patient was apparently free of disease. In one patient with Hurthle and squamous cell carcinoma the disease progressed rapidly, unaffected by treatment. In two patients the response to treatment is unknown. The low risk group, which contained no patient with cancer, was characterized by the absence of the criteria found in the high risk group. Fifteen patients had multinodular glands, four patients had diffuse induration of the thyroid or high titers of thyroid antibodies suggestive of Hashimoto’s thyroiditis, and three patients had a family history of goiter. None of these patients had dysphagia, recent hoarseness, or enlargement of the nodule, and none had been exposed to external radiation.
615
Clark and Demling
TABLE I Clinical Manifestations in 66 High Risk Patients and 11 Patients with Thyroid Malignancy High Risk Thyroid
Discrete cold nodule Hoarseness or dysphagia Recent enlargement Palpable cervical
No. of Patients
Percentage with Clinical Findings
of Pa-
Percentage with Clinical
tients
Findings
55 21 3 1
83 32 5 1
11 2 3 1
20 10 100 100
Nlalignancy
No.
TABLE II
Histologic Diagnosis in High and Low Risk Patients
No. of High Risk Patients
No. of Low Risk Patients
Benign Nodular goiter Adenoma Thyroiditis Involutionary nodule
21 15 9 6 4
cyst Malignant Differentiated Undifferentiated Total
(32%) (23%) (13%) (9%) (6%)
5 (8%) 6 (9%) 66 (100%)
15 (44%) 10 4 3 2
(29%) (12%) (9%) (6%)
0 0 34 (100%)
adenopathy
was
Comments
Choosing appropriate treatment for elderly patients with nontoxic nodular goiter may be difficult because an accurate diagnosis of the histology of the nodule cannot be made on clinical findings alone. Separation of these patients into those at high risk and those with negligible risk for cancer should eliminate some unnecessary diagnostic operations and increase the yield of the remainder. Shimaoka et al [I] found that skilled physicians could fairly accurately estimate the risk of thyroid cancer in nontoxic goiter. They found that only 2 per cent of 202 patients classified as “benign” on clinical evaluation proved to have thyroid cancer, whereas 28 per cent of those classified as “suspected of cancer” and 53 per cent of those classified as “probable cancer” had malignant goiters. In their patients malignancy
suspected if the nodules grew progressively, caused compression of neighboring structures, and were hard and fixed or if ipsilateral cervical nodes or vocal cord paralysis were present. Conversely, patients with benign lesions had asymptomatic nodules, unchanged in size for years. Some benign nodules enlarged rapidly. Greenspan [Z] found a 30 per cent incidence of thyroid cancer if any one or more of the following were present: irradiation to the neck, recent growth of the thyroid nodule, a large (more than 2 cm) firm solitary nodule clearly different from the rest of the gland, vocal cord paralysis, hoarseness, palpable regional lymph nodes, distant metastatic lesions, or failure to regress after full replacement doses of TABLE
IV
6 Patients with Poorly Differentiated Thyroid Neoplasms
Histology TABLE III
5 Patients with Differentiated Thyroid Carcinoma
Histology
Duration
of Nodule
Follow-up Alive, free of disease 3 yr postoperatively Alive, free of disease 2 yr postoperatively Dead of atherosclerotic cardiovascular disease 1 yr postoperatively
Papillary
1 mo
Papillary-follicular
Unknown
Papillary-follicular
6 wk
Papillary-follicular
Less than 1 yr
Alive, free of disease 4 yr postoperatively
Follicular
10 yr
Alive, free of disease 3 yr postoperatively
616
Duration of Nodule
Follow-Up
Poorly differentiated papillary carcinoma with squamous metaplasia Poorly differentiated carcinoma
40 yr (recent growth)
Unknown
Unknown
Anaplastic
Unknown
Died of carcinoma of thyroid 3 yr after operation Alive and free of disease 3 yr after operation Severe pain and inability to swallow 4 mo after operation Died 6 yr after operation of atherosclerotic cardiovascular disease Unknown
small cell
Hiirthle and squamous cell carcinoma
20 yr (recent growth
Reticulum cell sarcoma of thyroid
15 yr (recent growth
Poorly differentiated carcinoma
3 wk
The American Journal of Surgery
Thyroid Nodules in Elderly
