Papillary thyroid cancer is predominantly a sporadic disease that usually presents as an asymptomatic thyroid mass in a euthyroid patient. Irradiation to the neck during childhood significantly increases the subsequent risk of this cancer; the prognosis for radiation-related cancers is similar to spontaneous cases. Physical examination, thyroid scanning and ultrasound, and fine-needle aspiration are used to differentiate between benign lesions and papillary thyroid cancer. Near-total thyroidectomy with postoperative radioiodine ablation is currently advocated for most patients, and has excellent results with regard to survival. In children, papillary thyroid cancer often presents with extensive regional disease as well as diffuse lung metastases. Surgery and radioiodine are very effective in such cases, and survival remains excellent. As late recurrences may occur, patients require regular long-term follow-up regardless of the extent of initial disease.
Thyroid cancer accounts for more than 90% of all endocrine malignancies and for more than 50% of all deaths from endocrine cancer. The incidence of thyroid cancer has been increasing since the 1930s, most likely because of the practice of therapeutic irradiation in childhood. The abrupt rise in incidence around 1974 was probably due to the institution at that time of vigorous examination of individuals who had had prior neck irradiation .
American Cancer Society statistics for the past 25 years suggest that the incidence of thyroid cancer has risen slowly since the mid 1970s. Disease incidence increased from 7,800 cases per year in 1974 to 12,500 cases per year in 1992, with more than two-thirds of new cases occurring in women. However, mortality from thyroid cancer has changed little during this period (Figure 1).
Most patients have localized or regional disease at the time of diagnosis, and the 5-year survival rate has exceeded 80% since 1960 and 90% since 1970. Therefore, thyroid cancer remains a relatively modest oncologic concern, accounting for less than 2% of all cancers since 1974 and for less than 0.5% of all deaths from cancer (Figure 2).
Among patients with thyroid cancer, approximately 60% to 70% have differentiated, papillary thyroid cancer. This article presents a broad clinical overview of papillary thyroid cancer and emphasizes disease features that modify prognosis and affect clinical management.
The risk of radiation-induced thyroid cancer has been well documented; data on other causes of thyroid cancer are sparse. Prolonged thyroid-stimulating hormone (TSH) elevation has been implicated as a potential risk factor, but patients with primary hypothyroidism do not appear to have an increased risk of papillary thyroid cancer. Thyroid-stimulatory immunoglobulins present in patients with Graves' disease have also been implicated. Associations with Hashimoto's thyroiditis, Graves' disease, and multinodular goiter have been reported. However, causative relationships between these diseases and papillary thyroid cancer remain poorly documented.
In a recent epidemiologic review of thyroid cancer in the United States , important differences in incidence emerged among ethnic groups. Thyroid cancer was less common in Puerto Rican Hispanics and blacks than in white persons, but New Mexican Hispanics and Asian-Americans had higher rates. Genetic susceptibility is unlikely to account for all the differences. For example, Asians living in the United States are at higher risk for thyroid cancer than Asians living in their native countries.
Although papillary thyroid cancer is generally considered a sporadic disease, it is important to keep in mind that disease clusters have been reported in kindreds with familial polyposis and Gardner's syndrome . Reports of familial disease in the absence of either a hereditary syndrome or neck irradiation increase the likelihood that genetic predisposition plays a role in pathogenesis. In support of this thesis, several recent studies have demonstrated complex structural chromosomal aberrations and cytogenetic abnormalities of chromosome 10q in association with papillary thyroid cancer .
Irradiation in Childhood
During the early decades of the 20th century, low-dose irradiation (usually < 2.0 Gy) to the head and neck was often used for the treatment of benign childhood conditions, such as thymic enlargement, tonsillitis, otitis, hemangiomas, ringworm, and acne. This medical practice has clearly emerged as an important risk factor for the development of papillary thyroid cancer and is considered by many to be responsible for increasing its incidence.
The excess relative risk of thyroid cancer appears to depend on total radiation dose, fractionation schedule, and patient age at the time of irradiation . To date, medical use of radioactive iodine-131 has not been shown to confer a significant risk of papillary thyroid cancer (Table 1). A persistent concern has been the carcinogenic potential of radioactive fallout. However, careful review of available studies reveals methodologic inconsistencies that may have exaggerated risk estimates .
