Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group.

CONTEXT: High-dose iodine 131 is the treatment of choice in the United States for most adults with hyperthyroid disease. Although there is little evidence to link therapeutic (131)I to the development of cancer, its extensive medical use indicates the need for additional evaluation. OBJECTIVE: To evaluate cancer mortality among hyperthyroid patients, particularly after (131)I treatment. DESIGN: A retrospective cohort study. SETTING: Twenty-five clinics in the United States and 1 clinic in England. PATIENTS: A total of 35 593 hyperthyroid patients treated between 1946 and 1964 in the original Cooperative Thyrotoxicosis Therapy Follow-up Study; 91 % had Graves disease, 79% were female, and 65% were treated with (131)I. MAIN OUTCOME MEASURE: Standardized cancer mortality ratios (SMRs) after 3 treatment modalities for hyperthyroidism. RESULTS: Of the study cohort, 50.5% had died by the end of follow-up in December 1990. The total number of cancer deaths was close to that expected based on mortality rates in the general population (2950 vs 2857.6), but there was a small excess of mortality from cancers of the lung, breast, kidney, and thyroid, and a deficit of deaths from cancers of the uterus and the prostate gland. Patients with toxic nodular goiter had an SMR of 1.16 (95% confidence interval [CI], 1.03-1.30). More than 1 year after treatment, an increased risk of cancer mortality was seen among patients treated exclusively with antithyroid drugs (SMR, 1.31; 95% CI, 1.06-1.60). Radioactive iodine was not linked to total cancer deaths (SMR, 1.02; 95% CI, 0.98-1.07) or to any specific cancer with the exception of thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86). CONCLUSIONS: Neither hyperthyroidism nor (131)I treatment resulted in a significantly increased risk of total cancer mortality. While there was an elevated risk of thyroid cancer mortality following (131)I treatment, in absolute terms the excess number of deaths was small, and the underlying thyroid disease appeared to play a role. Overall, (131)I appears to be a safe therapy for hyperthyroidism.

Prolonged remission of metastatic follicular thyroid carcinoma.

Follicular thyroid carcinoma is associated with an extremely poor prognosis when metastatic lesions occur. Although radioiodine therapy for metastatic disease can extend patient survival for several years, its effect is usually only palliative. Herein we describe a 47-year-old man with metastatic follicular thyroid carcinoma who was in clinical remission for 30 years after surgical and radioiodine treatment of the original disease. To our knowledge, this is the longest reported remission of this disease. Possible reasons for the prolonged survival were "young" age at diagnosis, diploid DNA content of the tumor, skeletal lesions responsive to 131I therapy, and limited pulmonary disease.

Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970.

We retrospectively reviewed the medical records of 65 consecutive patients with medullary thyroid carcinoma, who had had their primary surgical treatment at the Mayo Clinic during the years 1946 through 1970. Of these patients, 58 had sporadic and 7 had familial medullary thyroid carcinoma. Thyroid nodules were the most common initial manifestation. Near-total thyroidectomy was the most frequent initial operation. Survival was affected by the following factors: male sex, familial inheritance, size of the tumor, stage of the tumor (American Joint Committee on Cancer), and completeness of initial resection of the tumor. The mean duration of follow-up was 23.5 years, and the maximal follow-up was 36 years. Among 52 patients without initial distant metastatic involvement and with complete resection of the tumor, 20-year survival free of distant metastatic lesions was 81%. Overall 10- and 20-year survival rates were 63% and 44%, respectively. Because of the substantial morbidity and mortality associated with medullary thyroid carcinoma, early diagnosis and thorough initial resection of the tumor are important.

Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome.

