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Asymptomatic Nodular Goiter—Diagnostic Aspects
Asymptomatic Nodular Goiter-Diagnostic Aspects MARTIN A. ADSON, M.D.
ALTHOUGH it is generally agreed that the surgeon has responsibility in the management of symptomatic benign nodular goiters and thyroid carcinoma, there continue to be confusion and controversy about the surgeon's role in the management of the nontoxic nodular goiter which produces no symptoms. Despite advances in thyroid physiology and the availability of some sophisticated diagnostic and therapeutic measures that do not require operatibn, management of the patient with nontoxic nodular goiter at this clinic has undergone little fundamental change over the years. Simple reiteration of this attitude seems out of place in a volume devoted to progress in surgery; but in the light of the progress in laboratory aids for diagnosis and the recent observations of other workers, it does seem appropriate to justify our practices. My colleagues and I believe that surgical evaluation of some asymptomatic thyroid nodules is warranted by the lack of reliable clinical criteria for differentiating benign from malignant disease, the limitations of laboratory tests and trial of desiccated thyroid as diagnostic guides, and the desirability of treating cancer before it becomes clinically obvious. DEFINITION OF THE PROBLEM
Although some internists! appear to believe that surgical evaluation and treatment of nodular goiter is never indicated, and at times the surgeon is characterized as one who advises operation for all thyroid nodules, these extreme attitudes appear to be uncommon. Differences in opinion about management relate chiefly to a relatively small proportion of nodular goiters which are considered neither "almost certainly benign" nor "probably or obviously malignant" on the basis of history and physical examination. The controversy has its roots in uncertainty and disagreement about the true incidence of malignancy in nodular goiter, the accuracy of nonsurgical differentiation between benign and malignant nodules, and the characteristic behavior of thyroid cancer as it relates to delay in
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treatment or reliance upon medical management. 9 Also relevant is the fact that interpretation of divergent opinion and contradictory data is made difficult by the excessive breadth of the prevailing "generalizations. The term "nodular goiter" describes several significantly different structural alterations in the thyroid gland, each of which may demonstrate different clinical behavior. Despite general recognition of this fact, confusion stems from the lack of a truly suitable classification of nodular goiters having various physical characteristics. As a result, subjective factors influence statistical analyses, selective processes may be overlooked or undefined, and groups of patients subjected to various forms of treatment by different physicians or groups may not be truly comparable. Almost any classification of nodular goiters based upon physical characteristics is vulnerable to criticism, but some classification is necessary to facilitate analysis of differing opinions and to serve as a basis for recommendations about management. The following groups, differing with respect to physical properties, the incidence of malignancy, and the frequency with which they are managed surgically, are not sharply separable but do provide a basis for subsequent discussion. 1. Probably the majority of all nodular goiters appear as multiple nodules in small, nearly symmetric, asymptomatic thyroid glands of normal and uniform consistency. The incidence of malignancy in these is less than in groups described below; occult cancers presenting in small soft nodules have truly favorable prognoses; and changes in size or consistency in such a thyroid gland can be detected easily. It is likely that this type of nodular goiter is seldom managed surgically in any institution. 2. At the opposite end of the clinical spectrum of nodular goiters are the obviously malignant lesions which may present with fixation to neighboring structures or skin, vocal-cord paralysis, or cervical adenopathy. Nodular goiters in young patients and firm or hard solitary nodules that are not sharply outlined are not always cancerous; but the incidence of malignancy is clearly greater in such cases than in the group described above, and there is general agreement that surgical evaluation is appropriate. Because there is little controversy about the indications for surgical management of symptomatic thyroid nodules and those of questionable toxicity, these nodular goiters also are included in this group. 3. Between these two extremes there is an uncertain group. Suspicion of malignancy is difficult to define, and it is not surprising that there is a gray area in the characterization of some physical characteristics; the result is disagreement with respect to the incidence of malignancy and the indications for surgery. Included in this group are the asymptomatic nodular glands of moderate size, asymmetric goiters, those with varia-
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tions of consistency, and apparently solitary soft or cystic sharplyoutlined nodules. Although such a classification is inexact and differences between groups cannot be sharply defined, it is clear that the term "nodular goiter" is used to describe a great variety of clinical conditions; and generalizations about management which ignore this fact are unjustified. The discussion of the controversial aspects of management is simplified if one has license to refer to nodular goiters as (1) "apparently innocent," (2) "clearly surgical," and (3) "controversial" with respect to management. Uncertainty of Incidence of Malignancy
The marked difference in incidence of malignancy among the many series of reported cases of nodular goiter is related to two factors: the varying degrees of unrecognized or unreported selection in different series; and the fact that, whereas the incidence of malignancy can be accurately determined with surgical treatment, estimates of this incidence in nonsurgical cases are uncertain unless based on extremely long-term follow-up. The surgeon who is unaware of the extent of the selective process upon which his practice depends is unaware of the predominance of "innocent" goiters and may conclude from his frequent encounters with malignancy that operation is indicated for all patients with nodular goiter. Conversely, the practitioner or internist who frequently feels minor alterations in thyroid structure and only occasionally sees thyroid cancer may conclude quite reasonally that only a small percentage of all nodular goiters are malignant. This impression is intensified if he has little opportunity for long-term follow-up of individual patients and if he is unaware of the natural history of many thyroid cancers. The incidence of clinically unrecognizable cancer in nodular goiters is neither so great as to justify surgical evaluation for all cases nor so insignificant as to permit neglect of every asymptomatic thyroid nodule. In this dilemma, the need for some useful classification based upon physical characteristics and some knowledge of the accuracy of clinical criteria for differentiation of benign and malignant nodular goiters is obvious. CLINICAL DIFFERENTIATION BETWEEN BENIGN AND MALIGNANT GOITER
