Key Words. Thyroid cancer Age Prognostic indicators Cancer stage

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1 The Oncologist The Oncologist CME Program is located online at To take the CME activity related to this article, you must be a registered user. Endocrinology Understanding the Relationship Between Age and Thyroid Cancer MEGAN R. HAYMART Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, USA Key Words. Thyroid cancer Age Prognostic indicators Cancer stage Disclosures Megan R. Haymart: None Section editors Herbert Chen and Stan B. Sidhu have disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. Target audience: Physicians who wish to advance their current knowledge of clinical cancer medicine in endocrinology. LEARNING OBJECTIVES 1. Evaluate age as a unique prognostic indicator for well-differentiated thyroid cancer. 2. Explain the relationship between advanced age and poor prognosis. 3. Tailor treatment based on patient age and other risk factors. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT Unique among malignancies, age is a key prognostic indicator for well-differentiated thyroid cancer. Patients aged <45 years can have the same degree of disease involvement and a distinctly different prognosis than those aged >45. Although the reason for the association between age and outcome is not entirely clear, it does imply that there is something intrinsic to either the cancer or the treatment that is age dependent. This article explores the characteristics of the normal thyroid and thyroid cancer that are age dependent. It then provides theories for the relationship between advanced age and poor prognosis, in addition to treatment options tailored to age at diagnosis. The Oncologist 2009;14: INTRODUCTION Multiple population-based studies, including the National Cancer Data Base report on 53,856 cases of thyroid cancer over a 10-year period and the Surveillance, Epidemiology, and End Results study on 15,698 thyroid cancer cases over an 18-year period, have found that age is an important in- Correspondence: Megan Rist Haymart, M.D., Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin, H4/568 Clinical Sciences Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA. Telephone: ; Fax: ; mrh@medicine.wisc.edu Received August 28, 2008; accepted for publication January 27, 2009; first published online in The Oncologist Express on March 6, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Haymart 217 Table 1. Prognostic factors and thyroid cancer Staging system Prognostic factor TNM MACIS AMES AGES MSKCC EORTC OSU NTCTCS Age X X X X X X 0 X Sex 0 0 X 0 0 X 0 0 Tumor size X X X X X 0 X X Extrathyroidal extension X X X X X X X X Distant metastases X X X X X X X X Lymph node X X 0 X X involvement Histologic grade X X Histologic type 0 X X X X X 0 X Multicentricity X X Incomplete resection 0 X X indicates that factor is used in the staging system; 0 indicates that factor is not used in the staging system. Abbreviations: AGES, patient age, histologic grade of tumor, tumor extent, size of primary tumor; AMES, patient age, presence of distant metastases, extent and size of primary tumor; EORTC, European Organization for Research and Treatment of Cancer; MACIS, metastasis, patient age, completeness of resection, local invasion, and tumor size; MSKCC, Memorial Sloan-Kettering Cancer Center; NTCTCS, National Thyroid Cancer Treatment Cooperative Study; OSU, Ohio State University; TNM, tumor node metastasis (American Joint Committee on Cancer staging system). Adapted with permission from Dean DS, Hay ID. Prognostic indicators in differentiated thyroid carcinoma. Cancer Control 2000;7: dependent prognostic indicator for well-differentiated thyroid cancer (WDTC) [1, 2]. Thyroid cancer is the only malignancy with age as a prognostic indicator in the majority of staging systems [3, 4] (Table 1). The mortality rate with thyroid cancer climbs gradually starting at age [5]. With the same degree of cancer involvement, patients aged 45 have a distinctly different prognosis than those aged 45. Using the tumor node metastasis staging system for WDTC, patients aged 45 years can have extensive distant metastases and, at maximum, have stage II disease, whereas if aged 45, tumor size, extrathyroidal extension, lymph node involvement, and distant metastases contribute to the classification of stage I IV disease [4]. The reason for the distinctly different prognosis based on age is not entirely clear. The fact that the relationship exists suggests that there is something intrinsic to either the cancer or the treatment that is age dependent. The significance of this association between age and thyroid cancer prognosis is becoming increasingly important as the population ages and the incidence of papillary thyroid cancer (PTC) continues to climb [6]. YOUTH AND THYROID CANCER (AGE <20 YEARS) The healthy thyroid tissue of youths differs from that of adults. The child s thyroid has smaller follicles and a higher expression of proteins involved in iodide metabolism [7]. There is also a different proliferative rate of normal thyroid cells in the fetal period, childhood, and adulthood [8]. This decreasing proliferative rate with advancing age may partially explain the greater thyroid sensitivity to external radiation exposure in the young [8]. In addition to the normal thyroid behaving differently in the child than