We retrospectively analyzed the outcome of all patients who received their primary treatment for follicular thyroid cancer at the Mayo Clinic between 1946 and 1970. The diagnosis was confirmed by reexamination of preserved tissue specimens. The 57 female and 43 male patients (mean age, 53 years) underwent follow-up for a maximum of 32 years (mean, 17.4 years). All patients were treated surgically, and total removal of primary tumor was thought to have been accomplished in all but three. Only 2 of the 88 patients without distant metastatic lesions at the time of initial diagnosis underwent ablation of the thyroid remnant. At the conclusion of the study, 52 patients had died, thyroid cancer being the cause of death in 19. On the basis of univariate survival analysis, age more than 50 years, tumor size that exceeded 3.9 cm, higher tumor grade, presence of marked vascular invasion, adjacent tissue invasion, and distant metastatic involvement at the time of initial diagnosis were associated with increased cancer mortality. Multivariate analysis (by Cox proportional hazards model), however, identified only age greater than 50 years, marked vascular invasion, and metastatic disease at the time of diagnosis to be independent predictors of follicular thyroid cancer-related mortality. Patients with two or more of these predictors were classified as being high risk. These patients had 5- and 20-year survival rates of 47% and 8%, respectively; the corresponding survival data for the low-risk group were 99% at 5 years and 86% at 20 years. The identification of these risk groups may facilitate a more rational approach to treatment of follicular thyroid cancer.

Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades.

Fifty-eight children (18 boys, 40 girls) less than 17 years of age, undergoing initial surgery because of papillary thyroid carcinoma (PTC) at Mayo Clinic from 1946 through 1975 and followed up for a median time of 27.6 years were compared with 981 adults (323 men, 658 women) treated during the same period and followed up for a median period of 19.5 years. At initial evaluation, mean tumor size (+/- SD) was greater in children (3.1 +/- 1.7 cm) than in adults (2.1 +/- 1.7 cm) (p less than 0.001); tumor DNA content was nondiploid in 10% of 39 children and in 25% of 110 adults (p = 0.047). Neck node metastases at diagnosis were detected in more children (89.7%) than adults (34.7%) (p less than 0.0001), but extrathyroidal invasion was not significantly more frequent in children (24.1%) than adults (15.8%) (p = 0.095). Distant metastases at diagnosis were detected in more children (6.9%) than adults (2.1%) (p = 0.022). Postoperatively, neck node metastases recurred more frequently in children (30%) than in adults (7%) (p less than 0.001), but local neck recurrences were not significantly more frequent in children (12%) than in adults (5%) (p = 0.083). Postoperative distant metastases occurred with similar frequency in children (6%) and adults (5%) (p = 0.98). Survival (all causes of death) for both adults and children up to 30 years after the initial surgery was no different from expected survival rates. Only adults aged more than 40 years had a significantly higher mortality from PTC than did children (p less than 0.0001). Fourteen percent of children had died of PTC by 15 years after diagnosis of distant metastases, whereas 68% of similarly affected adults were dead at 15 years (p = 0.014). PTC was more often metastatic to neck nodes and lungs before initial surgery and more often recurrent in neck lymph nodes postoperatively. However, PTC tended to be less fatal in children, and this may be related to the infrequency of nondiploid DNA content in the childhood PTC tumors.

Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important?

From a multivariate analysis of more than 20,600 patient-years' experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system was used as an adjustment variable for analyzing the role of different types of surgical treatment in the development of local recurrence (LR) in 963 PTC patients who underwent unilateral (15%), bilateral subtotal/near-total (69%), or total thyroidectomies (16%) from 1946 through 1975 at the Mayo Clinic. In 866 patients with AGES scores of 3.99 or less, the risk of LR developing at 10, 20, and 30 years was 7%, 14%, and 14% after unilateral resection and 1.5%, 2%, and 4% after bilateral resection (p less than 0.001). In 97 patients with AGES scores of 4 or more, the comparable rates were 26%, 45%, and 59% after unilateral resection and 13%, 20%, and 20% after bilateral resection (p less than 0.001). In neither the low- nor the high-risk group was there a significant difference in the frequency of LR comparing total thyroidectomy with bilateral subtotal/near-total thyroidectomy. At 30 years after diagnosis of LR, mortality from PTC was 48%; the risk of cancer death with an LR located outside the thyroid remnant was much greater than with a remnant recurrence alone. In this series of 52 patients, followed up for as many as 41 years, no patient with tumor recurrence limited to the thyroid remnant died of thyroid cancer.

Mortality from papillary thyroid carcinoma. A case-control study of 56 lethal cases.