Accuracy of Diagnosis from History and Physical Findings
There is good evidence to support the view that clinical criteria are reasonably accurate in differentiating benign from malignant disease, if one compares the two extremes of physical change found in abnormal
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thyroid glands. 7 Perhaps the best evidence for some degree of success in preoperative differentiation is the marked difference in the incidence of malignancy reported in surgical and nonsurgical series. However, the value of clinical criteria in recognizing major physical differences does not prove the worth of clinical judgments about minor ones; and the limitations of clinical criteria for differentiation become more apparent when one considers the midportion of the spectrum of this disease. In this regard a recent evaluation of the accuracy of clinical differentiation between thyroid cancer and benign goiter by Shimaoka and others is interesting. These authors classified 214 cases of nontoxic goiter as "benign," "suspected of cancer," and "probably cancer" on the basis of preoperative evaluation. Among the 202 considered benign, thyroid cancer was proved in 2 per cent; and among those in which malignancy was suspected or thought probable, it was proved in 40 per cent. Their figures indicate "that patients with goiter can be divided quite successfully into low and high cancer-risk groups and that preoperative selection is justified." The truth of this statement and the vallie of the study are not questioned; however, other aspects of the analysis deserve comment. Of the 202 patients considered to have benign disease, 63 underwent thyroidectomy within a year of the initial evaluation, and four of these (6 per cent) were found to have cancer. Among the remaining 139 patients, benignancy was proved in 14; but in 125 it was only presumed on the basis of follow-ups of three to six years. The absence of undifferentiated, aggressive malignancy in this group can be assumed; but observations by Beahrs and co-workers, that the goiter had been present for five or more years before thyroidectomy in 40 per cent of the cases of thyroid cancer and that a history of recent change in thyroid size was obtainable in only 27 per cent of cases, point up the uncertainty about the true incidence of malignancy in these 125 patients. These authors commented in the usual way about the clinical criteria for selection. In the controversial group (3, above) the uncertainty of physical features and the subjectivity of preoperative judgment were apparent; and these remarks should not be surprising when one considers the limitations on gross pathologic diagnosis of some surgical specimens. In Shimaoka's series, the incidence of cancer in surgically treated nodular goiters presumed to be benign on clinical grounds closely approximates the figure upon which we have based our policy of management3 for many years. To subscribe to a policy of operative examination of many asymptomatic thyroid nodules is not to suggest that it is ideal. The conscientious, conservative surgeon is troubled by the fact that, to provide optimal therapy for patients with thyroid carcinoma, many others must have an operation that retrospectively is unnecessary. It is hoped that future progress in thyroid physiology will greatly diminish
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the need for surgical evaluation, for truly adequate substitutes are not available today. Usefulness of the Gammagram
Because there is some correlation between the incidence of malignancy in thyroid nodules and their functional activity, the gammagram may be useful in the clinical appraisal of nodular goiters. 2 , 5, 6 Nodules having decreased function or none are much more often malignant than those showing normal or increased uptake of radioactive iodine. However, assessment of function is not a substitute for microscopic examination; so-called cold or cool nodules are not invariably malignant, and cancer is not excluded by the demonstration of a so-called warm or hot nodule. The limitations of this diagnostic adjunct are increased by the fact that clinically significant nodules may be obscured by surrounding tissue with normal function. Hence the gammagram supports but does not replace clinical judgment. It is most useful for detecting functioning thyroid tissue outside the neck, for evaluating thyroid function or structure after thyroidectomy, and for appraisal of the patient who has nodular goiter but is not a good surgical risk. Diagnostic Value of Exogenous Thyroid
Although disturbances in thyroid physiology must have a major influence in the pathogenesis of most benign nodular goiters and some thyroid cancers, these mechanisms are not completely defined; and studies of the use of desiccated thyroid for differentiation between benign and malignant goiter are inconclusive. It is unfortunate that Astwood and associates, who apparently believed that nearly all nodular goiters are benign, were not more specific about the length of follow-up in their cases and the possible influence of selection prior to their evaluation. Physical alterations in nodular goiter induced by thyroid medication are variable and their significance is uncertain. Changes ordinarily are confined to the normal parenchyma which surrounds nodules, and shrinkage or disappearance of the nodule indicates benignancy to some physicians and malignancy to others.8 This difference in interpretation would be less significant if there were agreement about the persistence of hormonal dependency in certain types of thyroid cancer. In contrast to the uncertainty concerning the use of exogenous thyroid for evaluation of adenomatous goiter, the use of this substance in the management of Hashimoto's thyroiditis is a well-established procedure.u Although change "from an anatomic to a physiologic approach in the management of thyroid nodules"8 may be hoped for, uncertainties inherent in the use of desiccated thyroid as a diagnostic agent lead us to rely primarily upon surgery for evaluation of the controversial (Group 3) thyroid nodule.
