thyroid cancer incidence patterns in the united states by histologic type, 1992–2006

Thyroid Cancer Incidence Patternsin the United States by Histologic Type, 1992–2006

Briseis Aschebrook-Kilfoy,1 Mary H. Ward,1 Mona M. Sabra,2,3 and Susan S. Devesa 4

Background: The increasing incidence of thyroid cancer in the United States is well documented. In this study,we assessed the incidence patterns by histologic type according to demographic and tumor characteristics tofurther our understanding of these cancers.Methods: We used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) programfor cases diagnosed during 1992–2006 to investigate patterns for the four major histologic types of thyroid cancerby gender, race/ethnicity, and age as well as registry, tumor stage, and size.Results: Among women, papillary thyroid cancer rates were highest among Asians (10.96 per 100,000 woman-years) and lowest among blacks (4.90 per 100,000 woman-years); follicular cancer rates did not vary substantiallyby race/ethnicity ( p-values >0.05), medullary cancer rates were highest among Hispanics (0.21 per 100,000woman-years) and whites (0.22 per 100,000 woman-years), and anaplastic rates were highest among Hispanics(0.17 per 100,000 woman-years). Among men, both papillary and follicular thyroid cancer rates were highestamong whites (3.58 and 0.58 per 100,000 man-years, respectively), medullary cancer rates were highest amongHispanics (0.18 per 100,000 man-years), and anaplastic rates were highest among Asians (0.11 per 100,000man-years). Racial/ethnic-specific rates did not vary notably across registries. In contrast to age-specific rates ofpapillary thyroid cancer that peaked in midlife (age 50), especially pronounced among women, rates for follicular,medullary, and anaplastic types continued to rise across virtually the entire age range, especially for anaplasticcarcinomas. Female-to-male incidence rate ratios among whites decreased with age most steeply for the folliculartype and least steeply for the medullary type; it was <1 until the very oldest ages for the anaplastic type.Conclusion: We conclude that the similar age-specific patterns and lack of geographical variation across the SEERracial/ethnic groups indicate that detection effects cannot completely explain the observed thyroid cancer inci-dence patterns as variation in the amount or quality of healthcare provided has been shown to vary by SEERracial/ethnic groups, gender, and age. We find that the variations in age-specific patterns by gender and acrosshistologic types are intriguing and recommend that future etiologic investigation focus on exogenous and en-dogenous exposures that are experienced similarly by racial/ethnic groups, more strongly among women, anddistinctively by age.

Introduction

A rise in thyroid cancer incidence, especially of thepapillary type, has been reported in several countries,

including the United States, during the past several decades(1–6), and the factors responsible for the increase remain un-known. Thus far, the majority of the descriptive epidemiology

of thyroid cancer has evaluated thyroid cancer overall or hasbeen limited to the investigation of the papillary histologictype. A comparison of thyroid cancer types by gender acrossSurveillance, Epidemiology, and End Results (SEER) racial/ethnic groups, by age at diagnosis, and by tumor character-istics presents an opportunity to consider the role of detectionand access to technology on incidence patterns. Consideration

1Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Department of Health andHuman Services, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

2Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, Baltimore, Maryland.3Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, Baltimore Veterans Health Administration Medicine Center,

Baltimore, Maryland.4Biostatistics Branch, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer

Institute, National Institutes of Health, Rockville, Maryland.

THYROIDVolume 21, Number 2, 2011ª Mary Ann Liebert, Inc.DOI: 10.1089/thy.2010.0021

125

of the descriptive patterns of thyroid cancer could provideclues about the role of changing risk factors and detectionmethods in the dramatically increasing disease rates.

Five groups recently examined time trends in thyroidcancer incidence overall, and papillary cancer in particular,using SEER data (1,3,4,7,8). Enewold et al. examined thyroidcancer incidence by demographic and tumor characteristicsand found that between 1992–1995 and 2003–2005, rates ofpapillary thyroid cancers increased nearly 100% among non-Hispanic white and black women but only 20%–50% amongHispanics, Asian/Pacific Islanders, and black men (4). Simi-larly, during a comparable period (1992–2004), Yu et al. foundthat the papillary carcinoma increases translated into an an-nual percent change of 5.6% among non-Hispanic whites,4.3% among non-Hispanic blacks, 2.8% among Hispanicwhites, and 1.5% among Asians (8). Additionally, both groupsreported increases in large as well as small tumors among allSEER racial/ethnic groups studied, and Yu et al. further re-ported that local stage tumors increased 24% among blacks,compared to 14.4% among Hispanic whites, 14.3% amongnon-Hispanic whites, and 4.0% among Asians.

