E it. Treating Differentiated Thyroid Carcinoma: Where Do We Draw the Line?

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1 E it I Treating Differentiated Thyroid Carcinoma: Where Do We Draw the Line? Spectrum ofbehavior.-the clinical behavior of well-differentiated-papillary and follicular-thyroidcarcinomahas become increasingly clearer in recent years. Almost all physicians now agree that these tumors display a wide spectrum of clinical behavior and that, from patient to patient, an astonishing difference may occur in the way they evolve. At one end of the spectrum, some tumors are so small and grow so slowlythatthey do not become apparent during the patient's lifetime. If they become clinically manifest, such indolent tumors typically pose no threat to the patient's survival. Even more aggressive tumors often have a protracted course that spans decades before their full malignant potential is expressed, producing distant metastatic lesions and causing death many years after their initial discovery. At the other end of the behavioral spectrum, a few tumors manifest with distant metastatic lesions and kill with such alarming speed that calling them well-differentiated carcinomas scarcely seems justifiable. Currently, this spectrum ofbehavioris widely acknowledged, and most clinicians agree that minimal therapy will achieve a good outcome in patients with more indolent tumors, whereas even aggressive treatment may not help those with the most virulent tumors. Several recognized prognostic variables can accurately predict the behavior of a tumor, and their presence or absence is now often being used to guide therapeutic decisions. Treatment Controversy.-At an international symposium! held in the Netherlands in Address reprint requests to Dr. E. L. Mazzaferri, Department of Internal Medicine, 215 Means Hall, The Ohio State University, 1654 Upham Drive, Columbus, OH Mayo Clin Proc 66: , , surgeons, endocrinologists, pathologists, and nuclear medicine specialists from 13 countries reached a consensus aboutthe treatment of differentiated thyroid carcinoma. They thought that, regardless of the patient's age, total thyroidectomy in conjunction with 13lJ ablation of the postoperative thyroid remnant was the treatment of choice except for certain clinical situations. The exceptions for which hemithyroidectomy was considered adequate were welldifferentiated papillary carcinomas confined to one thyroid lobe or with lymph node metastatic lesions on only the side of the tumor and welldifferentiatedfollicular thyroid carcinomaswith minimal capsular invasion confined to one lobe without metastatic involvement. In another international study, Baldet and associates- queried numerous thyroid experts from around the world about their choice of treatment. Total or near-total thyroidectomy was chosen by many experts for both papillary (60% of respondents) and follicular (74% of respondents) carcinomas, but few changed their opinion in relationship to the histologic type of the tumor. After total thyroidectomy for papillary thyroid carcinoma, most (81%) of the respondents recommended 60 to 115 mci 0[ to destroythe thyroid remnant. When the primary tumor was follicular carcinoma, almost all(97%) of the respondents recommended 13lJ therapy postoperatively. Most respondents recommended levothyroxine therapy postoperatively,with sensitive thyroid-stimulating hormone assays and thyroglobulin measurements to gauge suppression of thyroid-stimulating hormone. Despite this apparent consensus amongpractitioners, substantial uncertainty often surrounds proper therapy from patient to patient. Furthermore, sharp differences of opinion continue to be expressed among the experts, particularly about the extent of thyroid surgical treatment that is optimal and the postoperative use of 13lJ therapy. Thus, where to draw the line between tumors anticipated to display indolent and aggressive

2 106 EDITORIAL Mayo Clfn Proc, January 1991, Vol 66 behaviors-a line that now often dictates therapy-remains a controversial issue. Moreover, the position ofthe lineoften seemsto be a moving target that shifts, depending on the patient cohort being studied. Why does all this controversy exist? Clearly, the mostimportantreason is the lack of prospective therapeutic trials. In the absence of such studies, information has been provided primarily by retrospective studies of large patient cohorts. Although the features that predict outcome have become increasingly more explicit from these studies, their application in clinical practice remains inconsistent. Opinions differ about how several negative prognostic variables in a single patient will interact to modify outcome and what relative importance each should be given in clinical staging systems and in planning therapy. Prognostic Factors.