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IMPLICATIONS OF THE TYPICAL COURSE OF THYROID CARCINOMA
Some types of thyroid cancer are usually incurable, even by prompt surgical treatment; but the more common types of thyroid carcinoma grow slowly, metastasize late, and are fairly well controlled even when surgical treatment is delayed. These facts suggest that reasonable periods of delay for the purpose of evaluation without surgery may have little effect upon the curability of lesions ultimately proved to be malignant. Some workers justify evaluation by such means on the basis that some thyroid cancers may be controlled by administration of thyroid hormone,8 while others point up the fact that thyroid cancer may develop despite (or because of) prior partial thyroidectomy. 9 Clearly, biologic factors cannot be ignored; but specific principles of management based upon these observations are difficult to formulate. Potentially curable cancers may progress to a stage which compromises the chance of cure, and such a change is not always marked by clinical evidence. Certainly growth of a suspicious nodule is an indication for surgical evaluation; but such a change may be difficult to assess in the multinodular gland of moderate size, and metastasis may occur without clinically detectable growth of a nodule. When such change is undetected, does one then wait for unequivocal evidence of malignancy or for evidence of nodal or distant metastasis? Many patients do not cooperate in plans for long-term periodic examination and others will not accept the uncertainty which attends observation or nonsurgical management when the risks and principles of such a program cannot be defined accurately. Certainly the biologic nature of thyroid cancer is relevant to the management of the "controversial" group of nodular goiters. Reasonable delays in surgical evaluation are acceptable, but there is little justification for long-term observation of these patients. If observation with feeding of exogenous thyroid is undertaken, it is best to base decisions upon a prompt definite response with perhaps no more than a few months of observation. However, the value of desiccated thyroid as a diagnostic agent is uncertain and its use is best restricted to the postoperative patient whose disease has been defined, the patient for whom risk of surgery is excessive, and the subject for clinical research.
SELECTION FOR SURGICAL MANAGEMENT AT THE MAYO CLINIC
Factors in Selection
At this clinic, decisions about surgical management of the nontoxic nodular goiter are based chiefly upon the history, the physical findings,
1
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and the life expectancy of the patient. A formal study of the influence of gammagrams upon decisions in questionable cases has not been undertaken, but the limitations of this diagnostic measure have been mentioned above. Desiccated thyroid, employed commonly in the management of Hashimoto's thyroiditis, is not used in attempts to differentiate between benign and malignant nodular goiters. Within the mid spectrum of physical changes (Group 3), variations of consistency in portions of the gland, asymmetry, or nodules with irregular contour or lack of distinct margins provoke concern. Most often nodules that seem to be solitary are investigated surgically, particularly if they are more than 2 cm. in size or if they are more firm than the surrounding parenchyma. The age and life expectancy of the patient are of great importance in surgical judgments. Hayles and others emphasized the significance of youth, finding that among nodular goiters of children treated surgically at the Mayo Clinic between 1950 and 1955, cancer was present in 70 per cent. The significance of age or imperfect health in the patient whose longevity could not be affected by the common forms of thyroid cancer is obvious. RELATED DISEASES. Because the various types of thyroiditis may simulate adenomatous goiter or thyroid cancer and because they may exist in association with these entities, thyroiditis must be considered in any discussion of benign and malignant goiter. Woolner and associates12 in this clinic have reported recently on the surgical aspects of thyroiditis, so the discussion here will be brief. Riedel's struma, usually considered clinically to be a carcinoma, is clearly a surgical problem. Although the diagnosis of granulomatous thyroiditis ordinarily can be made on the basis of clinical and laboratory findings, needle biopsy is indicated in the atypical case. In approximately 10 per cent of cases an asymptomatic nodule is the only finding, and this requires surgical evaluation. Hashimoto's thyroiditis in its more common form usually can be suspected on the basis of clinical and laboratory data. Histologic confirmation based upon a biopsy specimen obtained with a Silverman needle is desirable, but treatment with desiccated thyroid may be undertaken on a presumptive diagnosis based on a diffuse symmetric goiter having rubbery consistency. At times Hashimoto's thyroiditis is indistinguishable clinically from nontoxic adenomatous goiter, and surgical intervention is advisable if the gland has suspicious nodularity or marked asymmetry or if the disease fails to respond to the administration of desiccated thyroid. Proportion of Cases with Surgical Management
A general impression about the extent of selection of patients for
