Eliminating the Age Cutoff in Staging of Differentiated Thyroid Cancer: The Safest Road?

Eliminating the Age Cutoff in Staging of Differentiated Thyroid Cancer: The Safest Road? Abstract Background Unlike virtually all other cancer types, thyroid cancer is unique in that patient age is a key component in its staging. Pathologists and clinicians worldwide have accepted an age cutoff of 45 years for staging; in 2018, this advances to age 55 years in the eighth edition of the American Joint Commission on Cancer staging system. Evidence Acquisition Clinical and basic research studies, reviews, and previous editions of consensus statements regarding thyroid cancer staging were reviewed, with particular focus on the influence of age in thyroid cancer prognosis. Purpose This perspective briefly reviews the basis for this practice and challenges it as no more appropriate than for other malignancies. Evidence Synthesis The majority of findings report an association of age with thyroid cancer survival but do not support a specific age cutoff; rather, they suggest that outcome is affected by age as a continuous variable. Conceivably, other factors interact with age on a continuous basis over time, affecting prognosis. When identified, these factors could alter our current concept of the importance of an age cutoff in staging. Conclusions Among all cancers, age has an important role in only thyroid cancer staging. The consideration of age as a continuous variable and the search for age-associated prognostic variables could elucidate a more accurate staging system. In patients with thyroid cancer, several pathologic and clinical characteristics have been shown to impact prognosis and consequently have served as predictors of tumor behavior and disease outcome. These observations have constituted the basis for staging of thyroid cancer, with most staging systems incorporating the principal factors of patient age, tumor size, and extent of the disease at presentation. Patient age at time of presentation has clearly affected ultimate outcome (1, 2), and the American Joint Committee on Cancer (AJCC) has incorporated age into tumor–node–metastasis (TNM) staging since 1983 (updated this year in the eighth edition) (3, 4). Curiously, in distinction to other cancer types, thyroid cancer has age incorporated into its staging. Although pathologists and clinicians worldwide have accepted an age cutoff as a unique component of staging for thyroid cancer, we challenge this practice as no more appropriate than for other malignancies. Evolution of Age Into the Staging System The AJCC staging system proposed in 1977 evolved from the European system developed by the Union Internationale Contre le Cancer. Age was subsequently confirmed as integral to thyroid cancer staging in the AJCC’s second edition, published in 1983, on the basis of studies by Halnan (5) and Cady et al. (6) in which age and thyroid cancer death were correlated in patients with differentiated thyroid cancer. Another important validation of age as a factor in outcome was reported by Ito et al. (7) in a study of 1740 patients with papillary thyroid carcinoma, and the relationship has been confirmed in several other studies (8, 9). Of note, patient age was more likely to be a factor for follicular thyroid cancer than for papillary cancer in one study (10) but not in another (11). As stated previously, on the basis of the AJCC/TNM staging system, all workers had accepted a cutoff point of 45 years, which did not change until the release of the eighth edition, in which a specific cutoff point has been maintained but has increased from 45 to 55 years (3, 4). Advancement of the age cutoff to 55 years was suggested by Nixon et al. (12) on the basis of a study involving 9484 patients with thyroid cancer from 10 institutions in which the higher cutoff increased the model’s validity, offering more accurate prognosis prediction. A report from Memorial Sloan-Kettering Cancer Center (MSKCC) involving 1807 patients suggested the same increased age cutoff (13). Although it is not uncommon to see children and adolescents with extensive lymph node involvement and/or distant metastases at presentation, these patients typically exhibit avid radioiodine uptake and experience good outcomes. Notwithstanding the latter patients, no clear explanation has justified a direct association between outcome and more advanced age. However, there may be several reasons why older patients at time of diagnosis tend to have worse outcomes than younger patients. Well-differentiated thyroid cancer is a slow-growing tumor, and in general, tumors discovered at a younger age are