-Some of these questions arise partly because two variables have emerged as the dominant factors in predicting outcome: the patient's age at the time of diagnosis and the stage of the tumor. Many other features such as the patient's sex, tumor histologic and other cellular features, primary tumor size, papillary tumor encapsulation, multicentricity, local invasion, lymph node or distant metastatic lesions, DNA aneuploidy, Graves' disease, and prior head and neck radiation therapy haveall been implicated as factors predictive of outcome in patients with well-differentiated thyroid carcinoma." Nevertheless, whether they are independent prognostic indicators in multivariate analyses or simply stem from other majorfeatures of the disease-most notably, the patient's age-continues to stimulate debate. Exactly how much weight one prognostic factor is given over another, particularlywhen a tumor is staged and therapy is planned, differs considerably among authors. Differences in how prognostic features are balanced against one another are perhaps best shown by consideringthe disparate clinical stagingsystems for differentiated thyroid carcinoma that have been proposed. The latest TNM (primary tumor, lymph node, and distant metastatic involvement) staging system, introduced in 1987 by the International Union Against Cancerand adoptedby the AmericanJoint Committee on Cancer, heavily emphasizes the patient's age but attributes relatively little weight to the stage ofthe tumor in young patients. The patient's age at the time of diagnosis has such a dominant effect on this classification that all tumors without associated distant metastatic lesions in patients 45 years of age oryounger are designated as stage I, despite the size of the tumor, the presence of local tumor invasion, or regional lymph nodal metastatic involvement. In sharp contrast, stage I tumors in patients 45 years ofage or older reflect the size of the tumor (1 em or smaller) and the absence oflocal invasionor lymph node metastaticinvolvement. J ustification for this classification rests heavily on the well-substantiated fact that children with this disease have an excellent prognosis. Indeed, most studies show that children with differentiated thyroid carcinoma commonly have more advanced disease at the time of initial detection than do adults, have a higher frequency of local invasion and distant metastatic lesions, and yet have an excellent prognosis." Although tumors commonly recur in children, cancer-related deaths are rare. Past age 20 years, however, the protection afforded by young age seems to wane. Cancer-associated deaths begin to occur more often in the subsequent decades, and by the fourth decade of life, they occur with high enough frequency that it seems unreasonable to ignore other tumor features on the basis of age alone. For example, Tscholl Ducommun and Hedinger" found that prognosis correlated significantly better with local tumor extension and concluded that, although patients younger than 50 years of age fared better than did olderpatients, age was by no means the most important factor for predicting prognosis. In recent years, several prognostic scoring systems have been devised in an attempt to assign a relative risk value to thyroid cancers. The European Organization for Research and TreatmentofCancerstudyreportedby Byarand colleagues" was the first innovative attempt to formulate a prognostic scoring system from a multivariate analysis of a large cohort of Euro-

3 Mayo Clin Proc, January 1991, Vol 66 EDITORIAL 107 pean patients with thyroid cancer. Their cohort consisted of patients with differentiated medullary and anaplastic thyroid carcinoma who had a median follow-up of 3.3 years. Six variables were found sufficient to predict survival: age, sex, principal cell type, presence of anaplastic thyroidcancer, stage ofthe tumor, and numberof metastatic sites. This scoring index did not consider the effect of therapy, an extremely important issue. In fact, the authors stated, "Technically, one is entitled to ignore therapy in studying prognostic factors only if it is known that therapy has no effect on the natural history of the disease. This is probably not the case in thyroid carcinoma." Since then, several multivariate analyses done by other authors have arrived at strikingly different conclusions about the relative importance of various prognostic factors. Variations in Patient Populations. Whether prognostic variables-and hence prognostic scoring systems-can be applied from institution to institution is a major question. Hannequin and co-workers? performed three separate Cox multifactorial analyses on a large group of patients with differentiated medullary and anaplastic thyroid carcinomas from their hospital in France. Despite use of the same patient groupings, variables, and analytic methods as those