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surgical evaluation at the Mayo Clinic can be obtained from the "General Summary of Diagnoses" tabulated each year by the Section of Biometry and Medical Statistics. In 1961 nontoxic nodular goiter (excluding thyroiditis) was indexed as a diagnosis for 1712 patients, and 495 of these were treated surgically. Review of similar reports for a 20-year period showed a remarkably similar ratio. It appears that between onefourth and one-third of the cases of nodular goiter seen at this institution are managed surgically. Probably the clinician sometimes fails to record all of his findings on the summary sheet; and to a corresponding extent, the proportion of patients managed surgically would be less. The present report affords no conclusion about malignancy in thyroid nodules, and these figures are presented only to indicate in a general way the number of patients with nodular goiter who are not managed surgically. In addition to the 495 patients who underwent surgery for benign nodular goiter without hyperthyroidism in 1961, 45 patients with thyroiditis had partial thyroidectomy, and 76 patients were treated surgically for carcinoma of the thyroid gland. Thus, of 616 surgical patients with nontoxic nodular goiter, 12 per cent did have thyroid cancer. However, this percentage is not relevant to any argument about the management of the controversial group of thyroid nodules, because it included also the many clinically obvious cancers. Study of surgical and pathologic reports revealed that in one-third of the 76 cases the preoperative evidence for malignancy was unequivocal, in one-third the malignancy was manifested clinically as an apparently solitary nodule, and in one-third the thyroid gland was multinodular. Verification of Malignancy
The incidence of malignancy in nontoxic nodular goiters treated surgically at the Mayo Clinic in previous years has been reported by Beahrs and associates. Among all patients having a preoperative diagnosis of nodular goiter without hyperthyroidism, occult carcinomas were found in 3.8 per cent; and when all cases of nodular goiter without hyperthyroidism-regardless of preoperative clinical impression-were considered, the incidence of cancer was found to be 7.5 per cent. Further evidence of the imperfections of clinical evaluation has appeared in a study by Woolner and co-workers,lO who reported on a series of cases of thyroid cancer seen at this clinic. Carcinoma was diagnosed or suspected preoperatively in only one-third of 509 cases of papillary carcinoma and in only six of 157 cases of follicular cancer. The limitations of clinical assessment were not so marked in other forms of carcinoma, but definite suspicion of malignancy was recorded in only 27 of 57 cases of solid carcinoma with amyloid stroma and 96 of 130 cases of anaplastic carcinoma. It is difficult to believe that the management
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of the patients thought to have had benign disease would have been simplified or improved by the use of desiccated thyroid for evaluation or by observation until an unequivocal diagnosis of cancer could be made on clinical grounds. SUMMARY AND CONCLUSION
The term "nodular goiter" denotes both a variety of structural abnormalities and a number of clinically different diseases of the thyroid gland. Clinical differentiation between groups of patients with nontoxic nodular goiter having low and high incidence of malignancy is possible, and the biologic nature of most thyroid cancers permits reasonable delays in diagnosis without compromise of curability. So far as these considerations extend, surgical evaluation is not indicated for all nodular goiters and the need for operation in questionable cases is seldom urgent. However, the limitations of clinical criteria for differentiating between benign and malignant nodules in some situations, the uncertainties of physiologic methods of diagnosis, and the advantages of treating thyroid cancer before it becomes clinically obvious are justification for resort to surgical evaluation of many asymptomatic nodular goiters. It is not suggested that this practice is ideal, but suitable alternatives are lacking. The need for more reliable measures for differentiation between benign and malignant thyroid nodules is obvious. REFERENCES 1. Astwood, E. B., Cassidy, C. E. and Aurbach, G. D.: Treatment of goiter and thyroid nodules with thyroid. J.A.M.A. 174: 459-464 (Oct. 1) 1960. 2. Bartels, E. C., Bell, G. O. and Geokas, M. C.: Evaluation of thyroid nodule. S. CLIN. NORTH AMERICA 42: 655-665 (June) 1962. 3. Beahrs, O. B., Pemberton, J. deJ. and Black, B. M.: Nodular goiter and malignant lesions of thyroid gland. J. Clin. Endocrinol. 11: 1157-1165 (Oct.) 1951. 4. Hayles, A. B., Kennedy, R. L. J., Woolner, L. B. and Black, B. M.: Nodular lesions of thyroid gland in children. J. Clin. Endocrinol. 16: 1580-1594 (Dec.) 1956. 5. Johnson, P. C. and Beierwaltes, W. H.: Reliability of scintiscanning nodular goiters in judging presence or absence of carcinoma. (Abstr.) J. Clin. Endocrinol. 15: 865 (July) 1955. 6. Meadows, P. M.: Scintillation scanning in management of clinically single thyroid nodule. J.A.M.A. 177: 229-234 (July 29) 1961. 7. Shimaoka, K., Badillo, J., Sokal, J. E. and Marchetta, F. C.: Clinical differentiation between thyroid cancer and benign goiter: An evaluation. J.A.M.A. 181: 179-185 (July 21) 1962. 8. Sloan, L. W., Crile, G., Jr., Frantz, V. K., Rawson, R. W. and Werner, S. C.: Management of solitary thyroid nodule: Transcription of a panel meeting on therapeutics. Bull. New York Acad. Med. 35: 178-204 (March) 1959. 9. Sokal, J. E.: Problem of malignancy in nodular goiter-recapitulation and a challenge. J.A.M.A. 170: 405-412 (May 23) 1959. 10. Woolner, L. B., Beahrs, O. H., Black, B. M., McConahey, W. M. and Keating,
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F. R., Jr.: Classification and prognosis of thyroid carcinoma: A study of 885 cases observed in a thirty-year period. Am. J. Surg. 102: 354-387 (Sept.) 1961. 11. Woolner, L. B., McConahey, W. M. and Beahrs, O. H.: Struma lymphomatosa (Hashimoto's thyroiditis) and related thyroidal disorders. J. Clin. Endocrino!' 19: 53-83 (Jan.) 1959. 12. Woolner, L. B., McConahey, W. M. and Beahrs, O. H.: Surgical aspects of thyroiditis. Am. J. Burg. 104: 666-671 (Nov.) 1962.