more likely to be confined to the thyroid gland or, at worst, extended to regional lymph nodes, perhaps only in the central compartment of the neck. As the years pass without diagnosis, however, these tumors have the opportunity to invade locally with regional involvement and to develop distant metastases, both of which are associated with worsened prognosis. Thus, the problem is not age, but simply the epiphenomenon overshadowing the more obvious and important cause of declining prognosis, that is, the extension of disease. Although not proven, it has been suggested that with time, well-differentiated tumors may mutate or dedifferentiate, becoming both more aggressively invasive and less likely to be sensitive to radioactive iodine, hence the poorer prognosis. An example of an age-related mutation was provided by Elisei et al. (14), who observed increased incidence of a BRAF V600E mutation with age and concluded that only the mutation and not age demonstrated an independent correlation with the worst outcome (P = 0.03) and with survival in multivariate analyses. This observation is fully consistent with recent data describing a linear relationship between age and mortality in patients with BRAF V600E mutation-positive tumors, which was not seen in patients with wild-type BRAF tumors. These authors concluded that age is an independent continuous risk factor for mortality, but only in BRAF V600E-positive patients (15). In considering why older patients with thyroid cancer do more poorly, one needs to take into account the likelihood that older patients obviously have health issues related to nonthyroidal disease that affect their mortality risk and that an adverse outcome or mortality in a patient with thyroid cancer is not always disease specific. Perhaps this is relevant regarding the previously mentioned MSKCC study, two aspects of which should be underscored. First, all patients who had evidence of active structural disease at the last follow-up and subsequently died were included in thyroid cancer-related deaths, increasing the possibility of including patients who died of other causes. Second, the study examined whether 55 years of age would be a better cutoff point than 45 years of age; however, they did not consider whether continuous consideration of age would be more appropriate. Age Effect, a Cutoff or a Continuous Variable? Recent studies analyzed age as a continuous variable rather than a dichotomic factor and found a better concordance with specific survival and thyroid cancer death rates. This is why it has been suggested that age should be considered as a spectrum rather than as a specific cutoff point. In a 2015 report involving 3664 patients with thyroid cancer at MSKCC, Ganly et al. (16) concluded that the mortality from differentiated thyroid cancer increased progressively with advancing age and that no specific age cutoff could be identified. The same conclusion was reached by Orosco et al. (17) and by Adam et al. (18) in a study of 31,802 patients from the Surveillance, Epidemiology, and End Result database in which an age cutoff point could not be identified and patient age was significantly associated with death in a linear fashion. The authors concluded that their results “challenge the appropriateness of a patient age cut point in current staging systems for papillary thyroid cancer (PTC) and argue for considering a revision in how we anticipate prognosis for patients with PTC” (18). Indeed, three of the authors contributing to the AJCC’s revised eighth edition acknowledged that “any single cut point for age is likely to perform less well than models that consider age as a continuous variable.” (18). A mentioned previously, that continuity of risk simply may relate to BRAF V600E mutational status (15). Basis for an Influence of Age The explanation for the association of age with thyroid cancer outcome has still to be elucidated; however, some hypotheses have been suggested (Table 1). Among the explanations discussed by Haymart (19) are that more functional sodium iodine symporter expression in young patients may explain why they are more likely to have radioiodine-avid cancer and a better prognosis and that the known increases in serum thyrotropin (TSH) level with aging could foster both higher thyroid cancer incidence and accelerated progression of tumor growth. Haymart (19) suggested that reduced sodium iodine symporter function may be related to aberrancy in TSH receptor gene expression with age. Thus, if avidity for radioiodine uptake tends to be lost with age and radioiodine-refractory tumors have the worse prognosis, is it not more reasonable to consider