thyroxine. Patients with a family history of goiter suggesting Hashimoto’s thyroiditis or dyshormonogenesis, patients with soft nodules or a multinodular goiter or a hot nodule on radioiodine scan, patients with significant regression of the nodule while receiving thyroxine therapy, and patients with high antithyroid antibody titers most often had benign thyroid neoplasms. Marchetta and Sako [3] reviewed thyroid lesions in patients sixty years of age and older and concluded that thyroid nodules in the elderly should be viewed with the same suspicion as thyroid nodules in younger individuals. In their patients, as in ours, half the malignant thyroid tumors were histologically anaplastic carcinoma. Our finding of a 17 per cent incidence of cancer in high risk patients and no cancer in the low risk patients indicates that separating elderly patients into these two groups would be valuable in determining who will benefit from operation. Thus, since elderly patients with soft nodules, high antibody titers, and asymptomatic multinodular goiter that have not changed in size almost certainly have benign lesions, observation rather than operation is indicated. It is of interest that dysphagia and hoarseness were such poor indicators of malignancy in this series. Only two (10 per cent) of twenty-one patients with hoarseness or dysphagia had malignant thyroid tumors. In fact, the accuracy in diagnosing thyroid malignancy was higher if the presence of cold nodules alone was used as the discriminator of malignancy (20 per cent) rather than including dysphagia and hoarseness as well (17 per cent). A possible explanation is that dysphagia or hoarseness unrelated to thyroid disease brought the patient’s or physician’s attention to the thyroid nodule. General experience has shown that dysphagia and hoarseness are usually more reliable in predicting thyroid malignancy than our figures would suggest, especially if there is an associated vocal cord palsy. In some patients the principal indication for operation may be relief of dysphagia (by removing the isthmus of the gland). Most clinicians would agree that if a thyroid nodule is enlarging, if it is associated with adjacent adenopathy or vocal cord paralysis, or if the patient has previously had x-ray treatment to the head and neck, operation is unequivocally indicated. A more difficult decision is what to recommend for the patient with a solitary nontender, smooth, firm, and mobile nodule. Such a lesion is usually benign, but it might be follicular or papillary carcinoma. The first step in such a patient should be to obtain a radioiodine scan. If the nodule is functional, or a “hot” nodule, it is rarely malignant, whereas 5 to 20 per cent of patients
Volume132, November 1976
with “cold” nodules harbor malignant tumors [z], as did 20 per cent of patients with cold nodules in our series. Malignant thyroid tumors rarely take up iodine because of a defect in iodide trapping [4,5]. When a cold nodule is discovered, thyroid echography will differentiate solid from cystic lesions [6]. Cysts less than 4 cm in diameter can be successfully treated by aspiration since they are rarely malignant [7]. Four (6 per cent) of the patients with cold solitary thyroid nodules in this series, could have been successfully treated by aspiration rather than operation. At present, other scanning agents such as technetium 99m, selenomethionine 75, cesium 131, gallium 67, and indium 111 bleomycin are being investigated, but as yet they are of little clinical value in differentiating benign from malignant lesion. In young adults with asymptomatic thyroid nodules, suppression of the nodule with full replacement doses of thyroxine may be tried as long as the patient is closely followed. The nodule should be considered benign only if it totally disappears, since both normal thyroid tissue and thyroid tumors may regress to some extent after suppression of thyrotropin (TSH) by exogenous thyroxine [8,9]. However, in the elderly, suppressive therapy is usually not recommended because of possible cardiovascular complications. Older patients are known to have a higher incidence of multinodular goiter than the young, but the incidence of malignant thyroid neoplasms is similar [IO]. Many patients who clinically are thought to have solitary nodules are found to have multinodular goiter at operation [II]. The higher incidence of multinodular goiter in patients more than sixty years old probably accounts for the lower incidence of cancer found at operation in the elderly. In this series, the 20 per cent incidence of thyroid malignancy in cold solitary thyroid nodules is only slightly lower than the 26 per cent incidence of thyroid malignancy found in cold solitary thyroid nodules in patients less than sixty years old treated at the University of California, Medical Center, San Francisco, during the same period as the present study [12]. A higher diagnostic yield could be obtained in the high risk group by using more restrictive criteria. The four patients with thyroid cysts could now be diagnosed by ultrasound and successfully treated by aspiration. Some of the nine patients with thyroiditis could probably also be eliminated from the high risk group, because of the more diffuse involvement of the gland and high antithyroid antibodies. It must be emphasized, however, that the presence of thyroiditis does not exclude the possibility of thyroid cancer so if other features of the high risk category are present, operation should not be delayed.
