Clinical Endocrinology (1992)57,398-401
Current therapy
Management of the single thyroid nodule M. C. Sheppard and J. A. Franklyn Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham 675 2TH, UK (Received 8 April 1992; returned for revision 17 June 1992; finally revised 2 July 1992; accepted 28 July 7992)
Thyroid nodules are common in the general population although prevalence data vary depending on the detection methodology employed, as well as the criteria used to define a nodule. A palpable ‘solitary’nodule was present in 3.2% of women studied in the Whickham survey in the North East of England (Tunbridge et al., 1977); similarly the Framingham study in the USA found that 4.2% of the surveyed population of 5127 had a thyroid nodule (6.4% in females, 1.6% in males) (Yander et al., 1968). In the latter study, follow-up for 15 years revealed 67 new nodules, representing a rate of development of 1.4% over that period or approximately 0.1 YO per annum. In the region surrounding Chernobyl, in the former USSR, palpable nodules were present in 2.9% of 484 adult subjects (F. A. Mettler, personal communication). In general, clinically apparent nodules are more common in women than men, increase in frequency with age, and occur in 20-30% of a radiation exposed population. Nodular thyroid disease is, however, even more common than suggested by such clinical epidemiological surveys because nodules less than 1 cm in diameter cannot be reliably detected by palpation. A substantial proportion of people (up to 40%) who have clinically apparent solitary nodules on palpation have multiple nodules detected by ultrasound (Scheible et ul., 1979), and in approximately 55% of patients with nodules found at autopsy these are located in a nonpalpable area of the gland. Thus, ultrasound studies have shown that up to 30% of asymptomatic adults who have not been exposed to radiation may have thyroid nodules (Carroll, 1982; Stark et al., 1983; Hay et al., 1984; Woestyn et al., 1985), and autopsy data have revealed that up to 50% of adults have easily visible single or multiple nodules (Mortensen et nl., 1955). In contrast to this high prevalence of nodular thyroid disease, thyroid cancer is rare, accounting for less than 0.5% of all new malignancies annually registered in England and Wales and less than 0.5% of all cancer deaths (Office of Population Censuses and Surveys, 1975). Thyroid cancer is reported to have been found in only between 6 and 14% of single thyroid nodules selected for surgery on clinical Correspondence: M. C. Sheppard, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham BIS 2TH,UK. 398
grounds (Messaris et al., 1974; Liechty et al., 1977; Molitch et al., 1985); the risk of malignancy is lower in multinodular goitre than in solitary nodules of the thyroid (Cole et al., 1949). The picture is, however, complicated by autopsy studies which describe the presence of ‘occult’cancer in up to 5% of thyroid glands normal to palpation (Mortensen et al., 1955). Most occult cancers, however, are only several millimetres in diameter and the substantial prevalence of occult cancer in patients who have died from unrelated causes suggests that this is an entity without clinical significance. The challenge in clinical practice therefore is to identify the small numbers of patients presenting with neoplastic disease from the majority without, in the process sparing up to 90% of patients with solitary nodules unnecessary surgery. Hlstory and cllnlcal examlnatlon
Previous exposure to ionizing radiation is a well documented risk factor for the development of thyroid cancer and a number of large studies have reported an increased incidence of both benign and malignant nodules after head and neck irradiation (Conard et al., 1970; Maxon et al., 1977). Increasing age may increase susceptibility but nodular thyroid disease is uncommon in children and its presence should be viewed with suspicion (Silverman et al., 1979). There is a greater risk of cancer in males than females and there are regional differences in the prevalence of cancer unrelated to prevalence of goitre. In general, thyroid diseases are not associated with thyroid cancer; however, an increased incidence of lymphoma has been reported in association with Hashimoto’s thyroiditis (Burke et al., 1977). Local symptoms such as dyspnoea, dysphagia and hoarseness, as well as rapid enlargement of the gland and fixation to surrounding structures may suggest compression or local invasion from a malignant lesion, but less than 5% of patients with thyroid cancer have such local symptoms (Hoffman et al., 1972; Walfish et al., 1977). Physical characteristics of the nodule are thus poor predictors of a malignant lesion although it is important to examine the neck carefully for the presence of lymph nodes. Laboratory tnvestlgatlons
No laboratory test is of any value in distinguishing benign from malignant lesions of the thyroid. Circulating concentrations of thyroid hormones and TSH should be measured, however, to exclude a toxic nodule which can then be treated by surgical removal or radioiodine; malignant change asso-
Clinical Endocrinology (1992) 37
Management of the single thyroid nodule
399
ciated with a hot nodule is rare. Similarly, it is important to exclude hypothyroidism, which if secondary to Hashimoto’s thyroiditis may be associated with a firm goitre or even an apparent single nodule on palpation. Serum thyroglobulin concentrations are elevated in patients with goitre but values are similar to those with benign and malignant nodules (Van Herle et a/., 1973). Measurement of serum thyroglobulin is of no value therefore in the initial assessment of a solitary nodule although it is of great importance in the follow-up and management of patients with differentiated thyroid cancer (Black e t a / . , 1987).