published previously by three other groups in Europe" and France.v" their results differed substantiallyfrom those reportedby the original authors. Only some of the originally significant prognostic factors remained significant, and other factors not reported by the original authors became significant. Hannequin and associates" reported that the practical conclusion of their study was that, in thyroid carcinoma, the significant prognostic factors can change from one population to another. Because of this lack of agreement, which seemed due to fundamental differencesinpatientcohorts, these authors advised that caution is needed if the results of studies published by other groups are applied to another population with thyroid carcinoma andthat performance ofone's ownmultifactorial analysis seems necessarybefore a prognostic index is determined. Size oftumor.-important studies from the Mayo Clinic have contributed substantially to our growing understanding ofthe elements that influence the prognosis of patients with papillary and follicular carcinoma. During the past 3 decades, classic studies by Lewis Woolner, William McConahey, and their associates at the Mayo Clinic have shown that, for papillary carcinoma, the size ofthe tumor plays an important role in predicting outcome. Recently, investigators at the Mayo Clinic found an almost 10-fold increase in cancer mortality rates at 20 years as papillary tumors increased from 2 to 3.9 em in diameter to 7 em ormore in diameter. 10 The size of the tumor is not always found to be an independent prognostic variable, however, perhaps because pathologists do not invariably record the size in a uniform fashion. It was not an independent prognostic variable for papillary thyroid carcinoma in a large multicenter Canadian studyreported by Simpsonand colleagues. 11 A recent study of papillary thyroid carcinomaby Hay and associates'" showed that the patient's age at the time of diagnosis and the histologic grade, extent (stage), and size ofthe tumor were independent prognostic variables in the large patient cohort treated at the Mayo Clinic. From these variables, Hay and co-workers 12 derived the "AGES" prognostic scoring system from a Cox multivariate analysis of 860 patients with papillary thyroid carcinoma. More than 85% of the patients were in the lowest category with AGES scores less than 4. The 25-year mortality rates increased from about 2% in patients with the lowest scores to about 93% in those with the highest scores. MortalityandTumorRecurrence.-Inthis issue of the Proceedings (pages 11 to 22), Brennan and his associates present a retrospective analysis of 100 patients with follicular thyroid carcinoma. Three variables independently predicted death from thyroid cancer: age more than 50 years at the time of diagnosis, extensive vascular invasion by tumor, and distant metastatic lesions. When two or more of these risk factors were present, the 10-year survival rate was only 30%, and by 20 years, almost all patients had died. In comparison, when fewer risk factors

4 108 EDITORIAL Mayo Clin Proc, January 1991, Vol 66 were present, almost all patients survived for a decade, but by 20 years, 14% of the "low-risk" group also had died. Identification of prognostic factors and classification of patients into risk groups offer an advantage ifone can select therapy on the basis of such a division and canmodifythe anticipated outcome by therapy. Thus far, however, few studies have been able to accomplish this. Brennan and associates were unable to show a significant effect of treatment, perhaps because most patients were treated with near-total thyroidectomy and only a few patients underwent total thyroidectomy or received 13lJ postoperatively. In the studies of papillary cancer by Hay and colleagues,12 patients with an AGES score of 4 or more who underwent only lobectomy had a 25-year cancer mortality rate of65%, whereas those who underwent bilateral resection had a cancer mortality rate of 36%-a fairly large difference that was not, however, statistically significant. Preliminary studies from the Mayo Clinic have failed to show an influence of therapy on rates of tumor recurrence or cancer mortality in patients with papillary thyroid carcinoma.12 Cady and Rossi13 reached similar conclusions after broadly categorizing 821 patients with differentiated thyroid carcinoma into low- or high-risk groups. Age at the time of diagnosis andsex were usedcollectivelyto define"younger" (men youngerthan 41 years andwomenyounger than 51 years) and "older" groups. This classification, similar to the TNM staging system, stronglyemphasizesthe patient's age but attributes relatively little weight to the stage of the tumor in younger patients. The patient's sex is given more weight in this staging system. Younger patients are considered low risk when they