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If one waited for more obvious disease, such as progressively enlarging or fixed painful lesions, hoarseness due to infiltration of the recurrent laryngeal nerve, the development of cervical lymph nodes, or distant metastasis, diagnostic accuracy could approach 100 per cent, but of course these are features of more advanced, incurable cancer and such a policy would sacrifice curability for the sake of diagnosis. None of our patients had had previous radiotherapy to the neck, but this markedly increases the possibility that a goiter contains cancer. For example, Winship and Rosvoll [13] found that 80 per cent of children less than fifteen years old who had carcinoma of the thyroid gland had received x-ray therapy to the thymus, tonsils, skin, or cervical lymph nodes. Frohman et al [14] reported that 36 per cent of patients with thyroid nodules who received x-ray therapy as children had thyroid cancer. Current estimates are that thyroid neoplasms will develop in between 4 and 7 per cent of all patients who have received x-ray treatment to the head and neck during childhood [15,16]. It is worrisome that the incidence of malignancy seems to increase for at least the first three decades after radiation exposure [17]. Eventually, a history of radiation exposure will be present in some patients more than sixty years old with thyroid nodules and should be regarded as an absolute indication for surgery. With further refinements, diagnostic technics such as ultrasound [18,19], thermography [20], xerography [21], fluorescent scanning [22], calcitonin [23], and thyroglobulin radioimmunoassays [24] will probably’ be of help in determining whether a thyroid nodule is malignant. Percutaneous needle biopsy has been found to be too unrepresentative of the pathology to be reliable [25]. Undifferentiated cancers are more common in the elderly and have a very poor prognosis [26]. Sloan [27] in 1954 was the first to suggest that the aggressiveness of thyroid cancer depends on the patient’s age at the time of diagnosis, a supposition that has been confirmed by McDermott et al [28], Woolner et al [29], and Halnan [30]. This is reflected by an especially high mortality rate in patients more than sixty years old [31] even when patients with undifferentiated thyroid tumors are excluded. The reason for the increased mortality in this group is not known, although some evidence suggests that thyroid tumors are less sensitive to thyrotropin in the elderly [32]. Altered hormonal balance and immunologic resistance may also be important factors. Winship and Rosvoll[33] in 1961 reported that the mortality from thyroid cancer in children less than seven years old
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was 61.4 per cent, whereas it was 12.8 per cent for children from seven to fifteen years old. Nathanson et al [34] in 1941 had previously documented a slight but significant increase in urinary estrogen and 17-ketosteroids between ages seven and eight years in healthy children, supporting the thesis that an indolent growth pattern for thyroid cancer is associated with adequate levels of sex steroids. Pincus et al [35] observed decreased urinary estrogens in women and decreased urinary estradiol and estrone in men with advancing age. Alteration of immune mechanisms with aging may also underlie age-related variations in behavior of thyroid cancer. Ram [36] ‘noted that the increased mortality due to thyroid cancer in early childhood and with senescence corresponds with a decreased natural immunity at these times. These factors may account for the more aggressive behavior of differentiated thyroid carcinomas in the elderly and for the greater frequency of undifferentiated thyroid tumors in this group. Three of the six patients with undifferentiated thyroid tumors had a history of preexisting goiter for at least fifteen years. Spindle and giant cell thyroid cancer, probably the most malignant tumor in humans, has