As race/ethnicity can be thought of as a proxy for health-care access in the United States given that blacks, Hispan-ics, Asian/Pacific Islanders, and American Indian/AlaskaNatives are more likely to be uninsured than non-Hispanicwhites (9), these results seem to contradict the notion thatthyroid cancer incidence is artificially inflated due to a de-tection effect (3) and suggest that more investigation into ratesby sex-specific demographic and geographic factors is war-ranted. Further, as the overall increases in thyroid cancer inprevious SEER studies were mainly due to rising papillaryrates while the rates of other histologic types changed little (4),this also suggests that perhaps diagnosis is not as significant afactor as recently proposed by others as one would expectsimilar increases for follicular and medullary tumors. As such,further investigation of the incidence patterns for the follicu-lar, medullary, and anaplastic subtypes by demographic andregional factors is of interest.

By considering the incidence patterns in light of differentregional and demographic factors that might impact thyroidcancer diagnosis, we suggest that clues into the role of de-tection and opportunities for further etiologic research may berevealed. In this study, we were interested in evaluating theincidence patterns for the four major histologic types of thy-roid cancer by gender, race/ethnicity, and age as well asregistry, tumor stage, and size. Our investigation of all fourthyroid cancer histologic types extends the recent analysesof trends for papillary thyroid carcinoma and explores factorsthat could further our understanding of recent incidencetrends and disease etiology.

Methods

We used the National Cancer Institute’s SEER 13 RegistriesDatabase, November 2008 Submission (10), to analyze maleand female thyroid carcinoma incidence rates (IRs) by histo-logic type based on cases diagnosed during 1992 through 2006among residents of the areas included in the 13 registries inAtlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, SanFrancisco–Oakland, Seattle–Puget Sound, Utah, Los Angeles,San Jose–Monterey, Rural Georgia, and the Alaska NativeTumor Registry, covering *14% of the U.S. population.

Invasive thyroid cancer cases were coded using the Inter-national Classification of Diseases for Oncology, third edition(ICD-O-3) (11), and our analysis included the four major his-tological types: papillary carcinoma (ICD-O-3 codes 8050, 8260,8340-8341, 8343-8344, and 8350), follicular carcinoma (ICD-O-3codes 8290, 8330-8332, and 8335), medullary carcinoma (ICD-O-3 codes 8345-8346 and 8510), and anaplastic carcinoma (ICD-O-3 codes 8012, 8020-8021, and 8030-8032). All other ICD-O-3codes were categorized as other or unknown.

In addition to analyzing thyroid cancer types by gender, weevaluated demographic and tumor characteristics, includingage at diagnosis, race/ethnicity, SEER historic stage A, andtumor size. SEER racial/ethnic groups included non-Hispanicwhites (hereafter referred to as whites), Hispanic whites(hereafter referred to as Hispanics), blacks, Asians/PacificIslanders (hereafter referred to as Asians), and American In-dians/Alaskan Natives combined. SEER historic stage A wasused to classify thyroid cancers as localized (limited to thethyroid gland), regional (limited to surrounding tissues), anddistant or systemic disease (11). Tumor size was the cancer’sgreatest diameter as recorded on surgical pathology reports,which we categorized as �1, >1, and �2 cm, >2 and �4 cm,and >4 cm based on the Extent of Disease-10 codes for 1992–2003 and the Collaborative Staging codes for 2004–2006 (10).

Data analysis

IRs were calculated using SEER*Stat 6.5.1 (12) and ex-pressed per 100,000 person-years, man-years, or woman-years. Age-adjusted IRs were standardized to the 2000 U.S.population. Relative risks were expressed as IR ratios (IRRs),where a given characteristic was compared to a referent grouprate assigned an IRR of 1.0 (13,14). Statistical significance ofrates and IRR were assessed at the p< 0.05 alpha level; allhypothesis tests were two sided. Disease IRs were reported ifthere were at least 10 cases in a category, and IRRs were re-ported if both rates were based on at least 10 cases. Age-specific IRs and IRRs by racial/ethnic group for each histo-logic type were plotted on a log y and linear x scale, such that aslope of 108 equaled a change in rates of 1% per year (i.e., 40years on the horizontal axis is the same length as one loga-rithmic cycle on the vertical axis) (15); single data points werenot shown. The presentation of tumor stage and size in tableswas restricted to whites due to small numbers of cases in otherracial/ethnic groups, although our analyses considered allSEER racial/ethnic groups.