thyroxine, perhaps related to dependency on TSH for growth. The incidence of malignant disease in patients who demonstrate an apparent response to thyroid hormone suppression is not known, but it is well established that some carcinomas may respond to suppression by reducing in size (Getaz et a/., 1980). Conversely, a lack of response to a trial of thyroid hormone suppression is not specific for malignancy, the incidence of cancer in non-responders being between 12 and 40% (Blum & Goldman, 1975).
Radlonucllde imaging
Aspiration cytology by fine-needle biopsy shows a good correlation with the histology of tissue removed at operation and has emerged as a valuable tool in the diagnosis and management of nodular thyroid disease. The technique requires practice in taking samples and making the smear preparation and, most importantly, the skills of an expert cytologist. The procedure can be performed in an outpatient department, is well tolerated by the patient, and can be repeated. The cytologist can determine that an adequate smear contains normal cells only, cells from benign nontumorous conditions such as lymphocytic thyroiditis, or colloid nodules. The cytology report that is indeterminate or suspicious of malignant change should be regarded as an indication to proceed to surgical exploration-in the same way as a report of unequivocal malignancy indicating medullary, papillary or follicular carcinoma. Prolonged evaluation of the technique, especially in Sweden where it has been applied for more than 25 years, has demonstrated that in the hands of a skilled cytologist excellent diagnostic accuracy (of up to 90%) can be achieved. A false positive report of malignant change is extremely rare but the rate of false negatives (i.e. tissue thought to be benign at cytology but found to show malignant change at surgery) is 5-10% in most series, even in the hands of an experienced cytologist (Lowhagen et al., 1981). This in part is due to difficulty in distinguishing benign adenomas from malignant follicular neoplasms (Lowhagen et a/., 1981); surgical excision of all such lesions is therefore required. A recent analysis from Cusick et ai. (1990) suggested, however, that the technique may be less reliable than is widely believed. Analysis of their original data revealed an overall accuracy of 92% (Al-Sayer et al., 1985); audit of a further prospective evaluation showed an accuracy of 69% (Cusick et al., 1990). Conflicting data in reported studies may relate to the clinical nature of the swellings included (multinodular, isolated or dominant), frequency of operation, and methods used to calculate accuracy. Since 1984 we have routinely carried out fine needle aspiration in all euthyroid patients presenting with a clini-
The objective of scanning the thyroid with isotopes such as l3lI, 99mTc-pertechnetate or, where available, 1231,is to classify nodules as ‘cold’ or ‘hot’ depending on their ability to concentrate isotope; theoretically, malignant tissue does not incorporate isotope. The technique, however, has a poor sensitivity and specificityin the diagnosis of malignancy. In a review of series in which all patients underwent surgery regardless of the findings of radionuclide scanning, 84% of nodules were cold, 10.5% were warm and 5.5% were hot. At surgery, malignancy was found in 16% of cold nodules, 9% of warm nodules, and 4% of hot nodules (Ashcraft & Van Herle, 1981a, b). Thus a cold nodule has the greatest probability of being malignant, but most are benign, and the appearance of a hot nodule does not exclude malignancy. Ultrasound scannlng
Ultrasound examination of the thyroid is an accurate means of assessing thyroid size and the presence of nodules, as well as of distinguishing solid from cystic lesions. Nodules can be classified as solid, cystic or mixed solid and cystic, with an accuracy of greater than 90%. In a review of published series of ultrasound scans, 69% of nodules were found to be solid, 19% cystic and 12% mixed. Of cases proceeding to surgery, 21% of the solid lesions were found to be malignant, compared with 12% of the mixed and 7% of the cystic lesions (Ashcraft & Van Herle, 1981, b). Thus a solid nodule has the greatest likelihood of harbouring malignancy, although most solid lesions are benign and the presence of a cystic lesion does not exclude malignancy. Once again the problem is that if all semi-solid or solid lesions were operated upon, malignant change would be found only in a small proportion. Thyroid hormone suppression
Attempts have been made to distinguish benign from malignant nodules by a change in size in response to
Flne needle asplration cytology
400
M. C. Sheppard & J. A. Franklyn