in the adult, childhood thyroid cancer has some unique characteristics. Juvenile WDTC is characterized by a larger tumor size at diagnosis, a higher incidence of multicentricity, a higher incidence of lymph node involvement, and a higher incidence of distant metastases [9, 10]. Children and young adults aged 20 have a higher cancer recurrence rate but an overall better survival rate over the evaluable time period [3, 9, 10]. In the majority of youths, thyroid cancer does not appear to alter life expectancy. Previous studies suggest that better survival in youths is related to responsiveness to radioactive iodine (RAI) [3, 9, 11, 12]. In juveniles, lungs are the primary metastatic location for WDTC, and their tumors tend to have sodium iodine symporter expression that is closer to that of normal thyroid tissue [9]. Relative to normal thyroid tissue, thyroid cancer is characterized by reduced sodium iodine symporter expression [12]. Because RAI is one of the three primary treatment regimens, the other two being surgery and suppressive doses of levothyroxine (LT4), the maintenance of tumor sodium iodine symporter activity closer to that of normal tissue is beneficial to the young. Although RAI

3 218 Age and Thyroid Cancer Table 2. Theories for why advanced age is associated with poor prognosis in thyroid cancer RAI responsiveness Patients aged 20 years have tumors with a sodium iodine symporter expression closer to that of normal thyroid tissue. Younger patients are more likely to have radioiodine-avid disease than older patients. TSH stimulation In the healthy population, the mean TSH level increases with age and a higher TSH level is associated with a higher incidence of thyroid cancer. LH and FSH homology The subunit of LH and FSH is identical to the subunit of TSH. LH and FSH rise after menopause and may stimulate thyroid cancer growth and invasion in older women via stimulation of the TSH receptor. Immune system decline The immune system may play a role in controlling cancer development and invasion. There may be a decline in immune response with age. Genetic variation Young patients may have different genetic mutations involved in cancer development. Whether or not a patient has a BRAF mutation or RET/PTC rearrangement may dictate RAI responsiveness, tumor aggressiveness, etc. Overall mortality Mortality from all causes increases with age and this may contribute to the overall rise in mortality with thyroid cancer and advanced age. Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; PTC, papillary thyroid cancer; RAI, radioactive iodine; RET, rearranged in transformation; TSH, thyroid-stimulating hormone. avidity likely explains the lower mortality rate, it is not entirely clear why young patients are more likely to have radioiodine-avid disease. There is controversy [9, 13, 14], but it is possible that specific genetic mutations, such as somatic rearranged forms of RET (RET/PEC rearrangements), have a higher incidence in youths, and BRAF mutations are more common in adults [9, 14]. It is not improbable that a predisposition for a specific genetic mutation involved in cancer development leads to unique tumor characteristics and better overall survival in youths (Table 2). EARLY ADULTHOOD AND THYROID CANCER (AGE 20 44YEARS) Unlike patients aged 20 or 60, the likelihood of cancer recurrence is lower in patients aged [3]. In addition, the likelihood of radioiodine-avid disease persists into early adulthood [11]. In a study of 121 patients with WDTC and lung metastases, at 20 years of follow-up, 50% of those with radioiodine-avid disease survived, versus 0% of those with radioiodine-resistant disease [11]. Age played a significant role in the survival disparity. The incidence of radioiodine-resistant disease was significantly lower in younger patients than in older patients (14.6% versus 44%, respectively; p.004), and the risk for mortality was 5.4 times higher if aged 45 years versus 45 years [11]. Even in the presence of distant metastases, age remains a strong prognostic indicator [15]. ADVANCED AGE AND THYROID CANCER (AGE >45 YEARS) Although the mortality rate starts to climb at age 45, the rate of recurrence is even higher starting at age 60 [3]. Again, this suggests that cancer recurrence and mortality do not have a one-to-one relationship. The association between older age and shorter survival cannot be explained by different stage at diagnosis, tumor differentiation, treatment, or socioeconomic variables [2, 16]. However, localized PTC or follicular thyroid cancer has an excellent prognosis and a weak dependence on age, whereas WDTC with regional or distant metastases has a survival rate that is strongly dependent on age [1, 2, 15 17]. In addition to the greater likelihood of radioiodineresistant disease with advanced age, there are other changes in the thyroid that occur with normal aging. With normal aging, the thyroid-stimulating hormone (TSH) distribution shifts toward higher concentrations [18]. Twenty-eight percent to 30% of TSH measurements in the range of miu/l shift to a higher concentration with aging irrespective of thyroid antibody status [18]. It is unclear if this shift is a result of a relative resistance to TSH at the level of the thyroid or a central resistance to thyroid hormone at the level of the pituitary. The fact that it occurs independent of antithyroid antibodies suggests the shift is not a result of gradual thyroid failure secondary to lymphocytic infiltrate from Hashimoto s thyroiditis. The reason for this shift in mean TSH with aging may be relevant to thyroid cancer because the TSH receptor plays a key role in the thyrocyte s ability to concentrate iodine. In addition to the decline in sodium iodine symporter activity, the loss of TSH receptor gene expression plays a role in the lower iodine concentrating ability of some thyroid cancers [19]. Aberrant DNA methylation may explain this TSH receptor gene silencing [19]. Alternatively, RET/PTC rearrangement can disrupt TSH action [14]. Although lower TSH receptor activity may contribute to less iodine uptake,