have no distant metastatic lesions, regardless ofthe characteristics ofthe primary tumor, such as local tumor invasion. Older patients are consideredlow riskwhentheirtumorsaresmaller than 5 em in diameter without distant metastatic involvement, providing the papillary carcinoma is intrathyroidal or the follicular carcinoma demonstrates only minor tumor capsular involvement. After a minimal follow-up of 5 years, only 5% of the low-risk group seen between 1961 and 1980 had experienced recurrence, and almost 2% had died of cancer. Cady and Rossi13 formulated the "AMES" scoring system (based on age at the time of diagnosis, the presence of distant metastatic lesions, and the extent and size of the primary tumor). Since 1961, 90% of the patients with thyroid carcinoma examined at the Lahey Clinic have been in the low-risk category. Cady and Rossi suggested that most patients with differentiated thyroid carcinoma may be treated effectively by a unilateral operation with removal of the isthmus so long as a reasonable margin of surrounding normal thyroid gland is achieved. Few such patients have been given therapy at their clinic. Ofnote, a small but important number of recurrences and cancer-related deaths occur in the "low-risk" group. I believe that failure to take into account the effects of other variables in the low-risk group, such as local tumor invasion or the presence of tumor multicentricity, may explain the inability of this scoring system to identify the small, albeit important, number of patients who eventually experience a poor outcome. Recently, DeGroot and associates'" reported the results of an analysis of 269 patients with papillary thyroid carcinoma managed at the University of Chicago. Patients were categorizedinclinical class 1 iftheyhadintrathyroidal disease, in class 2 iftheyhad cervical metastatic lesions, in class 3 ifextrathyroidal invasion had occurred, and in class 4 if distant metastatic involvement was present. Age was not used in this staging system. Although cervical lymph nodes were associated with increased tumor recurrence rates, deaths occurred primarily in patientswithclass 3 (local invasion) or 4 disease. Tumor size of more than 3 em increased the risk of death almost sixfold. Of importance, this studyshowedthatsurgicaltreatmentwithlobectomyandat leastcontralateral subtotal thyroidectomy was associated, by Cox proportional hazards analysis, with decreased recurrence rates in all patients and a reduced death rate in those with tumors larger than 1 em. Ablation of the thyroid remnant with 13lJ was associated

5 Mayo Clin Proc, January 1991, Vol 66 EDITORIAL 109 with a decreased recurrence rate in patients with tumors larger than 1 em and a decreased death rate in patients in classes 1 and 2 who had tumors larger than 1 em. DeGroot and associates recommended the use of more extensive initial surgical treatment and postoperative ablation ofthyroid remnant tissue in class 1 (intrathyroidal disease) and class 2 (cervical node metastatic disease) tumors larger than 1 em. Some ofthe differences intheliterature relate to how patients are grouped when the results of therapy are analyzed. Some authors have studied papillary and follicular thyroid cancer separately, whereas others simply group them togetheras differentiatedthyroidcarcinoma. Tenyear survival rates for papillary carcinoma are generally reported to range from 80 to 90%, whereas those for follicular carcinoma are lower (in the range of65 to 75%). Follicular carcinoma tends to be encapsulated, whereas papillary carcinoma usually is not; the former has the predilectionto vascularinvasion andearlymetastatic involvement, bothofwhichare high-riskfactors, as pointed out by Brennan and co-workers in this issue of the Proceedings. Differences in survival rates in patients with papillary and follicular carcinoma, however, may be more closely related to the patient's age, the degree of tumor differentiation, and the stageof thetumor than to the papillaryorfollicular histologic findings. Indeed, the typical manifestation of follicular carcinoma at an older age and a more advanced stage may contribute more to the poor prognosis than the histologic features of the tumor itself. Both papillary and follicular carcinomas that have less well-differentiated histologic characteristics behave more aggressively and are associated with a poor prognosis. When patients of comparable age and with similarly staged papillary and follicular carcinomas are compared, survival rates for the two groups are virtuallyidentical. Intrathyroidal papillarycarcinomas and follicular tumors with minimal capsular invasion both are associated with an excellent prognosis, whereas the outcome is equally serious with both tumors when they are locally invasive, less well differentiated, or metastatic to distant sites. Personal Study.