cally apparent single nodule or an increase in thyroid size (Franklyn et al., 1987). We have examined outcome in 413 consecutive patients followed for a minimum of 12 months after first aspirate. Patients were classified as having benign or suspicious/malignant cytological features after their first aspirate. The former group (87% of the total) was managed conservatively, apart from those requiring surgery because of thyroid size or patient preference, and the latter group (13%) proceeded to histological examination. In total, 76% of patients were observed and 24% underwent partial or subtotal thyroidectomy. Of 359 patients with benign cytological findings, clinical follow-up of all and surgery in a minority suggested that ‘true negative’ cytology was present in 354. There were five ‘false negative’ reports relating to sampling error: three cases of papillary carcinoma and two follicular adenomas. Fifteen ‘malignant’ cytological reports correctly identified thyroid malignancy; 39 ‘suspicious’ reports prompting surgery identified 20 ‘true positive’ cases of thyroid neoplasia (including cancers and follicular adenomas); 19 of this group had benign colloid goitre. These results indicate a diagnostic accuracy of the cytological findings of up to 94%. A diagnosis of thyroid cyst was made in 17% of our series of patients presenting with solitary nodules on clinical examination. These patients were investigated only by fine needle aspiration but had they proceeded to radionuclide scanning, such lesions would have appeared cold. Approximately 50% of such patients were cured by simple aspiration of cyst fluid, thus avoiding thyroid surgery. Injection of cysts with tetracycline as a sclerosant has been shown to be of value for recurrent cysts (Edmonds & Tellez, 1987). Thus in addition to its diagnostic role, aspiration of thyroid nodules may be of therapeutic importance. Strategy for investigation
The appropriate diagnostic evaluation of the patient presenting with nodular thyroid disease remains controversial, despite the frequency of the problem. Several alternative strategies have been proposed ranging from immediate surgery of all lesions to selective surgery after one or more of a series of investigations including radionuclide imaging, ultrasound scanning, a trial of thyroid hormone suppression and fine needle or large needle biopsy. Molitch et al. (1985) have applied decision analysis to examination of the value of these different strategies, balancing possible long-term benefits of increased life expectancy after surgery against the risk of operative complications, and the value of imperfect diagnostic techniques that alter surgical selection. This sort of analysis is complicated by the fact that for papillary and mixed follicular/papillary tumours, age-matched survival appears to be unchanged from control subjects when the
Clinical Endocrinology (1992) 37
diagnosis is made below the age of 40. In older patients relative survival rates are lower, falling to 80% at 20 years from diagnosis. The data for follicular carcinoma are similar to those for papillary carcinoma. In view of the good prognosis for most patients with differentiated thyroid cancer it is not surprising that only small differences can be demonstrated between the predicted values of each strategy for investigation and management. At age 20 aspiration cytology provides a benefit of 0.05% of life expectancy over thyroid hormone suppression, which in turn outweighs immediate surgery by 0.16%. Considerations other than life expectancy therefore need to be taken into account and fine needle aspiration cytology, as a sole investigation, followed by selective surgery, is emerging as an appropriate scheme for patient management. This scheme has resulted in a reduction in the number of scintigraphic and ultrasound scans and the number of operations performed in many clinics. In our own series, surgery was performed for removal of neoplastic tissue in 40% of cases, compared with a predicted rate of 9.6% if all solitary nodules have been removed. Al-Sayer et al. (1985) and Hamberger et af. (1982) have reported a 25% reduction in frequency of operation for single thyroid swellings and an increase in the proportion of operations for neoplastic disease from 31 to 50% after routine use of aspiration cytology. This approach not only spares many patients with benign disease unnecessary surgery but leads to substantial financial savings. In centres where large numbers of patients with solitary nodules are seen and where expert cytological skills are available, fine needle aspiration cytology is to be recommended for routine use in the diagnostic evaluation of such patients. In these circumstances we would recommend that patients with malignant or suspicious cytological findings, or where clinical suspicion is high, be referred for selective surgery. Definition of an optimum management strategy does depend, however, on the long-term follow-up of patients with negative results by such centres.