4 Haymart 219 RET/PTC rearrangement is thought to be associated with cancer in youths [14], which tends to be a radioiodine-avid disease, thus making the causality less clear. Recent studies have found a higher thyroid cancer incidence and advanced disease stage with higher TSH levels [20, 21]. Although there was initial speculation that this association may be secondary to advanced age, new data suggest that the association between higher TSH and cancer is independent of age [22]. Thus, the relationship between age and thyroid cancer is unlikely to be explained by TSH alone (Table 2). In women, the age-related worsening of prognosis with thyroid cancer starts closer to age 50 years, not 45 years. Because 51 is the mean age at onset of menopause, it is plausible that changes in either estrogen or luteinizing hormone (LH)/follicle-stimulating hormone (FSH) affect thyroid cancer growth and extension. Most logical, because FSH and LH have an identical subunit to TSH, it is possible that the LH and FSH rise with menopause stimulates thyroid cancer growth and invasion by stimulation of the TSH receptor. Alternative hypotheses for the association between advanced age and poor prognosis with thyroid cancer include a decline in immune system with age and a general increase in mortality from all causes with age. Because the thyroid cancer prognosis does not have the strong age-independent correlation to lymph node involvement that many other malignancies have [23], it is very possible that the lymphatic system limits invasion. Impaired immune response with age may explain worsening prognosis with age (Table 2). MANAGEMENT BASED ON AGE The mainstream management of thyroid cancer is total thyroidectomy, RAI ablation of the thyroid remnant, and suppressive doses of LT4 [24]. Because we have difficulty determining who will have aggressive disease versus indolent disease, we often overtreat our low-risk patients and undertreat our high-risk patients. BRAF is a molecular marker of importance because BRAF mutations are associated with extrathyroidal extension, lymph node metastases, advanced tumor stage, and cancer recurrence [25]. Further development and use of molecular markers may help endocrinologists tailor our therapy, but until molecular markers are fully evaluated and readily available we should rely on previous population studies of prognostic indicators to finetune our management. Although there is agreement on total thyroidectomy as the preferred surgical intervention for most thyroid cancer patients [24], there is disagreement as to the benefit of central neck dissection [26 28]. There is consensus that preoperative neck ultrasound (US) should be performed on all patients. Although US is not ideal for visualizing the central neck, if there are any visible lymph nodes seen ipsilateral, contralateral, or in the central neck, the benefits of central neck dissection increase. Because the tumor recurrence rate is higher in patients aged 20 years and 60 years and because staging is especially beneficial in those aged 45 years, the utility of aggressive surgery may be higher in these subgroups of patients. Prophylactic neck dissection can affect staging and indications for RAI [28]. After total thyroidectomy, RAI is used to reduce the likelihood of cancer recurrence and to treat residual disease. Studies have shown that RAI can decrease the likelihood of lymph node recurrence [29]. However, there is a small risk for secondary cancers in patients exposed to RAI [30], and thus the risk benefit ratio of RAI must be evaluated in each patient. Patients aged 20 years have the highest gain and the greatest risks from RAI. Younger patients are more likely to respond to RAI therapy [9, 11] and they are at a higher risk for a second malignancy [30]. If there is limited use of dosimetry, young patients with advanced disease may be ideal treatment candidates. Alternatively, both youths and adults with low-risk disease may not need RAI. When the cancer is locally contained and without high-risk features such as extrathyroidal extension, extensive lymph node involvement, or large tumor size, the utility of RAI is questionable in all patients and especially in those aged 20 44, who have a lower likelihood of both cancer recurrence and mortality. Recombinant human thyrotropin (rhtsh) has comparable remnant ablation rates to traditional thyroid hormone withdrawal [31]. If one were going to use rhtsh only in low-risk patients, patients aged years, who have a low risk for tumor recurrence and a low risk for overall mortality, may be prime candidates. However, because some older patients may be frail and not tolerate withdrawal, in some instances, rhtsh may be useful regardless of the extent of disease or risk assessment. Recent studies suggest that the efficacy of rhtsh is similar to withdrawal, and the use of rhtsh in a broader range of patients may become routine with time [31 34]. TSH is a growth factor, and suppressing TSH postoperatively is standard of care in thyroid cancer management. Suppressive doses of LT4 improve survival in patients with stage III and IV disease, and moderate TSH suppression is beneficial in patients with stage II disease [35]. Stage I thyroid cancer patients have an excellent prognosis regardless of therapy. Thus, treatment with suppressive doses of LT4 involves balancing the risks of arrhythmia and osteoporosis with the benefit of a lower likelihood of tumor growth. Two