-I have analyzed the prognostic factors in a cohort of 1,133 patients with papillary or follicular thyroid carcinoma cared for by US Air Force physicians or at the Ohio State University Hospital. Their median age at diagnosis was 32 years, and the median followup was about 10 years." Although patients with follicular carcinoma were slightly older at the time of diagnosis than those with papillary carcinoma, the actual difference in age between the two groups was small (34.0 ± 0.5 [SEM] versus 37.3 ± 1.0 years; P<0.002), and the entire cohort was approximately a decade younger than patients in most other thyroid cancer studies. At the time of initial diagnosis, 30 patients had distant metastatic lesions, a much more common feature in those with follicular carcinoma than in those with papillary carcinoma (7.9% versus 1.2%; P<O.OOOl). Patients with distant metastatic involvement at the time of initial diagnosis were much older than those without such involvement (50.9 ± 3.6 versus 34.2 ± 0.4 years; P<O.OOOl). The primary tumors that were associated with distant metastatic lesions at the time of initial diagnosis, regardless of theirhistologiccharacteristics,werelarger, were more often multiple, involved more of the thyroid, and were more often locally invasive than those without distant metastatic involvement. After a median follow-up of only 3 years, cancer mortality was 60% in patients who had distant metastatic tumors at the time of initial diagnosis. In sharp contrast, in those without distant metastatic lesions initially, the rates of tumor recurrence (19.0%), distant recurrence (3.0%), cancer-related death (4.0%), and overall survival (92.3%) were essentially the same, regardless of the papillary or follicular histologic features. The ages of patients with papillary and follicular carcinoma were almost the same in this subgroup (33.8 ± 0.05 versus 35.7 ± 0.9 years; P =0.034). Cox multivariate analysis of 1,103 patients without distant metastatic lesions at the time of initial diagnosis failed to identify tumor histologic findings as a significant prognostic variable. Depending on the endpoint used in the analysis-recurrence, distant recurrence, can-

6 110 EDITORIAL Mayo Clin Proc, January 1991, Vol 66 cer-related death, or overall mortality-various factors became significant in the Cox multivariate analysis. Regardless of the endpoint used, however, age at the time of diagnosis was a statistically significant factor, and recurrent disease (both local and distant recurrences) remained an important prognostic predictor of cancer-related death. Tumors were classified into four groups on the basis of size, degree of thyroid involvement, local invasion, and presence of distant metastatic lesions. Tumors smallerthan 1.5 em indiameteror ofanysizebut confined to one thyroid lobe (regardless of whether regional nodal metastatic lesions were present) and without local invasion or distant metastatic involvement (group 1) constituted 24.5% ofthe series. Tumors between 1.5 and 4.4 em or of any size thatinvolved two thyroid lobes, without local invasion or distant metastatic lesions (group 2), constituted 55.3% ofthe series. Tumors 4.5 em or larger or those that involved the entire thyroid gland, with local invasion but without distant metastatic lesions (group 3), constituted 17.6% of the series, and those associated with distant metastatic involvement at the time of diagnosis (group 4) constituted 2.6% of the group. Recurrences became progressively more frequent with advancing clinical stage (6.8%, 17.4%, 36.2%, and 50%), as did distant recurrence (0%, 1.3%, 9.1%, and 60%) and cancer-related death (0.4%, 1.3%,9.1%, and 60%). By Cox analysis, total thyroidectomy and therapyweresignificantvariablesthatpredicted fewer tumor recurrences of any type (P<O.OOOI) and distant recurrences (P<0.03). Patients treated with total or near-total thyroidectomy and had significantly fewer recurrences. Therapy with was given to 103 patients to ablate the remaining thyroid tissue when no apparent residual disease was present. Ofthese 103 patients, 15 were low risk (group 1), 73 were in group 2, and 15 were in group 3. Patients had fewer recurrences (P<O.OI) when the thyroid remnant was ablated than when either subtotal or total thyroidectomy was not followed by therapy. The difference in recurrence rates was even more impressive (P = 0.002) when only patients in groups 2 and 3 were considered. In addition, after a median follow-up of approximately 8 years, no patient given to ablate the thyroidremnanthad a distant recurrence or had died of carcinoma. Clearly, tumor recurrence, especially nodal papillary recurrence, is not synonymous with a fatal outcome. Nonetheless, tumor recurrenceis not a trivial event. Local recurrence often indicates a serious outcome, either before or at the time distant metastatic lesions are detected. Residual Disease.