To document the presentation, findings, therapy, and postoperative course of lethal papillary thyroid carcinoma (PTC), 56 fatal cases were studied in a retrospective case-matched control fashion. These patients and their controls were taken from a larger series receiving their primary treatment at one institution (Mayo Clinic; 1946-1970). Mean follow-up for the lethal cohort was 8.5 years and 16.6 years for controls. Age, sex, tumor size, histologic grade, extent of disease at presentation, European Organization for Research on Treatment of Cancer (EORTC) and AGES scores (patient's age, tumor grade, tumor extent, and tumor size), and DNA ploidy pattern were found to be significant prognostic factors. The immediate causes of death were most frequently either local airway obstruction or respiratory insufficiency from pulmonary metastases. The results suggest that it is possible, at the time of initial treatment, to assess an individual patient's risk of dying from PTC. Aggressive postoperative adjunctive therapy should be restricted to that minority of patients who are at highest risk of death from PTC.

Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system.

From a multivariate analysis of more than 14,200 patient-years' experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system can identify patients at increased risk of PTC mortality and was employed as an adjustment variable for analyzing the role of different types of surgical treatment in 860 PTC patients. Cancer mortality at 25 years in patients with an AGES score of 3.99 or less was 1% after ipsilateral lobectomy (n = 131) and 2% after bilateral resection (n = 603), whether subtotal or total (p = 0.15). Of patients with an AGES score of 4 or more, those who underwent lobectomy alone (n = 30) had a mortality rate from PTC at 25 years of 65%, while those undergoing bilateral resection (n = 86) had a lower rate of 35% (p = 0.06). For patients at minimal risk (score of 3.99 or less) of PTC death, no improvement in survival was demonstrable when patients underwent more than ipsilateral lobectomy. However, in a subgroup (score of 4 or more) identified to be at significant risk of PTC death, the survival after bilateral resection was much higher than after ipsilateral lobectomy alone. In neither the "minimal" nor the "higher" risk subgroup was PTC survival significantly improved by the performance of total thyroidectomy.

Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome.

We performed a retrospective study of 859 patients with papillary thyroid cancer, who had received their primary treatment at the Mayo Clinic during the period 1946 through 1970. The maximal follow-up was 39 years. All but 2 patients underwent a thyroid operation; 319 (37%) had metastatic cervical nodes. Of the 800 patients without distant metastatic lesions on initial examination who underwent a potentially curative surgical procedure, postoperatively 7% had nodal metastatic lesions, 6% had a local tumor recurrence, and 5% had a distant metastatic lesion. In patients who had intrathyroidal tumors initially, postoperative local recurrences or distant metastatic lesions resulted in a 10-year cancer mortality of 17 and 41%, respectively; in those with extrathyroidal tumors, postoperative recurrences were associated with significantly higher death rates. Death from thyroid cancer was highly associated with the following factors: age more than 50 years, male sex, tumor size, tumor grade, initial extent of disease, and absence of Hashimoto's disease. Earlier studies of Mayo patients treated between 1926 and 1960 described no deaths due to thyroid cancer in patients with occult tumors (1.5 cm or less). Four such patients were identified among our 859 patients; all had been examined and treated after 1961. To date, 56 (6.5%) of the 859 patients have died as a result of papillary thyroid cancer. In this study, in which 16% of patients underwent total thyroidectomy and 3% had radioiodine ablation, the overall mortality observed at 30 years was only 3% above that expected.

Hashimoto's thyroiditis. An uncommon cause of painful thyroid unresponsive to corticosteroid therapy.

The records of eight patients with thyroid tenderness secondary to Hashimoto's thyroiditis were reviewed. The pathologic characteristics of thyroid tissue sections from these patients were compared with those from patients with nontender Hashimoto's thyroiditis, and no difference was identified. Laboratory features helpful in distinguishing tender Hashimoto's thyroiditis from subacute (de Quervain's) thyroiditis include normal erythrocyte sedimentation rate, significant 131I uptake, and significant antithyroid antibody titer. Diagnosis should be confirmed by fine-needle aspiration biopsy. Corticosteroid therapy was unsuccessful in treating these patients; L-thyroxine and aspirin were successful more often. Two patients required thyroidectomy to control pain.