5 220 Age and Thyroid Cancer Table 3. Management strategy based on age Surgery Preoperative neck ultrasound should be used in all patients. Because mortality increases at age 45 and older and the recurrence rate is higher if the patient is aged 20 years or 60 years, consider more aggressive lymph node dissection in patients with a higher risk for tumor recurrence. Recombinant TSH Patients aged have a relatively low risk for recurrence and low rate of mortality from disease. Liberal use of rhtsh may be warranted in this subgroup. Older, frail patients who cannot tolerate withdrawal may benefit from rhtsh for alternative reasons. RAI The risks and benefits of RAI should be assessed in all patients prior to routine administration. Some low-risk patients do not need RAI, especially in the subgroup aged years, who have a lower likelihood of recurrence and of mortality. If resources are limited and dosimetry cannot be used routinely, consider referral for dosimetry use in patients aged 20 who have extensive disease. Young patients have greater benefit and greater risks from RAI therapy. Suppressive LT4 Suppressive doses of LT4 improve outcome in patients with advanced stage disease. Moderate TSH suppression is beneficial in patients with stage II disease. Because stage is age dependent, after patients are at least 2 years postintervention and there is no sign of recurrence, TSH suppression can be liberalized in patients aged Older low-risk patients at risk for arrhythmia should also have TSH suppression liberalized. Abbreviations: LT4, levothyroxine; RAI, radioactive iodine; rhtsh, recombinant human thyrotropin; TSH, thyroidstimulating hormone. to 3 years postintervention, when there is no sign of cancer recurrence, the TSH suppression goal of 0.06 can be liberalized to in the majority of low-risk patients. In addition, because older patients may be at a higher risk for arrhythmias, liberalizing the goal TSH may be beneficial in some older patients as well. Clinical judgment is involved in tailoring the degree of TSH suppression to the patient (Table 3). SUMMARY Thyroid cancer is unique among malignancies because age is an important prognostic indicator in the majority of staging systems. In normal thyroid physiology, there are changes associated with age, such as a rise in TSH and a decline in the thyrocyte proliferation rate. However, aging does not just affect normal thyroid tissue, there is also a pattern of worse prognosis with thyroid cancer if aged 45. Although unlikely to be the sole explanation for the altered survival rate, loss of radioiodine avidity with age likely plays a role. Older patients are more likely than younger patients to have radioiodine-resistant disease, and this is relevant because RAI is one of the three standard treatments for WDTC. The reason for this discrepancy in sodium iodine symporter activity and TSH receptor activity is not clear and again suggests that there may be a difference in thyroid cancers at a molecular level. With the increased use of genetic profiling and tissue microarray analysis, it is possible that the relationship between age and thyroid cancer will be unraveled in the near future. ACKNOWLEDGMENT The Academic Oncologist K12 Training Grant through the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center supports Megan R. Haymart s research. REFERENCES 1 Hundahl SA, Fleming ID, Fremgen AM et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., Cancer 1998;83: Gilliland FD, Hunt WC, Morris DM et al. Prognostic factors for thyroid carcinoma: A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program Cancer 1997;79: Greene FL, Page DL, Fleming ID et al., eds. Thyroid. In: American Joint Committee on Cancer: Cancer Staging Manual, Sixth Edition. New York: Springer-Verlag, 2002: Dean DS, Hay ID. Prognostic indicators in differentiated thyroid carcinoma. Cancer Control 2000;7: Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86: Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, JAMA 2006;295: Faggiano A, Coulot J, Bellon N et al. Age-dependent variation of follicular size and expression of iodine transporters in human thyroid tissue. J Nucl Med 2004;45: Saad AG, Kumar S, Ron E et al. Proliferative activity of human thyroid cells in various age groups and its correlation with risk of thyroid cancer after radiation exposure. J Clin Endocrinol Metab 2006;91: Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: A qualitative review. Endocr Relat Cancer 2005;12: Miccoli P, Minuto MN, Ugolini C et al. Papillary thyroid cancer: Patholog-

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