degree of radioiodine avidity as a characteristic influencing stage and mortality risk rather than age? This would be consistent with the poor prognosis seen with tall cell variant and Hürthle cell carcinomas, tumors that tend to be radioiodine refractory and more common in older subjects (20, 21). Incorporation of degree of radioiodine avidity into staging would affect the entire age spectrum of patients with thyroid cancer. Haymart (19) also noted the worse prognosis for older women described previously (7, 22), with speculation that perimenopausal changes with increased serum follicle-stimulating hormone and luteinizing hormone may stimulate cancer growth and invasion in this population via stimulation of the TSH receptor by the common α unit they share with TSH. Table 1. Possible Theories Explaining the Association of Age and Thyroid Cancer Prognosis Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; RAI, radioactive iodine; TSH, thyrotropin. a Loss of RAI avidity in older patients may be related to differences in underlying oncogenic alterations. View Large Table 1. Possible Theories Explaining the Association of Age and Thyroid Cancer Prognosis Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; RAI, radioactive iodine; TSH, thyrotropin. a Loss of RAI avidity in older patients may be related to differences in underlying oncogenic alterations. View Large Patients who are older at time of diagnosis of a number of common nonthyroid cancers have also had a worse prognosis than their younger counterparts. According to UK cancer statistics, almost half (47%) of female breast cancer deaths in the United Kingdom each year are in females 75 years and older, and mortality rates for both male and female breast cancers in the United Kingdom are highest in patients aged >90 years. Almost half of the people in England diagnosed with lung cancer at age 15 to 39 years survive their disease for 5 years or more, compared with only 5% of people diagnosed at age 80 years and over. The bowel cancer survival rate in England is higher for people diagnosed at age 15 to 39 years and those diagnosed at age 6 to 69 years than for those diagnosed at other ages; 70% of people in England diagnosed with bowel cancer at age 15 to 39 years survive their disease for 5 years or more compared with only 40% of people diagnosed at age 80 years and over. Almost 95% of men in England diagnosed with prostate cancer at age 50 to 59 or 60 to 69 years survive their disease for 5 years or more compared with 66% of men diagnosed at age 80 years and over (23). So it would seem undeniable that age at diagnosis influences outcome; however, the point is that among all cancer types, only thyroid cancer has the peculiarity of incorporating age in staging. In the 34 years we have been using age to stage cancer in our patients, a physiopathologic mechanism justifying why age should have such a prominent a role in the staging and prognosis of thyroid cancer has yet to be elucidated. Over the course of these decades, the AJCC/TNM classification system has undergone eight revisions, testimony to perceived inadequacies of each preceding classification version. We have learned a great deal about the diagnosis and management of thyroid cancer during these years, and much of that knowledge has shaped the revised classification system, thereby improving its relevancy to our clinical practice. In regard to clinical practice, we are reminded that the focus of AJCC/TNM classification is patient mortality and that day-to-day management of thyroid cancer rests more often on the patient’s risk for recurrence, as clearly defined in the American Thyroid Association guidelines (24). Nevertheless, inconsistencies in the AJCC classification system remain. For example, the downstaging of most cancer to low risk (stage I) simply on the basis of an age cutoff is troublesome. We do not believe that advanced and invasive locoregional disease in a 54-year-old patient merits classification as stage I any more than the same disease in a 44-year-old would have in the seventh edition. Also, although the presence of distant metastasis raises disease to stage II, classifying extensive non‒radioiodine-avid lung and bone metastases in the same 54-year-old as only stage II fails to appreciate the mortality risk of such a patient. In our view, the recent analyses of larger patient cohorts indicating the effect of age as a continuous variable disqualifies an age cutoff as a major component of staging. However, before the current staging system is abandoned, specific underlying oncogenic alterations that could be currently overshadowed by age should be