Acknowledgements
We are grateful to Dr Jennifer Young and other members of the Department of Pathology for their expert cytological interpretation and to Mr G. D. Oates for his continued encouragement and advice.
References Al-Sayer, H.M., Krukowski, Z.H., Williams, W.M.M. & Matheson, N.A. (1985) Fine needle aspiration cytology in isolated thyroid swellings; a prospective two year evaluation. British Medical Journal, 290, 1490-1492.
Clinical Endocrinology (1992) 37
Ashcraft, M.W. &Van Herle, A.J. (1981a) Management of thyroid nodules. I History and physical examination, blood tests, X-ray tests and ultrasonography. Head and Neck Surgery, 3,216-230. Ashcraft, M.W. &Van Herk, A.J. (1981b)Management ofthyroid nodules. I1 Scanning techniques, thyroid suppressive therapy and fine needle aspiration. Head and Neck Surgery, 3,297-322. Black, E.G., Sheppard, M.C. & Hoffenberg, R. (1987)Serial Serum thyroglobulin measurements in the management of differentiated thyroid carcinoma. Clinical Endocrinology, 21, 115-1 19. Blum, M. & Goldman, A.B. (1975) Improved diagnosis of nondelineated thyroid nodules by oblique scintillation scanning and echography. Journal of Nuclear Medicine, 16,7 13-715. Burke, J.S., Butler, J.J. &Fuller, L.M. (1977)Malignant lymphoma of the thyroid. Cancer, 39, 1587-1598. Carroll, B.A. (1982) Asymptomatic thyroid nodules; incidental sonographic detection. American Journal of Radiology, 133,449501. Cole, W.H., Majarakis, J.D. & Slaughter, D.P. (1949)Incidence of carcinoma of the thyroid in nodular goitre. Journal of Clinical Endocrinology and Metabolism, 9, 1007-I01 1. Conard, R.A., Dobyns, B.M. & Sutow, W.W. (1970) Thyroid neoplasia as a late effect of exposure to radioactive iodine in fall out. Journal of the American Medical Association, 214,316-324. Cusick, E.L., MacIntosh, C.A., Krukowski, Z.H., Williams,
V.M.M.,Ewen,S.W.B.&Matheson,N.A.(1990)Managementof isolated thyroid swellings: a prospective six year study of fine needle aspiration cytology in diagnosis. British Medical Journal, 301,318-321. Edmonds, C.J. & Tellez, M. (1987) Thyroid cysts and their management. British Medical Journal, 295,529. Franklyn, J.A., Fitzgerald, M.G., Oates, G.D. & Sheppard, M.C. (I987) Fine needle aspiration cytology in the management of euthyroid goitre. Quarterly Journal of Medicine, 248,997-1003. Getaz, E.P., Shimaoka, K., Razack, M., Friedman, M. & Rao, U. (1980)Suppressive therapy for post-irradiation thyroid nodules. Canadian Journal of Surgery, 23,558-562. Hamberger, B., Gharib, H., Melton, L.J., Goellner, J.R. & Zinsmeister, A.R. (1982) Fine needle aspiration biopsy of thyroid nodules: impact on thyroid practice and cost of care. American Journal of Medicine, 73, 381 -383. Hay, I.D., Reading, C.C. & Charboneau, J.W. (1984)High resolution real time ultrasonography and unsuspected micronodular thyroid disease. Lancet, 21,916. Hoffman, G.L., Thompson, N.W. & Heffron, C. (1972)The solitary thyroid nodule: a reassessment. Archives of Surgery, 74,44748. Liechty, R.D., Stoffel, P.T., Zimmerman, D.E. & Silverberg, S.G. (1977)Solitary thyroid nodules. Archiues of Surgery, 112,59-61.