The time between the irradiation and diagnosis of the thyroid tumor averages 10 years but may be more than 30 years. In a recent study, Schneider et al  demonstrated that radiation-induced thyroid neoplasms are rare in the first 5 to 10 years after treatment and cluster between 20 and 40 years post-therapy. Women have a 40% higher rate of radiation-induced thyroid cancer than men, but the slopes of dose-response curves, which reach maximal rates 25 to 29 years after radiation exposure, appear similar for the two genders.
Increased awareness of thyroid radiosensitivity, especially in children, has resulted in the virtual elimination of irradiation for benign conditions and is generating a reassessment of medical radiation use. Thus, radiation-related thyroid cancer is expected to subside as a public health concern in the coming years.
Radiotherapy for Hodgkin's and Non-Hodgkin's Lymphomas
The efficacy of radiotherapy in controlling Hodgkin's and non-Hodgkin's lymphomas has been instrumental in achieving high cure rates. Consequently, radiotherapy is likely to continue as an important component of the therapeutic armamentarium for these cancers. Because many young cancer survivors can expect a near-normal lifespan after neck irradiation, it is important to define their particular risks of thyroid cancer and to design appropriate surveillance and therapeutic strategies.
Radiation doses to the thyroid of more than 200 cGy, especially when given at a young age, have been linked to an increased risk of both benign and malignant thyroid neoplasms . Tucker et al found a 13-fold increase in the risk of thyroid cancer in this group , and Hancock et al noted that benign thyroid abnormalities are even more common . Systematic evaluation of the irradiated thyroid gland reveals significant pathologic  as well as radiologic  abnormalities.
We also have found a heightened risk of thyroid cancer after therapeutic neck (mantle) irradiation for Hodgkin's disease during childhood (Table 2). Among 166 patients irradiated at or before age 16 years and for whom a minimum of 15 years of follow-up is available, 12 have been treated for thyroid cancer to date (unpublished data; patient population identified through a search of the database maintained by the Department of Patient Studies at M.D. Anderson). The presence of papillary thyroid carcinoma in 7% of irradiated Hodgkin's disease survivors exceeds the prevalence of thyroid cancer in the general population, and suggests that prior therapeutic irradiation represents an important risk factor for thyroid cancer.
In our patients, thyroid cancer was found 7 to 19 years after irradiation by investigation of either palpable thyroid nodules or ultrasound abnormalities; all have proven to be papillary thyroid cancers, and all patients remain alive. During the same period and using the same database, only two cases of thyroid cancer were diagnosed among 750 adults treated for Hodgkin's disease, emphasizing the importance of age as a cofactor for the carcinogenic potential of radiation. Fortunately, patients with radiation-related papillary thyroid cancer appear to have the same excellent prognosis as do patients with sporadic disease, even though the former may have more extensive disease at diagnosis .
Because hyperparathyroidism also may occur with increased frequency after neck irradiation , it is particularly important to investigate previously irradiated patients very carefully for parathyroid dysfunction before thyroid surgery, to avoid the potential need for reoperation.
Papillary thyroid cancer is predominantly a sporadic disease. Patients typically present with a dominant thyroid mass or enlarged cervical lymph nodes . Thyroid nodules are relatively common, but less than 15% of clinically detectable solitary thyroid nodules are malignant [14,15].
Histologically, many tumors have both papillary and follicular elements and are referred to as "follicular variants of papillary carcinoma;" such tumors are classified as papillary lesions because their clinical behavior resembles that of pure papillary cancers. In adults, the size of papillary thyroid cancer can vary considerably, from microscopic cancers to large tumors that may invade the thyroid capsule and even infiltrate adjacent structures.
Up to 40% of adults present with cervical lymph node metastases; the figure is much higher in persons younger than 20 years. At the time of presentation, affected lymph nodes are generally on the same side as the primary tumor, but bilateral and mediastinal metastases are encountered in a few patients. Although regional lymph node invasion is fairly common, there is very little tendency toward systemic dissemination.
Sites of distant metastases, in order of decreasing frequency, are the lung, bone, and, rarely, other soft tissues. Older patients are more likely to present with invasive tumors and have a higher risk for distant metastases [16,17].