Results

A total of 43,644 thyroid cancer cases were diagnosed from1992 through 2006, including 36,583 cases of papillary, 4560cases of follicular, 976 cases of medullary, 556 cases of ana-plastic, and 969 other or unspecified thyroid cancer. The overallincidence was 7.7 per 100,000 person-years, with a rate of 11.3per 100,000 woman-years and 4.1 per 100,000 man-years.

Thyroid cancer by gender, type, and SEERracial/ethnic group

The proportion of thyroid cancer types was generallysimilar across sex and SEER racial/ethnic groups. Papillarycarcinoma rates among women were 2.9–3.8 times thoseamong men, and the IRRs for follicular carcinomas were

126 ASCHEBROOK-KILFOY ET AL.

somewhat lower (IRR ¼ 1.9–3.6); all the female-to-male IRRsfor both papillary and follicular carcinomas were significantlyelevated for each racial/ethnic group (Table 1). Although allthe IRRs for the medullary type were>1.0, it was significantlyelevated only among whites (IRR¼ 1.3). In contrast, for theanaplastic type, the IRR was 1.0 among whites, but it was asignificant 2.9 among Hispanics.

Papillary carcinoma rates among both men and womenwere higher among whites than among Hispanics andAmerican Indians/Alaskan Natives, and lowest amongblacks; compared with whites, rates among Asians were sig-nificantly higher among women while lower among men. Thefollicular carcinoma rate among each female non-white groupwas about 90% that of whites; among men, racial differenceswere more pronounced, with rates significantly lower amongHispanics and Asians than among whites. Medullary carci-noma rates were virtually the same for whites and Hispanicsof each gender, but they were significantly lower than amongwhites for each gender among both blacks and Asians. Incontrast, the anaplastic carcinoma rate among each non-white

female SEER racial/ethnic group was elevated compared towhites and significantly so among Hispanics; among men, theracial/ethnic differences were unremarkable.

Age-specific thyroid cancer incidence by typeand racial/ethnic group

The age-specific incidence curves for men and women bytype and racial/ethnic group are presented in Figure 1. Forpapillary carcinoma, the similarity in the incidence patternsamong the SEER racial/ethnic groups within each gender isnotable. The age-specific rates for whites, Asians, and His-panics are quite similar, whereas the rates for black men andwomen are somewhat lower at all ages than for the othergroups. For all SEER racial/ethnic groups, a clear differencebetween men and women is apparent for papillary carcinoma,with rates rising rapidly among women during reproductiveyears and then later in life falling to similar levels as men; ratesamong men rose less rapidly than among women untilthe older ages when they turned down among whites and

Table 1. Thyroid Cancer Incidence in the Surveillance, Epidemiology, and End Results 13-Registry

Database (1992–2006) by Gender, Type, and Racial/Ethnic Group

Women MenFemale/

male 95% CIRace/WNH

women IRR IRRRace/WNH

men IRR IRR

(n¼ 43,644) n Rate SE n Rate SE IRR LL UL IRR LL UL IRR LL UL

TotalWhites 21,681 12.06 0.08 7908 4.59 0.05 2.63 2.56 2.70 1.00 1.00Hispanics 4570 11.39 0.18 1075 3.26 0.11 3.50 3.25 3.78 0.94 0.91 0.98 0.71 0.66 0.76Asians 4122 12.54 0.20 1064 3.93 0.12 3.19 2.98 3.43 1.04 1.01 1.08 0.86 0.80 0.91Blacks 1951 6.44 0.15 537 2.37 0.11 2.72 2.46 3.01 0.53 0.51 0.56 0.52 0.47 0.57AI/ANs 232 9.69 0.66 58 3.51 0.51 2.76 2.01 3.86 0.80 0.70 0.92 0.77 0.56 1.01

PapillaryWhites 18,523 10.39 0.08 6218 3.58 0.05 2.90 2.82 2.98 1.00 1.00Hispanics 3995 9.72 0.16 879 2.57 0.10 3.78 3.48 4.11 0.94 0.90 0.97 0.72 0.66 0.78Asians 3619 10.96 0.18 882 3.20 0.11 3.43 3.18 3.70 1.05 1.02 1.09 0.89 0.83 0.96Blacks 1504 4.90 0.13 366 1.56 0.09 3.14 2.78 3.55 0.47 0.45 0.50 0.44 0.39 0.49AI/ANs 197 8.12 0.60 46 2.68 0.44 3.03 2.14 4.43 0.78 0.67 0.91 0.75 0.53 1.02