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Lowhagen, T., Willems, J.S., Lundell,G., Sundblad, R.&Granberg, P.O.(1981)Aspiration biopsy cytology in the diagnosis of thyroid cancer. World Journal of Surgery, 5, 61-73. Maxon, H.R., Thomas, S.R., Saenger, E.L., Buncher, C.R. & Kereiakes, J.G. (1977) Ionizing irradiation and the induction of clinically significant disease in the human thyroid gland. American Journal of Medicine, 63,967-978. Messaris, G., Kyriakou, K., Vasilopoulos, P. & Tountas, C. (1974) The single thyroid nodule and carcinoma. British Journal of Surgery, 61,943-944. Molitch, M.E., Beck, J.R., Dreisman, M., Gottlieb, J.E. & Pauker, S.G. (1985)The cold thyroid nodule: an analysis of diagnostic and therapeutic options. Endocrine Reviews, 5, 185-199. Mortensen, J.D., Woolner, L.B. & Bennett, W.A. (1955)Gross and microscopic findings in clinically normal thyroid gland. Journal of Clinical Endocrinology and Metabolism, IS, 1270-1280. Office of Population Censuses and Surveys (1975)Cancer statistics. Cases of diagnosed cancer registered in England and Wales. Series MBI no. 5. London: Her Majesty’s Stationery Office. Scheible, W., Leopold, G.R., Woo, V.L. & Gosink, B.B. (1979) High-resolution real time ultrasonography of thyroid nodules. Radiology, 133,413417, Silverman, S.H., Nussbaum, N. & Rausen, A.R. (1979) Thyroid nodules in children: a ten year experience at one institution. Mount Sinai Journal of Medicine, 46,460-465. Stark, D.D., Clark, O.H., Gooding, G.A. & Moss, A.A. ( 1983)High resolution ultrasonography and computed tomography of thyroid lesions in patients with hyperparathyroidism. Surgery, 94, 863-868. Tunbridge, W.M.G., Evered, D.C., Hall, R., Appleton, D., Brewis, M., Clark, F., Grimley Evans, J., Young, E. & Smith, P.A. (1977) The spectrum of thyroid disease in a community: the Whickham Survey. Clinical Endocrinology, 7.48 1493. Vander, J.B., Gaston, E.A. & Dawber, T.R. (1968)The significance of non-toxic thyroid nodules: final report of a 15 year study of the incidence of thyroid malignancy. Annals of Internal Medicine, 69, 537-540. Van Herle, A.J., Uller, R.P., Matthews, N.L. & Brown, J. (1973) Radioimmunoassay for measurement of thyroglobulin in human serum. Journal of Clinical Investigation, 52, 1320-1327. Walfish, P.G., Hazani, E., Strawbridge, H.T.G., Miskin, M. & Rosen, I.B. (1977)Combined ultrasound and needle aspiration cytology in the assessment and management of hypofunctioning thyroid nodules. Annals of Internal Medicine, 87,270-274. Woestyn, J., Ashcrift, M., Schelstraete, K. & Vermeulen, A. (1985) Demonstration of nodules in normal thyroid by echography. British Journal of Radiology, 58, 1179-1 182.