identified. Studies based on large databases that account for all variables are required. A future practical and useful revision of a staging system should incorporate prognostic factors such as the type and extent of lymph node metastases, radioactive iodine avidity, and perhaps BRAF V600E or other mutational status. Although the significance of BRAF status on survival has not been determined (25), an independent linear association between age and mortality has been shown in patients with BRAF V600E but not in either typically seen PTC or patients with wild-type BRAF (15). Thus, recent observations suggest that an effect of age on mortality obtains not as a precipitous cutoff but rather as a gradual or continuous variable. To quote C.S. Lewis, “The safest road…is the gradual one – the gentle slope, soft underfoot, without sudden turnings, without milestones, without signposts” (26). Abbreviations: Abbreviations: AJCC American Joint Committee on Cancer MSKCC Memorial Sloan-Kettering Cancer Center PTC papillary thyroid cancer TNM tumor–node–metastasis TSH thyrotropin Acknowledgments Disclosure Summary: D.Y. has nothing to declare. K.D.B.: clinical trials, Eisei, AstraZeneca, and IBSA; consultant, UpToDate and LioTriDev. D.V.N.: speaker and consultant for Genzyme/Sanofi and Jubilant DraxImage. L.W.: speaker bureau, Genzyme/Sanofi. References 1. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP. Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab . 1997; 82( 11): 3553– 3562. Google Scholar CrossRef Search ADS PubMed  2. Sobin LH, Gospodarowicz MK, Wittekind Ch. International Union against Cancer. TNM Classification of Malignant Tumours . Hoboken, NJ: Wiley-Blackwell; 2009. 3. Tuttle M, Haugen B, Perrier D. Updated American Joint Committee on Cancer  /tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why? Thyroid. 2017;27(6):751–756. 4. Amin MB, Edge SB, Greene F, Byrd D, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley J, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR, eds. AJCC Cancer Staging Manual . 8th ed. New York, NY: Springer International Publishing; 2017. Google Scholar CrossRef Search ADS   5. Halnan KE. Influence of age and sex on incidence and prognosis of thyroid cancer: three hundred forty-four cases followed for ten years. Cancer . 1966; 19( 11): 1534– 1536. Google Scholar CrossRef Search ADS PubMed  6. Cady B, Sedgwick CE, Meissner WA, Wool MS, Salzman FA, Werber J. Risk factor analysis in differentiated thyroid cancer. Cancer . 1979; 43( 3): 810– 820. Google Scholar CrossRef Search ADS PubMed  7. Ito Y, Miyauchi A, Jikuzono T, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Ichihara K, Kuma K. Risk factors contributing to a poor prognosis of papillary thyroid carcinoma: validity of UICC/AJCC TNM classification and stage grouping. World J Surg . 2007; 31( 4): 838– 848. Google Scholar CrossRef Search ADS PubMed  8. Sugino K, Ito K, Nagahama M, Kitagawa W, Shibuya H, Ohkuwa K, Yano Y, Uruno T, Akaishi J, Kameyama K, Ito K. 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Nixon IJ, Wang LY, Migliacci JC, Eskander A, Campbell MJ, Aniss A, Morris L, Vaisman F, Corbo R, Momesso D, Vaisman M, Carvalho A, Learoyd D, Leslie WD, Nason RW, Kuk D, Wreesmann V, Morris L, Palmer FL, Ganly I, Patel SG, Singh B, Tuttle RM, Shaha AR, Gönen M, Pathak KA, Shen WT, Sywak M, Kowalski L, Freeman J, Perrier N, Shah JP. An international multi-institutional validation of age 55 years as a cutoff for risk stratification in the AJCC/UICC staging system for well-differentiated thyroid cancer. Thyroid . 2016; 26( 3): 373– 380. Google Scholar CrossRef Search ADS PubMed  13. Nixon IJ, Kuk D, Wreesmann V, Morris L, Palmer FL, Ganly I, Patel SG, Singh B, Tuttle RM, Shaha AR, Gönen M, Shah JP. Defining a valid age cutoff in staging of well-differentiated thyroid cancer. Ann Surg Oncol . 2016; 23( 2): 410– 415. Google Scholar CrossRef Search ADS PubMed  14. Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F. 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Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid . 2016; 26( 1): 1– 133. Google Scholar CrossRef Search ADS PubMed  25. Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O’Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Clifton-Bligh R, Tallini G, Holt EH, Sýkorová V. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol . 2015; 33( 1): 42– 50. Google Scholar CrossRef Search ADS PubMed  26. Lewis CS. The Screwtape Letters, London, UK: Geoffrey Bles; 1942:64-65. Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Eliminating the Age Cutoff in Staging of Differentiated Thyroid Cancer: The Safest Road?