FollicularWhites 2137 1.16 0.03 992 0.58 0.02 1.99 1.85 2.15 1.00 1.00Hispanics 382 1.04 0.06 94 0.29 0.03 3.55 2.75 4.64 0.90 0.80 1.01 0.50 0.39 0.64Asians 345 1.07 0.06 110 0.42 0.04 2.53 2.03 3.19 0.92 0.82 1.03 0.72 0.59 0.89Blacks 309 1.03 0.06 110 0.53 0.06 1.92 1.53 2.45 0.89 0.78 1.00 0.92 0.74 1.13AI/Ans 22 1.02 0.23 9 — — — — — 0.88 0.53 1.37 — — —

MedullaryWhites 400 0.22 0.01 290 0.17 0.01 1.28 1.10 1.50 1.00 1.00Hispanics 75 0.21 0.03 56 0.18 0.03 1.19 0.80 1.80 0.98 0.75 1.27 1.06 0.74 1.47Asians 46 0.14 0.02 27 0.10 0.02 1.47 0.89 2.47 0.65 0.47 0.89 0.57 0.37 0.85Blacks 34 0.11 0.02 27 0.10 0.02 1.09 0.63 1.90 0.51 0.35 0.73 0.60 0.38 0.91AI/Ans 4 — — 0 — — — — — — — — — — —

AnaplasticWhites 225 0.10 0.01 168 0.10 0.01 0.99 0.81 1.22 1.00 1.00Hispanics 41 0.17 0.03 10 0.06 0.02 2.92 1.45 6.77 1.62 1.12 2.27 0.55 0.25 1.03Asians 39 0.14 0.02 23 0.11 0.02 1.32 0.77 2.34 1.36 0.94 1.91 1.02 0.62 1.58Blacks 32 0.13 0.02 14 0.08 0.02 1.65 0.84 3.53 1.26 0.84 1.83 0.76 0.38 1.34AI/Ans 1 — — 2 — — — — — — — — — — —

Whites include non-Hispanic only, Hispanics include whites only, and AI/ANs include CHSDA counties only. There were 969 poorlyspecified/unknown type cancers that were not included in the analysis.

AI, American Indian; ANs, Alaska Natives; CI, confidence interval; n, number of cases; rate per 100,000 person-years, man-years, orwoman-years (age-adjusted to the 2000 U.S. standard population); SE, standard error; IRR, incidence rate ratios based on unrounded rates; —,not calculated and/or not applicable; CHSDA, contract health service delivery areas; LL, low 95% limit; WNH, White non-Hispanic; UL,upper 95% limit.

INCIDENCE OF THYROID CANCER TYPES BY RACE/ETHNICITY, GENDER, AND AGE 127

Hispanics, plateaued among blacks, and continued to increaseamong Asians. For follicular carcinoma, the rates for the SEERracial/ethnic groups are more similar among women thanmen, and the consistently rising rates until the oldest agegroup among both genders are striking. The patterns for themedullary type among women and men were notably similar;in contrast, rates for the anaplastic type among both gendersrose rapidly later in life.

Female-to-male age-specific IRRs by typeand racial/ethnic group

The age-specific female-to-male IRR patterns were quiteconsistent across the SEER racial/ethnic groups for the pap-illary and follicular types (Fig. 2). Female-to-male IRRs amongwhites decreased most steeply from more than six at ages20–29 years to 1.1 at ages 70–79 years for the follicular type,less steeply from 5.1 to 1.5 for the papillary type, and leaststeeply from 2.2 to 0.9 for the medullary type; it was <1 untilthe very oldest ages for the anaplastic type. IRRs were gen-erally higher among Hispanics and lower among whites forboth the papillary and follicular types.

Thyroid cancer incidence by type and racial/ethnic groupby SEER registry

Thyroid cancer incidence within type and racial/ethnicgroup varied barely twofold across registries (Table 2). Pa-pillary carcinoma rates varied among whites from 3.9 in ruralGeorgia to 9.2 in New Mexico, among Hispanics from 4.9 inDetroit to 9.0 in Connecticut, among blacks from 2.6 in SanFrancisco to 4.2 in Hawaii, among Asians from 5.3 in Con-

necticut to 9.5 in Iowa, and among American Indians/Alas-kan Natives from 5.0 in New Mexico to 7.8 in Utah. Follicularcarcinomas rates ranged among whites from 0.6 in SanFrancisco to 1.4 in rural Georgia, among Hispanics from 0.6 inSan Jose to 1.3 in Connecticut, among blacks from 0.5 in SanFrancisco to 1.6 in Iowa, and among Asians from 0.7 in LosAngeles to 1.0 in Atlanta. Medullary and anaplastic carci-noma rates among whites varied little geographically.