been shown to arise from preexisting papillary and follicular carcinoma [37]. Small foci of undifferentiated tumors are not infrequently observed within papillary, mixed, and follicular thyroid cancers and a focus of differentiated thyroid tumor is often found in undifferentiated thyroid neoplasms [38]. An ominous outlook can be predicted when a goiter that has been stationary for years begins to increase in size, causing discomfort and a sense of constriction. If poorly differentiated and undifferentiated thyroid tumors arise from preexisting differentiated thyroid cancers, then one important step towards preventing undifferentiated thyroid cancer would be to remove existing thyroid nodules that contain differentiated thyroid carcinoma. Summary
Eleven malignant thyroid tumors were found in 100 consecutive patients more than sixty years old having thyroid operations. Based on preoperative findings, these 100 patients could be separated into two groups according to high and low risk for malignancy. Clinical manifestations in the high risk group were presence of a discrete cold thyroid nodule, hoarseness, dysphagia, an enlarging mass, or palpable ipsilateral cervical adenopathy; and in the low risk group, asymptomatic multinodular goiter, diffusely enlarged glands with elevated antithyroid antibody
The American Journal 01 SW&IW
Thyroid
titers, and a family history of goiter. All eleven patients with malignant thyroid tumors were found in the sixty-six patients considered at high risk, whereas no malignant lesions were found in the low risk patients. Six of the malignant thyroid tumors were undifferentiated and in three of these a thyroid nodule had been present for more than fifteen years. There were no operative deaths and only one significant complication, a recurrent laryngeal nerve injury. Thyroidectomy is indicated for elderly patients with thyroid nodules who have features of the high risk group, whereas patients in the low risk group can be safely followed. Acknowledgment: We are greatly indebted to our colleagues in endocrinology, nuclear medicine, and surgery. Many of the patients were cared for by Doctors Francis S. Greenspan, Ralph R. Cavalieri, Malcolm Powell, Andrea Blum, Leon Goldman, J. Englebert Dunphy, Maurice Galante, and Thomas Hunt. We would also like to thank Doctor Lawrence W. Way for his helpful suggestions and James Gorring for his excellent clerical assistance. References 1. Shimaoka K, Badillo J, Sokal JE. Marchetta FC: Clinical differentiation between thyroid cancer and benign goiter. JAMA 181: 179, 1962. 2. &senspan FS: Thyroid ncdufes and thyroki cancer. West J h4sd 121: 359.1974. 3. Marchetta FC. Sako K: The enlarged thyroid in the elderly patient. Geriatrics 23: 181. 1968. 4. DeGroot LJ: Lack of iodide trapping in “cold” nodules. Acta Endocrinol Panam 1: 27. 1970. 5. Field JB, Larsen PR. Yamashita K, Mashiter K, Dekker A: Demonstration of iodide transport defect but normal iodide organification in non-functioning nodules of human thyroid glands. J C/in invest 51: 1109. 1972. 6. Clark DH. Greenspan FS, Ccggs GC. Goldman L: Evaluation of solitary cold thyroid nodules by echography and thermography. Am J Surg 130: 206, 1975. 7. Blum A, Goldman AB. Herskovic A, Hernberg J: Clinical ap plications of thyroid echography. N Engl J Med 287: 1184, 1972. 8. Astwood CB, Casskfy CE. Aubach GD Treaant of goiter and thyroid nodules with thyroid. JAMA 174: 459, 1980. 9. Crile G Jr: Endocrine dependency of papillary carcinomas of the thyroid. JAMA 195: 721, 1966. 10. Taylor S: Carcinoma of the thyroid gland. JR Co// Surg Edinb 14: 183, 1969. 11. Beales JSM, Nundy S. Taylor S: Thyroid lymphography. Br J Surg58: 168. 1971. 12. Clark OH, Goldman L: Thyroid and parathyroid disease, p 254. Current Surgical Diagnosis and Treatment (Dunphy JE. Way LW. ed). Los Altos, California. Lange Medical, 1975. 13. Winship T. Rosvoll RV: Cancer of the thyroid in children. p 75. Thyroid Cancer (Hedinger CE, ed). Berlin, Springer-Verlag.