Current therapy
Management of the single thyroid nodule M. C. Sheppard and J. A. Franklyn Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham 675 2TH, UK (Received 8 April 1992; returned for revision 17 June 1992; finally revised 2 July 1992; accepted 28 July 7992)
Thyroid nodules are common in the general population although prevalence data vary depending on the detection methodology employed, as well as the criteria used to define a nodule. A palpable ‘solitary’nodule was present in 3.2% of women studied in the Whickham survey in the North East of England (Tunbridge et al., 1977); similarly the Framingham study in the USA found that 4.2% of the surveyed population of 5127 had a thyroid nodule (6.4% in females, 1.6% in males) (Yander et al., 1968). In the latter study, follow-up for 15 years revealed 67 new nodules, representing a rate of development of 1.4% over that period or approximately 0.1 YO per annum. In the region surrounding Chernobyl, in the former USSR, palpable nodules were present in 2.9% of 484 adult subjects (F. A. Mettler, personal communication). In general, clinically apparent nodules are more common in women than men, increase in frequency with age, and occur in 20-30% of a radiation exposed population. Nodular thyroid disease is, however, even more common than suggested by such clinical epidemiological surveys because nodules less than 1 cm in diameter cannot be reliably detected by palpation. A substantial proportion of people (up to 40%) who have clinically apparent solitary nodules on palpation have multiple nodules detected by ultrasound (Scheible et ul., 1979), and in approximately 55% of patients with nodules found at autopsy these are located in a nonpalpable area of the gland. Thus, ultrasound studies have shown that up to 30% of asymptomatic adults who have not been exposed to radiation may have thyroid nodules (Carroll, 1982; Stark et al., 1983; Hay et al., 1984; Woestyn et al., 1985), and autopsy data have revealed that up to 50% of adults have easily visible single or multiple nodules (Mortensen et nl., 1955). In contrast to this high prevalence of nodular thyroid disease, thyroid cancer is rare, accounting for less than 0.5% of all new malignancies annually registered in England and Wales and less than 0.5% of all cancer deaths (Office of Population Censuses and Surveys, 1975). Thyroid cancer is reported to have been found in only between 6 and 14% of single thyroid nodules selected for surgery on clinical Correspondence: M. C. Sheppard, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham BIS 2TH,UK. 398
grounds (Messaris et al., 1974; Liechty et al., 1977; Molitch et al., 1985); the risk of malignancy is lower in multinodular goitre than in solitary nodules of the thyroid (Cole et al., 1949). The picture is, however, complicated by autopsy studies which describe the presence of ‘occult’cancer in up to 5% of thyroid glands normal to palpation (Mortensen et al., 1955). Most occult cancers, however, are only several millimetres in diameter and the substantial prevalence of occult cancer in patients who have died from unrelated causes suggests that this is an entity without clinical significance. The challenge in clinical practice therefore is to identify the small numbers of patients presenting with neoplastic disease from the majority without, in the process sparing up to 90% of patients with solitary nodules unnecessary surgery. Hlstory and cllnlcal examlnatlon
Previous exposure to ionizing radiation is a well documented risk factor for the development of thyroid cancer and a number of large studies have reported an increased incidence of both benign and malignant nodules after head and neck irradiation (Conard et al., 1970; Maxon et al., 1977). Increasing age may increase susceptibility but nodular thyroid disease is uncommon in children and its presence should be viewed with suspicion (Silverman et al., 1979). There is a greater risk of cancer in males than females and there are regional differences in the prevalence of cancer unrelated to prevalence of goitre. In general, thyroid diseases are not associated with thyroid cancer; however, an increased incidence of lymphoma has been reported in association with Hashimoto’s thyroiditis (Burke et al., 1977). Local symptoms such as dyspnoea, dysphagia and hoarseness, as well as rapid enlargement of the gland and fixation to surrounding structures may suggest compression or local invasion from a malignant lesion, but less than 5% of patients with thyroid cancer have such local symptoms (Hoffman et al., 1972; Walfish et al., 1977). Physical characteristics of the nodule are thus poor predictors of a malignant lesion although it is important to examine the neck carefully for the presence of lymph nodes. Laboratory tnvestlgatlons
No laboratory test is of any value in distinguishing benign from malignant lesions of the thyroid. Circulating concentrations of thyroid hormones and TSH should be measured, however, to exclude a toxic nodule which can then be treated by surgical removal or radioiodine; malignant change asso-
Clinical Endocrinology (1992) 37
Management of the single thyroid nodule
399
ciated with a hot nodule is rare. Similarly, it is important to exclude hypothyroidism, which if secondary to Hashimoto’s thyroiditis may be associated with a firm goitre or even an apparent single nodule on palpation. Serum thyroglobulin concentrations are elevated in patients with goitre but values are similar to those with benign and malignant nodules (Van Herle et a/., 1973). Measurement of serum thyroglobulin is of no value therefore in the initial assessment of a solitary nodule although it is of great importance in the follow-up and management of patients with differentiated thyroid cancer (Black e t a / . , 1987).
thyroxine, perhaps related to dependency on TSH for growth. The incidence of malignant disease in patients who demonstrate an apparent response to thyroid hormone suppression is not known, but it is well established that some carcinomas may respond to suppression by reducing in size (Getaz et a/., 1980). Conversely, a lack of response to a trial of thyroid hormone suppression is not specific for malignancy, the incidence of cancer in non-responders being between 12 and 40% (Blum & Goldman, 1975).