ALTHOUGH it is generally agreed that the surgeon has responsibility in the management of symptomatic benign nodular goiters and thyroid carcinoma, there continue to be confusion and controversy about the surgeon's role in the management of the nontoxic nodular goiter which produces no symptoms. Despite advances in thyroid physiology and the availability of some sophisticated diagnostic and therapeutic measures that do not require operatibn, management of the patient with nontoxic nodular goiter at this clinic has undergone little fundamental change over the years. Simple reiteration of this attitude seems out of place in a volume devoted to progress in surgery; but in the light of the progress in laboratory aids for diagnosis and the recent observations of other workers, it does seem appropriate to justify our practices. My colleagues and I believe that surgical evaluation of some asymptomatic thyroid nodules is warranted by the lack of reliable clinical criteria for differentiating benign from malignant disease, the limitations of laboratory tests and trial of desiccated thyroid as diagnostic guides, and the desirability of treating cancer before it becomes clinically obvious. DEFINITION OF THE PROBLEM
Although some internists! appear to believe that surgical evaluation and treatment of nodular goiter is never indicated, and at times the surgeon is characterized as one who advises operation for all thyroid nodules, these extreme attitudes appear to be uncommon. Differences in opinion about management relate chiefly to a relatively small proportion of nodular goiters which are considered neither "almost certainly benign" nor "probably or obviously malignant" on the basis of history and physical examination. The controversy has its roots in uncertainty and disagreement about the true incidence of malignancy in nodular goiter, the accuracy of nonsurgical differentiation between benign and malignant nodules, and the characteristic behavior of thyroid cancer as it relates to delay in
1097
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treatment or reliance upon medical management. 9 Also relevant is the fact that interpretation of divergent opinion and contradictory data is made difficult by the excessive breadth of the prevailing "generalizations. The term "nodular goiter" describes several significantly different structural alterations in the thyroid gland, each of which may demonstrate different clinical behavior. Despite general recognition of this fact, confusion stems from the lack of a truly suitable classification of nodular goiters having various physical characteristics. As a result, subjective factors influence statistical analyses, selective processes may be overlooked or undefined, and groups of patients subjected to various forms of treatment by different physicians or groups may not be truly comparable. Almost any classification of nodular goiters based upon physical characteristics is vulnerable to criticism, but some classification is necessary to facilitate analysis of differing opinions and to serve as a basis for recommendations about management. The following groups, differing with respect to physical properties, the incidence of malignancy, and the frequency with which they are managed surgically, are not sharply separable but do provide a basis for subsequent discussion. 1. Probably the majority of all nodular goiters appear as multiple nodules in small, nearly symmetric, asymptomatic thyroid glands of normal and uniform consistency. The incidence of malignancy in these is less than in groups described below; occult cancers presenting in small soft nodules have truly favorable prognoses; and changes in size or consistency in such a thyroid gland can be detected easily. It is likely that this type of nodular goiter is seldom managed surgically in any institution. 2. At the opposite end of the clinical spectrum of nodular goiters are the obviously malignant lesions which may present with fixation to neighboring structures or skin, vocal-cord paralysis, or cervical adenopathy. Nodular goiters in young patients and firm or hard solitary nodules that are not sharply outlined are not always cancerous; but the incidence of malignancy is clearly greater in such cases than in the group described above, and there is general agreement that surgical evaluation is appropriate. Because there is little controversy about the indications for surgical management of symptomatic thyroid nodules and those of questionable toxicity, these nodular goiters also are included in this group. 3. Between these two extremes there is an uncertain group. Suspicion of malignancy is difficult to define, and it is not surprising that there is a gray area in the characterization of some physical characteristics; the result is disagreement with respect to the incidence of malignancy and the indications for surgery. Included in this group are the asymptomatic nodular glands of moderate size, asymmetric goiters, those with varia-
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tions of consistency, and apparently solitary soft or cystic sharplyoutlined nodules. Although such a classification is inexact and differences between groups cannot be sharply defined, it is clear that the term "nodular goiter" is used to describe a great variety of clinical conditions; and generalizations about management which ignore this fact are unjustified. The discussion of the controversial aspects of management is simplified if one has license to refer to nodular goiters as (1) "apparently innocent," (2) "clearly surgical," and (3) "controversial" with respect to management. Uncertainty of Incidence of Malignancy
The marked difference in incidence of malignancy among the many series of reported cases of nodular goiter is related to two factors: the varying degrees of unrecognized or unreported selection in different series; and the fact that, whereas the incidence of malignancy can be accurately determined with surgical treatment, estimates of this incidence in nonsurgical cases are uncertain unless based on extremely long-term follow-up. The surgeon who is unaware of the extent of the selective process upon which his practice depends is unaware of the predominance of "innocent" goiters and may conclude from his frequent encounters with malignancy that operation is indicated for all patients with nodular goiter. Conversely, the practitioner or internist who frequently feels minor alterations in thyroid structure and only occasionally sees thyroid cancer may conclude quite reasonally that only a small percentage of all nodular goiters are malignant. This impression is intensified if he has little opportunity for long-term follow-up of individual patients and if he is unaware of the natural history of many thyroid cancers. The incidence of clinically unrecognizable cancer in nodular goiters is neither so great as to justify surgical evaluation for all cases nor so insignificant as to permit neglect of every asymptomatic thyroid nodule. In this dilemma, the need for some useful classification based upon physical characteristics and some knowledge of the accuracy of clinical criteria for differentiation of benign and malignant nodular goiters is obvious. CLINICAL DIFFERENTIATION BETWEEN BENIGN AND MALIGNANT GOITER