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1969. 14. Frohman L, Arnold J, Arnold M. Colman M. Favus M, Pinsky M, Pinsky S, Ryo Y. Schneider A, Stachura M: Thyroid tumors occurring as late effects of head and neck irradiation: preliminary report. C/in Res 22: 599A. 1974. 15. Pincus RA. Reichlin S, Hempelmann LH: Thyroid abnormalities after radiation exposue in infancy. Ann /n&m Med66:1154, 1967. 16. Refetoff S, Harrison J. Karanfilski BT, Kaplan EL, DeGroot LJ, Bekerman C: Continuing occurrence of thyroid, carcinoma after irradiation to the neck in infancy and childhood. N Engl JMed292: 171, 1975. 17. DeGroot LJ: Thyroid carcinoma. h&d C/in North Am 59: 1233, 1975. 18. Rosen IB, Walfish PG. Miskin M: The use of B mode ultrasonoqaphy in changing indications fcr thyroid operations. Sug Gynecol Obstet 139: 193, 1974. 19. Thijs LG, Wiener JD: Ultrascntc examination of the thyroid gland. Am J h4ed 60: 96, 1976. 20. Samuels BE: Thermography: a valuable tool in the detection of thyroid disease. Radiology 102: 59. 1972. 21. Holinger PH. Lutterbeck EF, Bulger R: Xeroradiography of the larynx. Ann Otol Rhino1 Laryngol81: 806. 1972. 22. Patton JA, Hollifield JW, Brill AB. Lee GS, Patton DD: Differentiation between malignant and benign solitary thyroid nodules by fluorescent scanning. J Nucl Med 17: 17, 1976. 23. Melvin KEW: The paraneoplastic syndromes associated with carcinoma of the thyroid gland. Ann NY Acad Sci 230: 378, 1974. 24. Van Herle AJ, Uller RP: Elevated serum thyroglobulin. J C/in Invest 56: 272 1975. 25. Boeme CJ. Winship T, Lindsay S, Kypridakis G: An evaluation of needle biopsy of the thyroid gland. Surg Gynecol06s~ 119: 831. 1964. 26. Thomas CG. Buckwalter JA: Poorly differentiated neoplasms of the thyroid gland. Ann Surg 177: 632. 1973. 27. Sloan WL: Of origin, characteristics and behavior of thyroid cancer. J C/in EndocrinolMatab 14: 1309, 1954. 28. McDermott WV, Morgan WS, Hamlin E Jr, Cope 0: Cancer of the thyroid. J C/in Endocrinol Metab 14: 1336, 1954. 29. Woolner LB, Beahrs OH, Black BM. McConahey WM, Keating FR: Classification and prognosis of thyroid carcinoma. Am J Surg 102: 354. 1961. 30. Halnan KE: Influence of age and sex on incidence and prognosis of thyroid cancer. Cancer 19: 1534, 1966. 31. Rawson RW, Leeper R: Factors influencing benignancy vmsus malignancy of thyroid neoplasms, p 159. Thyroid Neoplasia (Young S. lnman DR. ed). London and New York, Academic Press. 1968. 32. Crile G Jr: Treatrnsnt of carcinomas of the thyroid, p 39. Thyroid Neoplasia (Young S, lnrnan DR. ed). London and New York, Academic Press, 1968. 33. Winship T. Rosvoll RV: Childhood thyroid carcinoma. Cancer 14: 734, 1961. 34. Nathanson IT, Towne LE, Aub JC: Normal excretion of sex hormones in childhood. Endocrinology28: 851. 1941. 35. Pincus G. Dorfman RI, Rornanoff L, Rubin BL. Block E, Carlo J, Freeman H: Sterobd rnetabofism in aging men and women. Recent frog l-&m Res 11: 307. 1955. 36. Ram JS: Aging and immunological phenomena-a review. J Gerontol22: 92, 1967. 37. Russell WO, lbanex ML. Clark RL. White EC: Thyroid carcinoma. Cancer 16: 1425, 1963. 38. Frazell EL. Foote FW Jr: Papillary cancer of the thyroid. Cancer 11: 895. 1958.
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