Radlonucllde imaging
Aspiration cytology by fine-needle biopsy shows a good correlation with the histology of tissue removed at operation and has emerged as a valuable tool in the diagnosis and management of nodular thyroid disease. The technique requires practice in taking samples and making the smear preparation and, most importantly, the skills of an expert cytologist. The procedure can be performed in an outpatient department, is well tolerated by the patient, and can be repeated. The cytologist can determine that an adequate smear contains normal cells only, cells from benign nontumorous conditions such as lymphocytic thyroiditis, or colloid nodules. The cytology report that is indeterminate or suspicious of malignant change should be regarded as an indication to proceed to surgical exploration-in the same way as a report of unequivocal malignancy indicating medullary, papillary or follicular carcinoma. Prolonged evaluation of the technique, especially in Sweden where it has been applied for more than 25 years, has demonstrated that in the hands of a skilled cytologist excellent diagnostic accuracy (of up to 90%) can be achieved. A false positive report of malignant change is extremely rare but the rate of false negatives (i.e. tissue thought to be benign at cytology but found to show malignant change at surgery) is 5-10% in most series, even in the hands of an experienced cytologist (Lowhagen et al., 1981). This in part is due to difficulty in distinguishing benign adenomas from malignant follicular neoplasms (Lowhagen et a/., 1981); surgical excision of all such lesions is therefore required. A recent analysis from Cusick et ai. (1990) suggested, however, that the technique may be less reliable than is widely believed. Analysis of their original data revealed an overall accuracy of 92% (Al-Sayer et al., 1985); audit of a further prospective evaluation showed an accuracy of 69% (Cusick et al., 1990). Conflicting data in reported studies may relate to the clinical nature of the swellings included (multinodular, isolated or dominant), frequency of operation, and methods used to calculate accuracy. Since 1984 we have routinely carried out fine needle aspiration in all euthyroid patients presenting with a clini-
The objective of scanning the thyroid with isotopes such as l3lI, 99mTc-pertechnetate or, where available, 1231,is to classify nodules as ‘cold’ or ‘hot’ depending on their ability to concentrate isotope; theoretically, malignant tissue does not incorporate isotope. The technique, however, has a poor sensitivity and specificityin the diagnosis of malignancy. In a review of series in which all patients underwent surgery regardless of the findings of radionuclide scanning, 84% of nodules were cold, 10.5% were warm and 5.5% were hot. At surgery, malignancy was found in 16% of cold nodules, 9% of warm nodules, and 4% of hot nodules (Ashcraft & Van Herle, 1981a, b). Thus a cold nodule has the greatest probability of being malignant, but most are benign, and the appearance of a hot nodule does not exclude malignancy. Ultrasound scannlng
Ultrasound examination of the thyroid is an accurate means of assessing thyroid size and the presence of nodules, as well as of distinguishing solid from cystic lesions. Nodules can be classified as solid, cystic or mixed solid and cystic, with an accuracy of greater than 90%. In a review of published series of ultrasound scans, 69% of nodules were found to be solid, 19% cystic and 12% mixed. Of cases proceeding to surgery, 21% of the solid lesions were found to be malignant, compared with 12% of the mixed and 7% of the cystic lesions (Ashcraft & Van Herle, 1981, b). Thus a solid nodule has the greatest likelihood of harbouring malignancy, although most solid lesions are benign and the presence of a cystic lesion does not exclude malignancy. Once again the problem is that if all semi-solid or solid lesions were operated upon, malignant change would be found only in a small proportion. Thyroid hormone suppression
Attempts have been made to distinguish benign from malignant nodules by a change in size in response to
Flne needle asplration cytology
400
M. C. Sheppard & J. A. Franklyn