1. Schneider AB, Ron E, Lubin J, et al: Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab 77:362-369, 1993.
2. Spitz MR, Sider LG, Newell GR: Ethnic patterns of thyroid cancer incidence in the United States 1973-1981. Int J Cancer 42:549-553, 1988.
3. Stoffer SS, Van Dyke DL, Bach JV, et al: Familial papillary carcinoma of the thyroid. Am J Med Genet 25:775-782, 1986.
4. Herrmann MA, Hay ID, Bartelt DH, et al: Cytogenetic and molecular genetic studies of follicular and papillary thyroid cysts. J Clin Invest 88:1596-1604, 1991.
5. Shore RE: Issues and epidemiologic evidence regarding radiation-induced thyroid cancer. Radiat Res 131:98-111, 1992.
6. Constine LS, Donaldson SS, McDougall IR, et al: Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 53:878-883, 1984.
7. Tucker LA, Morris Jones PH, Doise JD, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 51:2885-2888, 1991.
8. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599-605, 1991.
9. Carr RF, Livolsi VA: Morphologic changes in the thyroid after irradiation for Hodgkin's and non-Hodgkin's lymphoma. Cancer 64:825-829, 1989.
10. Stewart RR, David CL, Eftekhari F, et al: Thyroid gland: US patients with Hodgkin's disease treated with radiation therapy in childhood. Radiolology 172:159-169, 1989.
11. Samaan, NA, Schultz PN, Ordonez NG, et al: A comparison of thyroid carcinoma in those who have and have not had head and neck irradiation. J Clin Endocrinol Metab 64:219-225, 1987.
12. Beard CM, Heath H, O'Fallon WM, et al: Therapeutic irradiation and hyperparathyroidism: A case-control study in Rochester, Minn. Arch Intern Med 149:1887-1890, 1989.
13. McConahey WM, Hay ID, Woolner LB, et al: Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: Initial manifestations, pathological findings, therapy and outcome. Mayo Clin Proc 61:978-996, 1986.
14. Mazzaferri EL: Thyroid cancer in thyroid nodules: Finding a needle in the haystack. Am J Med 93:359-362, 1992.
15. Belfiore A, LaRosa GL, LaPorta GA: Cancer risk in patients with cold thyroid nodules: Relevance of iodine uptake, sex, age and multinodularity. Am J Med 93:363-369, 1992.
16. Samaan NA, Schultz PN, Hickey RC, et al: The results of various modalities of treatment of well differentiated thyroid cancer: A retrospective review of 1599 patients. J Clin Endocrinol Metab 75:714-720, 1992.
17. Mazzaferri EL: Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Semin Oncol 14:315-332, 1987.
18. DeGroot LJ, Kaplan EL, McCormick M, et al: Natural history, treatment and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71:414-424, 1990.
19. Jensen MH, Kim DR, Derrick L: Thyroid cancer: A computer-assisted review of 5287 cases. Otolaryngol Head Neck Surg 102:51-56, 1990.
20. Clark OH, Duh QY: Thyroid cancer. Med Clin North Am 75:211-234, 1990.
21. Ruegemer JJ, Bergstralh EJ, Ryan JJ, et al: Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 67:501-508, 1988.
22. Robbins J, Merino MJ, Boice JD, et al: Thyroid cancer: A lethal endocrine neoplasm. Ann Intern Med 115:133-147, 1991.
23. Crile H, Autunez AR, Esselstyn CB, et al: The advantages of subtotal thyroidectomy and suppression of TSH in the primary treatment of papillary carcinoma of the thyroid. Cancer 55:2691-2697, 1985.
24. Hay ID, Grant CS, Taylor WF, et al: Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102:1088-1094, 1987.
25. Katoh R, Sasaki H, Kurihara H, et al: Multiple thyroid involvement in papillary thyroid carcinoma. Cancer 70:1585-1590, 1992.
26. Pasieka JL, Thompson NW, McLeod MK: The incidence of bilateral well-differentiated thyroid cancer found at completion thyroidectomy. World J Surg 16:711-717, 1992.