Accuracy of Diagnosis from History and Physical Findings
There is good evidence to support the view that clinical criteria are reasonably accurate in differentiating benign from malignant disease, if one compares the two extremes of physical change found in abnormal
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thyroid glands. 7 Perhaps the best evidence for some degree of success in preoperative differentiation is the marked difference in the incidence of malignancy reported in surgical and nonsurgical series. However, the value of clinical criteria in recognizing major physical differences does not prove the worth of clinical judgments about minor ones; and the limitations of clinical criteria for differentiation become more apparent when one considers the midportion of the spectrum of this disease. In this regard a recent evaluation of the accuracy of clinical differentiation between thyroid cancer and benign goiter by Shimaoka and others is interesting. These authors classified 214 cases of nontoxic goiter as "benign," "suspected of cancer," and "probably cancer" on the basis of preoperative evaluation. Among the 202 considered benign, thyroid cancer was proved in 2 per cent; and among those in which malignancy was suspected or thought probable, it was proved in 40 per cent. Their figures indicate "that patients with goiter can be divided quite successfully into low and high cancer-risk groups and that preoperative selection is justified." The truth of this statement and the vallie of the study are not questioned; however, other aspects of the analysis deserve comment. Of the 202 patients considered to have benign disease, 63 underwent thyroidectomy within a year of the initial evaluation, and four of these (6 per cent) were found to have cancer. Among the remaining 139 patients, benignancy was proved in 14; but in 125 it was only presumed on the basis of follow-ups of three to six years. The absence of undifferentiated, aggressive malignancy in this group can be assumed; but observations by Beahrs and co-workers, that the goiter had been present for five or more years before thyroidectomy in 40 per cent of the cases of thyroid cancer and that a history of recent change in thyroid size was obtainable in only 27 per cent of cases, point up the uncertainty about the true incidence of malignancy in these 125 patients. These authors commented in the usual way about the clinical criteria for selection. In the controversial group (3, above) the uncertainty of physical features and the subjectivity of preoperative judgment were apparent; and these remarks should not be surprising when one considers the limitations on gross pathologic diagnosis of some surgical specimens. In Shimaoka's series, the incidence of cancer in surgically treated nodular goiters presumed to be benign on clinical grounds closely approximates the figure upon which we have based our policy of management3 for many years. To subscribe to a policy of operative examination of many asymptomatic thyroid nodules is not to suggest that it is ideal. The conscientious, conservative surgeon is troubled by the fact that, to provide optimal therapy for patients with thyroid carcinoma, many others must have an operation that retrospectively is unnecessary. It is hoped that future progress in thyroid physiology will greatly diminish
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the need for surgical evaluation, for truly adequate substitutes are not available today. Usefulness of the Gammagram
Because there is some correlation between the incidence of malignancy in thyroid nodules and their functional activity, the gammagram may be useful in the clinical appraisal of nodular goiters. 2 , 5, 6 Nodules having decreased function or none are much more often malignant than those showing normal or increased uptake of radioactive iodine. However, assessment of function is not a substitute for microscopic examination; so-called cold or cool nodules are not invariably malignant, and cancer is not excluded by the demonstration of a so-called warm or hot nodule. The limitations of this diagnostic adjunct are increased by the fact that clinically significant nodules may be obscured by surrounding tissue with normal function. Hence the gammagram supports but does not replace clinical judgment. It is most useful for detecting functioning thyroid tissue outside the neck, for evaluating thyroid function or structure after thyroidectomy, and for appraisal of the patient who has nodular goiter but is not a good surgical risk. Diagnostic Value of Exogenous Thyroid
Although disturbances in thyroid physiology must have a major influence in the pathogenesis of most benign nodular goiters and some thyroid cancers, these mechanisms are not completely defined; and studies of the use of desiccated thyroid for differentiation between benign and malignant goiter are inconclusive. It is unfortunate that Astwood and associates, who apparently believed that nearly all nodular goiters are benign, were not more specific about the length of follow-up in their cases and the possible influence of selection prior to their evaluation. Physical alterations in nodular goiter induced by thyroid medication are variable and their significance is uncertain. Changes ordinarily are confined to the normal parenchyma which surrounds nodules, and shrinkage or disappearance of the nodule indicates benignancy to some physicians and malignancy to others.8 This difference in interpretation would be less significant if there were agreement about the persistence of hormonal dependency in certain types of thyroid cancer. In contrast to the uncertainty concerning the use of exogenous thyroid for evaluation of adenomatous goiter, the use of this substance in the management of Hashimoto's thyroiditis is a well-established procedure.u Although change "from an anatomic to a physiologic approach in the management of thyroid nodules"8 may be hoped for, uncertainties inherent in the use of desiccated thyroid as a diagnostic agent lead us to rely primarily upon surgery for evaluation of the controversial (Group 3) thyroid nodule.