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Abstract

Abstract Background Unlike virtually all other cancer types, thyroid cancer is unique in that patient age is a key component in its staging. Pathologists and clinicians worldwide have accepted an age cutoff of 45 years for staging; in 2018, this advances to age 55 years in the eighth edition of the American Joint Commission on Cancer staging system. Evidence Acquisition Clinical and basic research studies, reviews, and previous editions of consensus statements regarding thyroid cancer staging were reviewed, with particular focus on the influence of age in thyroid cancer prognosis. Purpose This perspective briefly reviews the basis for this practice and challenges it as no more appropriate than for other malignancies. Evidence Synthesis The majority of findings report an association of age with thyroid cancer survival but do not support a specific age cutoff; rather, they suggest that outcome is affected by age as a continuous variable. Conceivably, other factors interact with age on a continuous basis over time, affecting prognosis. When identified, these factors could alter our current concept of the importance of an age cutoff in staging. Conclusions Among all cancers, age has an important role in only thyroid cancer staging. The consideration of age as a continuous variable and the search for age-associated prognostic variables could elucidate a more accurate staging system. In patients with thyroid cancer, several pathologic and clinical characteristics have been shown to impact prognosis and consequently have served as predictors of tumor behavior and disease outcome. These observations have constituted the basis for staging of thyroid cancer, with most staging systems incorporating the principal factors of patient age, tumor size, and extent of the disease at presentation. Patient age at time of presentation has clearly affected ultimate outcome (1, 2), and the American Joint Committee on Cancer (AJCC) has incorporated age into tumor–node–metastasis (TNM) staging since 1983 (updated this year in the eighth edition) (3, 4). Curiously, in distinction to other cancer types, thyroid cancer has age incorporated into its staging. Although pathologists and clinicians worldwide have accepted an age cutoff as a unique component of staging for thyroid cancer, we challenge this practice as no more appropriate than for other malignancies. Evolution of Age Into the Staging System The AJCC staging system proposed in 1977 evolved from the European system developed by the Union Internationale Contre le Cancer. Age was subsequently confirmed as integral to thyroid cancer staging in the AJCC’s second edition, published in 1983, on the basis of studies by Halnan (5) and Cady et al. (6) in which age and thyroid cancer death were correlated in patients with differentiated thyroid cancer. Another important validation of age as a factor in outcome was reported by Ito et al. (7) in a study of 1740 patients with papillary thyroid carcinoma, and the relationship has been confirmed in several other studies (8, 9). Of note, patient age was more likely to be a factor for follicular thyroid cancer than for papillary cancer in one study (10) but not in another (11). As stated previously, on the basis of the AJCC/TNM staging system, all workers had accepted a cutoff point of 45 years, which did not change until the release of the eighth edition, in which a specific cutoff point has been maintained but has increased from 45 to 55 years (3, 4). Advancement of the age cutoff to 55 years was suggested by Nixon et al. (12) on the basis of a study involving 9484 patients with thyroid cancer from 10 institutions in which the higher cutoff increased the model’s validity, offering more accurate prognosis prediction. A report from Memorial Sloan-Kettering Cancer Center (MSKCC) involving 1807 patients suggested the same increased age cutoff (13). Although it is not uncommon to see children and adolescents with extensive lymph node involvement and/or distant metastases at presentation, these patients typically exhibit avid radioiodine uptake and experience good outcomes. Notwithstanding the latter patients, no clear explanation has justified a direct association between outcome and more advanced age. However, there may be several reasons why older patients at time of diagnosis tend to have worse outcomes than younger patients. Well-differentiated thyroid cancer is a slow-growing tumor, and in general, tumors discovered at a younger age are more likely to be confined to the thyroid gland or, at worst, extended to regional lymph nodes, perhaps only in the central compartment of the neck. As the years pass without diagnosis, however, these tumors have the opportunity to invade locally with regional involvement and to develop distant metastases, both of which are associated with worsened prognosis. Thus, the problem is not age, but simply the epiphenomenon overshadowing the more obvious and important cause of declining prognosis, that is, the extension of disease. Although not proven, it has been suggested that with time, well-differentiated tumors may mutate or dedifferentiate, becoming both more aggressively invasive and less likely to be sensitive to radioactive iodine, hence the poorer prognosis. An example of an age-related mutation was provided by Elisei et al. (14), who observed increased incidence of a BRAF V600E mutation with age and concluded that only the mutation and not age demonstrated an