cally apparent single nodule or an increase in thyroid size (Franklyn et al., 1987). We have examined outcome in 413 consecutive patients followed for a minimum of 12 months after first aspirate. Patients were classified as having benign or suspicious/malignant cytological features after their first aspirate. The former group (87% of the total) was managed conservatively, apart from those requiring surgery because of thyroid size or patient preference, and the latter group (13%) proceeded to histological examination. In total, 76% of patients were observed and 24% underwent partial or subtotal thyroidectomy. Of 359 patients with benign cytological findings, clinical follow-up of all and surgery in a minority suggested that ‘true negative’ cytology was present in 354. There were five ‘false negative’ reports relating to sampling error: three cases of papillary carcinoma and two follicular adenomas. Fifteen ‘malignant’ cytological reports correctly identified thyroid malignancy; 39 ‘suspicious’ reports prompting surgery identified 20 ‘true positive’ cases of thyroid neoplasia (including cancers and follicular adenomas); 19 of this group had benign colloid goitre. These results indicate a diagnostic accuracy of the cytological findings of up to 94%. A diagnosis of thyroid cyst was made in 17% of our series of patients presenting with solitary nodules on clinical examination. These patients were investigated only by fine needle aspiration but had they proceeded to radionuclide scanning, such lesions would have appeared cold. Approximately 50% of such patients were cured by simple aspiration of cyst fluid, thus avoiding thyroid surgery. Injection of cysts with tetracycline as a sclerosant has been shown to be of value for recurrent cysts (Edmonds & Tellez, 1987). Thus in addition to its diagnostic role, aspiration of thyroid nodules may be of therapeutic importance. Strategy for investigation
The appropriate diagnostic evaluation of the patient presenting with nodular thyroid disease remains controversial, despite the frequency of the problem. Several alternative strategies have been proposed ranging from immediate surgery of all lesions to selective surgery after one or more of a series of investigations including radionuclide imaging, ultrasound scanning, a trial of thyroid hormone suppression and fine needle or large needle biopsy. Molitch et al. (1985) have applied decision analysis to examination of the value of these different strategies, balancing possible long-term benefits of increased life expectancy after surgery against the risk of operative complications, and the value of imperfect diagnostic techniques that alter surgical selection. This sort of analysis is complicated by the fact that for papillary and mixed follicular/papillary tumours, age-matched survival appears to be unchanged from control subjects when the
Clinical Endocrinology (1992) 37
diagnosis is made below the age of 40. In older patients relative survival rates are lower, falling to 80% at 20 years from diagnosis. The data for follicular carcinoma are similar to those for papillary carcinoma. In view of the good prognosis for most patients with differentiated thyroid cancer it is not surprising that only small differences can be demonstrated between the predicted values of each strategy for investigation and management. At age 20 aspiration cytology provides a benefit of 0.05% of life expectancy over thyroid hormone suppression, which in turn outweighs immediate surgery by 0.16%. Considerations other than life expectancy therefore need to be taken into account and fine needle aspiration cytology, as a sole investigation, followed by selective surgery, is emerging as an appropriate scheme for patient management. This scheme has resulted in a reduction in the number of scintigraphic and ultrasound scans and the number of operations performed in many clinics. In our own series, surgery was performed for removal of neoplastic tissue in 40% of cases, compared with a predicted rate of 9.6% if all solitary nodules have been removed. Al-Sayer et al. (1985) and Hamberger et af. (1982) have reported a 25% reduction in frequency of operation for single thyroid swellings and an increase in the proportion of operations for neoplastic disease from 31 to 50% after routine use of aspiration cytology. This approach not only spares many patients with benign disease unnecessary surgery but leads to substantial financial savings. In centres where large numbers of patients with solitary nodules are seen and where expert cytological skills are available, fine needle aspiration cytology is to be recommended for routine use in the diagnostic evaluation of such patients. In these circumstances we would recommend that patients with malignant or suspicious cytological findings, or where clinical suspicion is high, be referred for selective surgery. Definition of an optimum management strategy does depend, however, on the long-term follow-up of patients with negative results by such centres.
Acknowledgements
We are grateful to Dr Jennifer Young and other members of the Department of Pathology for their expert cytological interpretation and to Mr G. D. Oates for his continued encouragement and advice.
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