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IMPLICATIONS OF THE TYPICAL COURSE OF THYROID CARCINOMA
Some types of thyroid cancer are usually incurable, even by prompt surgical treatment; but the more common types of thyroid carcinoma grow slowly, metastasize late, and are fairly well controlled even when surgical treatment is delayed. These facts suggest that reasonable periods of delay for the purpose of evaluation without surgery may have little effect upon the curability of lesions ultimately proved to be malignant. Some workers justify evaluation by such means on the basis that some thyroid cancers may be controlled by administration of thyroid hormone,8 while others point up the fact that thyroid cancer may develop despite (or because of) prior partial thyroidectomy. 9 Clearly, biologic factors cannot be ignored; but specific principles of management based upon these observations are difficult to formulate. Potentially curable cancers may progress to a stage which compromises the chance of cure, and such a change is not always marked by clinical evidence. Certainly growth of a suspicious nodule is an indication for surgical evaluation; but such a change may be difficult to assess in the multinodular gland of moderate size, and metastasis may occur without clinically detectable growth of a nodule. When such change is undetected, does one then wait for unequivocal evidence of malignancy or for evidence of nodal or distant metastasis? Many patients do not cooperate in plans for long-term periodic examination and others will not accept the uncertainty which attends observation or nonsurgical management when the risks and principles of such a program cannot be defined accurately. Certainly the biologic nature of thyroid cancer is relevant to the management of the "controversial" group of nodular goiters. Reasonable delays in surgical evaluation are acceptable, but there is little justification for long-term observation of these patients. If observation with feeding of exogenous thyroid is undertaken, it is best to base decisions upon a prompt definite response with perhaps no more than a few months of observation. However, the value of desiccated thyroid as a diagnostic agent is uncertain and its use is best restricted to the postoperative patient whose disease has been defined, the patient for whom risk of surgery is excessive, and the subject for clinical research.
SELECTION FOR SURGICAL MANAGEMENT AT THE MAYO CLINIC
Factors in Selection
At this clinic, decisions about surgical management of the nontoxic nodular goiter are based chiefly upon the history, the physical findings,
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and the life expectancy of the patient. A formal study of the influence of gammagrams upon decisions in questionable cases has not been undertaken, but the limitations of this diagnostic measure have been mentioned above. Desiccated thyroid, employed commonly in the management of Hashimoto's thyroiditis, is not used in attempts to differentiate between benign and malignant nodular goiters. Within the mid spectrum of physical changes (Group 3), variations of consistency in portions of the gland, asymmetry, or nodules with irregular contour or lack of distinct margins provoke concern. Most often nodules that seem to be solitary are investigated surgically, particularly if they are more than 2 cm. in size or if they are more firm than the surrounding parenchyma. The age and life expectancy of the patient are of great importance in surgical judgments. Hayles and others emphasized the significance of youth, finding that among nodular goiters of children treated surgically at the Mayo Clinic between 1950 and 1955, cancer was present in 70 per cent. The significance of age or imperfect health in the patient whose longevity could not be affected by the common forms of thyroid cancer is obvious. RELATED DISEASES. Because the various types of thyroiditis may simulate adenomatous goiter or thyroid cancer and because they may exist in association with these entities, thyroiditis must be considered in any discussion of benign and malignant goiter. Woolner and associates12 in this clinic have reported recently on the surgical aspects of thyroiditis, so the discussion here will be brief. Riedel's struma, usually considered clinically to be a carcinoma, is clearly a surgical problem. Although the diagnosis of granulomatous thyroiditis ordinarily can be made on the basis of clinical and laboratory findings, needle biopsy is indicated in the atypical case. In approximately 10 per cent of cases an asymptomatic nodule is the only finding, and this requires surgical evaluation. Hashimoto's thyroiditis in its more common form usually can be suspected on the basis of clinical and laboratory data. Histologic confirmation based upon a biopsy specimen obtained with a Silverman needle is desirable, but treatment with desiccated thyroid may be undertaken on a presumptive diagnosis based on a diffuse symmetric goiter having rubbery consistency. At times Hashimoto's thyroiditis is indistinguishable clinically from nontoxic adenomatous goiter, and surgical intervention is advisable if the gland has suspicious nodularity or marked asymmetry or if the disease fails to respond to the administration of desiccated thyroid. Proportion of Cases with Surgical Management
A general impression about the extent of selection of patients for