-Simpson and associates'" reported their experience from 13 Canadianhospitalsinwhich321 patientsweretreated with 131 1, primarily to ablate residual normal thyroid tissue. Postoperatively, local disease in patients with either papillary or follicular microscopic residual tumor was controlled, respectively, in 26% and 38% with thyroid hormone, in 90% and 53% with external radiotherapy, in 82% and 77% after 13 11, andin 86% and 70% after and external irradiation-differences that were highly significant (P<O.OOOOI). The same comparisons made in patients with no obvious residual disease revealed no significant differences. After 20 years, survival was much better in patients treated with or external irradiation than in those treated surgically with or without thyroid hormone (about 40% versus 90%; P = 0.004). Conclusion.-What reasonable conclusions canbe derivedfrom this disparategroup of data? The patient's age at the time of diagnosis is irrefutably a key factor for predicting the risk of cancer mortality. The disputed issues are the age at which the protective feature of youth is lost, the potential behavior of retained tumor decades after the initial therapy, and the planning of therapy exclusively on the basis of the age ofthe patient. It seems reasonable that the stage ofthe tumor and other important prognostic features should not be ignored simply because of the patient's age. The relative weight assigned to each variable is likely to be based more on the patientcohort being studiedthanon the disease itself. It also seems reasonable to propose more aggressive therapy for some tumors, especially those that are very large, involve much of the thyroid gland, are highly

7 Mayo Clin Proc, January 1991, Vol 66 EDITORIAL 111 invasive follicular cancers, involve neck structures other than regional nodes, or are metastatic to distant sites. Patients with intrathyroidal papillary carcinoma, papillary carcinoma metastatic to regional nodes on the same side as the primary tumor, follicular thyroid carcinoma that shows minimal capsular or vascular invasion, or a moderate amount of residual thyroid tissue in whom the exact status of retained tumoris unknown will continue to excite debate. Exactlywhere to draw the line between indolent and aggressive tumors is likely to remain a controversial issue for some time. Ernest L. Mazzaferri, M.D. Department of Internal Medicine The Ohio State University Columbus, Ohio REFERENCES 1. Van de Velde CJH, Hamming JF, Goslings BM, Schelfhout LJDM, Clark OH, Smeds S, Bruining HA, Krenning EP, Cady B: Report of the consensus developmentconference on the managementof differentiated thyroid cancer in the Netherlands. Eur J Cancer Clin Oncol 24: , Baldet L, Manderscheid J-C, Glinoer D, Jaffiol C, Coste-Seignovert B, Percheron C: The management of differentiated thyroid cancer in Europe in 1988: results of an international survey. Acta Endocrinol (Copenh) 120: , Mazzaferri E: Controversies in the management of differentiatedthyroid cancer. In ProgramSyllabus of The Endocrine Society's 42nd Postgraduate Assembly, Honolulu, Hawaii, Oct 28 to Nov 1, 1990, pp De Keyser LFM, Van Herle AJ: Differentiated thyroid cancer in children. Head Neck Surg 8: , Tscholl-Ducommun J, Hedinger CE: Papillary thyroidcarcinomas: morphology andprognosis. Virchows Arch [A] 396:19-39, ByarDP, GreenSB, DorP, WilliamsED,ColonJ, van Gilse HA, MayerM, SylvesterRJ, VanGlabbekeM: A prognosticindexfor thyroidcarcinoma: a studyof the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer 15: , Hannequin P, Liehn JC, Delisle MJ: Multifactorial analysis of survival in thyroid cancer: pitfalls of applying the results of published studies to another population. Cancer 58: , FourquetA,AsselainB,JolyJ: Cancerdelathyrorde: analyse multidimensionnelle des facteurs pronostiques. Ann Endocrinol (Paris) 44: , Tubiana M, Schlumberger M, Rougier P, Laplanche A, Benhamou E, Gardet P, Caillou B, Travagli J-P, Parmentier C: Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 55: , Hay ID: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am (in press) 11. Simpson WJ, McKinney SE, Carruthers JS, Gospodarowicz MK, Sutcliffe SB, Panzarella T: Papillary and follicular thyroid cancer: prognostic factors in 1,578 patients. Am J Med 83: , Hay ID, Grant CS, Taylor WF, McConahey WM: Ipsilateral lobectomy versus bilateral lobar resection inpapillarythyroidcarcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102: , Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104: , DeGroot LJ, Kaplan EL, McCormick M, Straus FH: Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71: , Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB: Papillary and follicular thyroidcancer: impactoftreatmentin 1578 patients. Int J Radiat Oncol BioI Phys 14: , 1988