independent correlation with the worst outcome (P = 0.03) and with survival in multivariate analyses. This observation is fully consistent with recent data describing a linear relationship between age and mortality in patients with BRAF V600E mutation-positive tumors, which was not seen in patients with wild-type BRAF tumors. These authors concluded that age is an independent continuous risk factor for mortality, but only in BRAF V600E-positive patients (15). In considering why older patients with thyroid cancer do more poorly, one needs to take into account the likelihood that older patients obviously have health issues related to nonthyroidal disease that affect their mortality risk and that an adverse outcome or mortality in a patient with thyroid cancer is not always disease specific. Perhaps this is relevant regarding the previously mentioned MSKCC study, two aspects of which should be underscored. First, all patients who had evidence of active structural disease at the last follow-up and subsequently died were included in thyroid cancer-related deaths, increasing the possibility of including patients who died of other causes. Second, the study examined whether 55 years of age would be a better cutoff point than 45 years of age; however, they did not consider whether continuous consideration of age would be more appropriate. Age Effect, a Cutoff or a Continuous Variable? Recent studies analyzed age as a continuous variable rather than a dichotomic factor and found a better concordance with specific survival and thyroid cancer death rates. This is why it has been suggested that age should be considered as a spectrum rather than as a specific cutoff point. In a 2015 report involving 3664 patients with thyroid cancer at MSKCC, Ganly et al. (16) concluded that the mortality from differentiated thyroid cancer increased progressively with advancing age and that no specific age cutoff could be identified. The same conclusion was reached by Orosco et al. (17) and by Adam et al. (18) in a study of 31,802 patients from the Surveillance, Epidemiology, and End Result database in which an age cutoff point could not be identified and patient age was significantly associated with death in a linear fashion. The authors concluded that their results “challenge the appropriateness of a patient age cut point in current staging systems for papillary thyroid cancer (PTC) and argue for considering a revision in how we anticipate prognosis for patients with PTC” (18). Indeed, three of the authors contributing to the AJCC’s revised eighth edition acknowledged that “any single cut point for age is likely to perform less well than models that consider age as a continuous variable.” (18). A mentioned previously, that continuity of risk simply may relate to BRAF V600E mutational status (15). Basis for an Influence of Age The explanation for the association of age with thyroid cancer outcome has still to be elucidated; however, some hypotheses have been suggested (Table 1). Among the explanations discussed by Haymart (19) are that more functional sodium iodine symporter expression in young patients may explain why they are more likely to have radioiodine-avid cancer and a better prognosis and that the known increases in serum thyrotropin (TSH) level with aging could foster both higher thyroid cancer incidence and accelerated progression of tumor growth. Haymart (19) suggested that reduced sodium iodine symporter function may be related to aberrancy in TSH receptor gene expression with age. Thus, if avidity for radioiodine uptake tends to be lost with age and radioiodine-refractory tumors have the worse prognosis, is it not more reasonable to consider degree of radioiodine avidity as a characteristic influencing stage and mortality risk rather than age? This would be consistent with the poor prognosis seen with tall cell variant and Hürthle cell carcinomas, tumors that tend to be radioiodine refractory and more common in older subjects (20, 21). Incorporation of degree of radioiodine avidity into staging would affect the entire age spectrum of patients with thyroid cancer. Haymart (19) also noted the worse prognosis for older women described previously (7, 22), with speculation that perimenopausal changes with increased serum follicle-stimulating hormone and luteinizing hormone may stimulate cancer growth and invasion in this population via stimulation of the TSH receptor by the common α unit they share with TSH. Table 1. Possible Theories Explaining the Association of Age and Thyroid Cancer Prognosis Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; RAI, radioactive iodine; TSH, thyrotropin. a Loss of RAI avidity in older patients may be related to differences in underlying oncogenic alterations. View Large Table 1. Possible Theories Explaining the Association of Age and Thyroid Cancer Prognosis Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Theory  Explanation  RAI aviditya  Thyroid cancer cells from young patients usually have good expression of sodium iodine symporter. This allows radioiodine avidity and a better prognosis.  TSH stimulation  Increases in serum TSH level with aging could both increase thyroid cancer incidence and accelerate progression of tumor growth.  Genetic variation  The type of genetic mutations in thyroid cancer differs with age. Clinical aspects of tumor behavior with RAI treatment, response to medical therapy, and aggressiveness are influenced by the mutation(s) present, which can then alter the prognosis.  