Anaplastic carcinoma of the thyroid: a clinicopathologic study of 82 cases.

Anaplastic carcinoma of the thyroid accounts for about 10% to 15% of all thyroid carcinomas in the United States. Its lethality is evidenced by a 5-year survival rate of 3.6% and a median survival of 4 months. Rapid growth of a thyroid mass, frequently in a preexisting goiter, is the most common manifestation; the diagnosis should be considered and expeditiously pursued in all patients who present with this finding. Relatively favorable prognostic features seem to be unilateral tumors, a tumor diameter of less than 5 cm, no invasion of adjacent tissue, and absence of nodal involvement. For resectable lesions, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor seems to constitute a safe, appropriately aggressive surgical approach. Total thyroidectomy and radical neck dissection results in an increased complication rate and has no advantage over a more conservative approach. Radiotherapy, chemotherapy, immunotherapy, and combination radiotherapy and chemotherapy need further evaluation.

Invasive Hürthle cell carcinoma of the thyroid: natural history and management.

Debate surrounds the natural history and appropriate management of Hürthle cell neoplasms of the thyroid. Some of the uncertainty stems from difficulty in the differentiation of benign from malignant lesions. We report the presentation, management, and outcome of patients with invasive Hürthle cell carcinoma who were examined at this institution between 1946 and 1971. We believe that our review allows us to make reasonable recommendations concerning the management of patients with this type of carcinoma.

Breast cancer in hypothyroid women using thyroid supplements.

The risk of breast cancer associated with thyroid supplementation for iatrogenic hypothyroidism was investigated in women treated for hyperthyroidism at the Mayo Clinic, Rochester, Minn. One or more years after the diagnosis of hypothyroidism, there were 47 cases of breast cancer observed among 1,665 women compared with 52.9 cases expected, a ratio of observed to expected cases (standardized incidence ratio [SIR]) of 0.9. There was also no breast cancer excess among women who remained euthyroid (SIR = 1.0). Breast cancer risks were not influenced by various factors associated with the management of hyperthyroidism or subsequent hypothyroidism. No increased risk was observed in hypothyroid women categorized by breast cancer risk factors except for women who reported a previous breast biopsy, an excess also observed among euthyroid patients. The results of this study indicate that use of thyroid supplements does not increase the risk of breast cancer developing.

Breast cancer following iodine-131 therapy for hyperthyroidism.

A retrospective cohort study of women treated for hyperthyroidism at the Mayo Clinic between 1946 and 1964 was conducted to determine if 1,005 women treated with iodine-131 (131I) were at increased risk of breast cancer compared with 2,141 women traced, and a response (death certificate or questionnaire) was received for 99% of the traced women. The average duration of follow-up was 15 years for the 131I-treated women and 21 years for women treated surgically. No increased risk of breast cancer was observed in the 131I-treated women (adjusted relative risk = 0.8). No patterns were found of increased breast cancer risk by age at first treatment, by time since treatment, or by total exposure to 131I. Failure to detect an increased risk of breast cancer in the 131I-treated women was attributed to the moderately low doses from 131I therapy and the relatively small number of exposed women. The study also failed to find any increased risk of breast cancer associated with hyperthyroidism.

Cancer incidence following treatment of hyperthyroidism.

A retrospective cohort study of women treated for hyperthyroidism at the Mayo Clinic was conducted to evaluate the risk of cancer according to type of therapy. One or more years after the start of treatment, there were 105 cases of cancer observed among 1005 women treated with radioiodine (131I) and 247 cases among 2141 women treated with surgery. No difference was observed between the two study groups for total cancer incidence (RR = 1.0), breast cancer (RR = 0.8), or leukaemia (RR = 0.6). Although based on small numbers of cases, an elevated risk of cancer was observed in organs that concentrate 131I (salivary glands, digestive tract, kidney and bladder) (RR = 1.8). While the findings are suggestive, they indicate the need for larger surveys to evaluate the carcinogenic potential of 131I.