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surgical evaluation at the Mayo Clinic can be obtained from the "General Summary of Diagnoses" tabulated each year by the Section of Biometry and Medical Statistics. In 1961 nontoxic nodular goiter (excluding thyroiditis) was indexed as a diagnosis for 1712 patients, and 495 of these were treated surgically. Review of similar reports for a 20-year period showed a remarkably similar ratio. It appears that between onefourth and one-third of the cases of nodular goiter seen at this institution are managed surgically. Probably the clinician sometimes fails to record all of his findings on the summary sheet; and to a corresponding extent, the proportion of patients managed surgically would be less. The present report affords no conclusion about malignancy in thyroid nodules, and these figures are presented only to indicate in a general way the number of patients with nodular goiter who are not managed surgically. In addition to the 495 patients who underwent surgery for benign nodular goiter without hyperthyroidism in 1961, 45 patients with thyroiditis had partial thyroidectomy, and 76 patients were treated surgically for carcinoma of the thyroid gland. Thus, of 616 surgical patients with nontoxic nodular goiter, 12 per cent did have thyroid cancer. However, this percentage is not relevant to any argument about the management of the controversial group of thyroid nodules, because it included also the many clinically obvious cancers. Study of surgical and pathologic reports revealed that in one-third of the 76 cases the preoperative evidence for malignancy was unequivocal, in one-third the malignancy was manifested clinically as an apparently solitary nodule, and in one-third the thyroid gland was multinodular. Verification of Malignancy
The incidence of malignancy in nontoxic nodular goiters treated surgically at the Mayo Clinic in previous years has been reported by Beahrs and associates. Among all patients having a preoperative diagnosis of nodular goiter without hyperthyroidism, occult carcinomas were found in 3.8 per cent; and when all cases of nodular goiter without hyperthyroidism-regardless of preoperative clinical impression-were considered, the incidence of cancer was found to be 7.5 per cent. Further evidence of the imperfections of clinical evaluation has appeared in a study by Woolner and co-workers,lO who reported on a series of cases of thyroid cancer seen at this clinic. Carcinoma was diagnosed or suspected preoperatively in only one-third of 509 cases of papillary carcinoma and in only six of 157 cases of follicular cancer. The limitations of clinical assessment were not so marked in other forms of carcinoma, but definite suspicion of malignancy was recorded in only 27 of 57 cases of solid carcinoma with amyloid stroma and 96 of 130 cases of anaplastic carcinoma. It is difficult to believe that the management
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of the patients thought to have had benign disease would have been simplified or improved by the use of desiccated thyroid for evaluation or by observation until an unequivocal diagnosis of cancer could be made on clinical grounds. SUMMARY AND CONCLUSION
The term "nodular goiter" denotes both a variety of structural abnormalities and a number of clinically different diseases of the thyroid gland. Clinical differentiation between groups of patients with nontoxic nodular goiter having low and high incidence of malignancy is possible, and the biologic nature of most thyroid cancers permits reasonable delays in diagnosis without compromise of curability. So far as these considerations extend, surgical evaluation is not indicated for all nodular goiters and the need for operation in questionable cases is seldom urgent. However, the limitations of clinical criteria for differentiating between benign and malignant nodules in some situations, the uncertainties of physiologic methods of diagnosis, and the advantages of treating thyroid cancer before it becomes clinically obvious are justification for resort to surgical evaluation of many asymptomatic nodular goiters. It is not suggested that this practice is ideal, but suitable alternatives are lacking. The need for more reliable measures for differentiation between benign and malignant thyroid nodules is obvious. REFERENCES 1. Astwood, E. B., Cassidy, C. E. and Aurbach, G. D.: Treatment of goiter and thyroid nodules with thyroid. J.A.M.A. 174: 459-464 (Oct. 1) 1960. 2. Bartels, E. C., Bell, G. O. and Geokas, M. C.: Evaluation of thyroid nodule. S. CLIN. NORTH AMERICA 42: 655-665 (June) 1962. 3. Beahrs, O. B., Pemberton, J. deJ. and Black, B. M.: Nodular goiter and malignant lesions of thyroid gland. J. Clin. Endocrinol. 11: 1157-1165 (Oct.) 1951. 4. Hayles, A. B., Kennedy, R. L. J., Woolner, L. B. and Black, B. M.: Nodular lesions of thyroid gland in children. J. Clin. Endocrinol. 16: 1580-1594 (Dec.) 1956. 5. Johnson, P. C. and Beierwaltes, W. H.: Reliability of scintiscanning nodular goiters in judging presence or absence of carcinoma. (Abstr.) J. Clin. Endocrinol. 15: 865 (July) 1955. 6. Meadows, P. M.: Scintillation scanning in management of clinically single thyroid nodule. J.A.M.A. 177: 229-234 (July 29) 1961. 7. Shimaoka, K., Badillo, J., Sokal, J. E. and Marchetta, F. C.: Clinical differentiation between thyroid cancer and benign goiter: An evaluation. J.A.M.A. 181: 179-185 (July 21) 1962. 8. Sloan, L. W., Crile, G., Jr., Frantz, V. K., Rawson, R. W. and Werner, S. C.: Management of solitary thyroid nodule: Transcription of a panel meeting on therapeutics. Bull. New York Acad. Med. 35: 178-204 (March) 1959. 9. Sokal, J. E.: Problem of malignancy in nodular goiter-recapitulation and a challenge. J.A.M.A. 170: 405-412 (May 23) 1959. 10. Woolner, L. B., Beahrs, O. H., Black, B. M., McConahey, W. M. and Keating,
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F. R., Jr.: Classification and prognosis of thyroid carcinoma: A study of 885 cases observed in a thirty-year period. Am. J. Surg. 102: 354-387 (Sept.) 1961. 11. Woolner, L. B., McConahey, W. M. and Beahrs, O. H.: Struma lymphomatosa (Hashimoto's thyroiditis) and related thyroidal disorders. J. Clin. Endocrino!' 19: 53-83 (Jan.) 1959. 12. Woolner, L. B., McConahey, W. M. and Beahrs, O. H.: Surgical aspects of thyroiditis. Am. J. Burg. 104: 666-671 (Nov.) 1962.