Increased mortality  Older patients have other comorbidities of nonthyroidal disease that affect their mortality risk. In older patients with thyroid cancer, these confound whether mortality was disease specific.  LH and FSH increase  Increases of serum FSH and LH in menopausal women may stimulate cancer growth and invasion via stimulation of the TSH receptor by the common α subunit they share with TSH.  Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; RAI, radioactive iodine; TSH, thyrotropin. a Loss of RAI avidity in older patients may be related to differences in underlying oncogenic alterations. View Large Patients who are older at time of diagnosis of a number of common nonthyroid cancers have also had a worse prognosis than their younger counterparts. According to UK cancer statistics, almost half (47%) of female breast cancer deaths in the United Kingdom each year are in females 75 years and older, and mortality rates for both male and female breast cancers in the United Kingdom are highest in patients aged >90 years. Almost half of the people in England diagnosed with lung cancer at age 15 to 39 years survive their disease for 5 years or more, compared with only 5% of people diagnosed at age 80 years and over. The bowel cancer survival rate in England is higher for people diagnosed at age 15 to 39 years and those diagnosed at age 6 to 69 years than for those diagnosed at other ages; 70% of people in England diagnosed with bowel cancer at age 15 to 39 years survive their disease for 5 years or more compared with only 40% of people diagnosed at age 80 years and over. Almost 95% of men in England diagnosed with prostate cancer at age 50 to 59 or 60 to 69 years survive their disease for 5 years or more compared with 66% of men diagnosed at age 80 years and over (23). So it would seem undeniable that age at diagnosis influences outcome; however, the point is that among all cancer types, only thyroid cancer has the peculiarity of incorporating age in staging. In the 34 years we have been using age to stage cancer in our patients, a physiopathologic mechanism justifying why age should have such a prominent a role in the staging and prognosis of thyroid cancer has yet to be elucidated. Over the course of these decades, the AJCC/TNM classification system has undergone eight revisions, testimony to perceived inadequacies of each preceding classification version. We have learned a great deal about the diagnosis and management of thyroid cancer during these years, and much of that knowledge has shaped the revised classification system, thereby improving its relevancy to our clinical practice. In regard to clinical practice, we are reminded that the focus of AJCC/TNM classification is patient mortality and that day-to-day management of thyroid cancer rests more often on the patient’s risk for recurrence, as clearly defined in the American Thyroid Association guidelines (24). Nevertheless, inconsistencies in the AJCC classification system remain. For example, the downstaging of most cancer to low risk (stage I) simply on the basis of an age cutoff is troublesome. We do not believe that advanced and invasive locoregional disease in a 54-year-old patient merits classification as stage I any more than the same disease in a 44-year-old would have in the seventh edition. Also, although the presence of distant metastasis raises disease to stage II, classifying extensive non‒radioiodine-avid lung and bone metastases in the same 54-year-old as only stage II fails to appreciate the mortality risk of such a patient. In our view, the recent analyses of larger patient cohorts indicating the effect of age as a continuous variable disqualifies an age cutoff as a major component of staging. However, before the current staging system is abandoned, specific underlying oncogenic alterations that could be currently overshadowed by age should be identified. Studies based on large databases that account for all variables are required. A future practical and useful revision of a staging system should incorporate prognostic factors such as the type and extent of lymph node metastases, radioactive iodine avidity, and perhaps BRAF V600E or other mutational status. Although the significance of BRAF status on survival has not been determined (25), an independent linear association between age and mortality has been shown in patients with BRAF V600E but not in either typically seen PTC or patients with wild-type BRAF (15). Thus, recent observations suggest that an effect of age on mortality obtains not as a precipitous cutoff but rather as a gradual or continuous variable. To quote C.S. Lewis, “The safest road…is the gradual one – the gentle slope, soft underfoot, without sudden turnings, without milestones, without signposts” (26). Abbreviations: Abbreviations: AJCC American Joint Committee on Cancer MSKCC Memorial Sloan-Kettering Cancer Center PTC papillary thyroid cancer TNM tumor–node–metastasis TSH thyrotropin Acknowledgments Disclosure Summary: D.Y. has nothing to declare. K.D.B.: clinical trials, Eisei, AstraZeneca, and IBSA; consultant, UpToDate and LioTriDev. D.V.N.: speaker and consultant for Genzyme/Sanofi and Jubilant DraxImage. 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Lewis CS. The Screwtape Letters, London, UK: Geoffrey Bles; 1942:64-65. Copyright © 2018 Endocrine Society

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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: May 7, 2018

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