27. Blahd WH: Serum thyroglobulin in the management of thyroid cancer. J Nucl Med 31:1771-1773, 1990.
28. Comtois R, Theriault C, Del Vecchil P: Assessment of the efficacy of iodine-131 for thyroid ablation. J Nucl Med 34:1927-1930, 1993.
29. Maxon HR, Englaro EE, Thomas SR, et al: Radioiodine-131 therapy for well differentiated thyroid cancer-a quantitative radiation dosimetric approach: Outcome and validation of 85 patients. J Nucl Med 33:1132-1136, 1992.
30. Seidlin SM, Marinelli LDM, Oshry E: Radioactive iodine therapy: Effect on functioning metastases of adenocarcinoma of the thyroid. JAMA 132:838-847, 1946.
31. Edmonds CJ, Smith T: The long term hazards of the treatment of thyroid cancer with radioiodine. Br J Radiol 59:45-51, 1986.
32. Sarkar SD, Beierwalters WH, Gill SP, et al: Subsequent fertility and birth histories of children and adolescents treated with 131-I for thyroid cancer. J Nucl Med 17:460-464, 1976.
33. Handelsman DJ, Tuttle JR: Testicular damage after radioactive iodine (131-I) therapy for thyroid cancer. Clin Endocrinol 18:465-472, 1983.
34. Speigel W, Borner W: Sialadenitis following iodine-131 therapy for thyroid cancer. J Nucl Med 26:816-818, 1985.
35. Laupa MS, Toth BB, Keene HJ, et al: The effect of radioactive iodine therapy of salivary flow rates and oral Streptococcus mutans prevalence in thyroid cancer patients. Oral Surg Oral Med Oral Pathol 75:312-317, 1993.
36. Ibis E, Wilson CS, Collier BD, et al: Iodine-131 contamination from thyroid cancer patients. J Nucl Med 33:2110-2115, 1992.
37. Diamond T, Nery L, Hales I: A therapeutic dilemma: Suppressive doses of thyroxine significantly reduce bone mineral measurements in both premenopausal and postmenopausal women with thyroid carcinoma. J Clin Endocrinol Metab 72:1184-1188, 1990.
38. Frankenthaler RA, Vassilopoulou-Sellin R, Cangir A, et al: Lymph node metastasis from papillary-follicular thyroid carcinoma in young patients. Am Surg 160:341-343, 1990.
39. Samuel AM, Sharma S: Differentiated thyroid carcinomas in children and adolescents. Cancer 67:2186-2195, 1991.
40. Schlumberger M, De Vatharire F, Travagli JP, et al: Differentiated thyroid carcinoma in childhood: Long term follow-up of 72 patients. J Clin Endocrinol Metab 65:1088-1094, 1987.
41. Harness JK, Thompson NW, McLeod MK, et al: Differentiated thyroid carcinoma in children and adolescents. World J Surg 16:547-554, 1992.
42. Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al: Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 71:1348-1352, 1993.
43. Silverberg SG, Vidone RA: Carcinoma of the thyroid in surgical and postmortem material. Ann Surg 164:291-295, 1966.
44. Bisi H, Fernandes VSO, Asato di Camargo R, et al: The prevalence of unsuspected thyroid pathology in 300 sequential autopsies with special reference to the incidental carcinoma. Cancer 64:1988-1993, 1989.
45. Allo MD, Christianson W, Koivunen D: Not all "occult" papillary carcinomas are "minimal." Surgery 104:971-976, 1988.
46. Vassilopoulou-Sellin R, Weber RS: Metastatic thyroid cancer as an incidental finding during neck dissection: Significance and management. Head Neck 14:459-463, 1992.
47. Massin JP, Savoie JC: Pulmonary metastases in differentiated thyroid carcinoma. Cancer 53:982-992, 1984.
48. Vassilopoulou-Sellin R, Sneige N: Pleural effusion in patients with differentiated thyroid cancer. South Med J 1994 (in press).
49. Akslen LA, Haldorsen T, Thoresen SO: Survival and causes of death in thyroid cancer: A population-based study of 2479 cases from Norway. Cancer Res 51:1234-1241, 1991.
50. Meir CA, Braverman LE, Ebner SA: Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study). J Clin Endocrinol Metab 78:188-196, 1994.