Thyroid cancer incidence by gender, type,and tumor stage

Among whites, the incidence by type, gender, and tumorstage is presented in Table 3. For the papillary, follicular, andmedullary types, the largest number of cases and the highestrates were for the localized stage compared to regional ordistant stage tumors. In addition, the female-to-male IRR forpapillary carcinomas decreased monotonically from 3.6 forlocalized stage to 2.2 for regional and 1.3 for distant stagedisease. For follicular carcinomas, the IRRs declined from 2.4to 1.6 and 1.3, and for medullary types from 1.8 to 1.1 and 0.8,respectively. In contrast, for the anaplastic type among bothmen and women, the rates for regional and distant stage wereeach higher than that for localized stage cancers; the female-to-male IRR was significantly elevated only for regional stagedisease. Among Hispanics, blacks, Asians, and American In-dians/Alaskan Natives, the female-to-male IRR for papillarythyroid cancer from localized to distant disease stagesdecreased monotonically as well (data not shown). Thefemale-to-male papillary IRRs among Hispanics decreasedfrom 5.0 for the localized stage to 3.3 for regional and 1.3 for

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FIG. 1. Age-specific thyroid cancer incidence by type and racial/ethnic group, Surveillance, Epidemiology, and End Results(SEER)-13. All panels based on 10-year age groups except for the medullary type for Hispanics and the medullary andanaplastic types for Asians and blacks where the age groups were 0–49, 50–69, and 70þ. All data points shown include 10cases or more.


distant stage disease, and among blacks declined from 3.6 to3.0 and 1.3. Similar monotonic decreases in female-to-maleIRRs by tumor stage were apparent for Asians and AmericanIndians/Alaskan Natives.

Thyroid cancer incidence by gender, type,and tumor size

A clear decline in cases and rates according to tumor sizewas apparent only for papillary carcinomas among whitewomen; among white men, similar numbers of cases werediagnosed at sizes <1.0, 1.0 to <2.0, and 2.0–4.0 cm (Table 4).In contrast, the highest follicular rates were for tumor sizes2.0–4.0 cm among white women and 4þ cm among whitemen; for medullary type, the 2.0–4.0 cm size was the mostfrequent. There were very few anaplastic cancers diagnosedsmaller than 2.0 cm, and most were at least 4.0 cm among bothwomen and men. The female-to-male IRRs for whites with thepapillary type decreased with tumor size from 3.7 to 1.3. TheIRRs also generally declined with tumor size for the follicularand medullary types, and it was significantly <1.0 for thelargest (4.0þ cm) size follicular carcinomas. In contrast, all theIRRs for anaplastic carcinomas were similar to 1.0. In general,among the non-white SEER racial/ethnic groups, larger fe-male-to-male IRRs were observed for every tumor size for the

papillary type when compared with whites (data not shown).For the follicular type among the non-white SEER racial/ethnic groups, the IRR was highest (4.5) for 1.0–2.0 cm tumorsand was significantly <1 (0.8) for the largest tumor size(4.0þ cm). For the medullary and anaplastic types among thenon-white SEER racial/ethnic groups, the IRR was also<1.0 cm for tumors 4.0þ cm.

Discussion

Papillary carcinoma was the most common type of thyroidcancer among both men and women and for all SEER racial/ethnic groups included in this study. Although papillarycarcinoma rates among both men and women were higheramong whites than Hispanics and American Indians/Alas-kan Natives, and lowest among blacks, the age-specific pat-terns were similar. Specifically, for the papillary type, all fourSEER racial/ethnic groups illustrated a similar pattern ofgender disparities, with the burden among women peakingaround 40 years of age. A similar pattern was seen for follic-ular and medullary types among women, whereas amongmen, rates were highest among whites but lowest amongHispanics. The incidence of all the histologic types of thyroidcancer varied by gender and by racial/ethnic group with two-to almost fourfold female-to-male IRRs for both papillary and

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FIG. 2. Female-to-male age-specific thyroid cancer incidence rate ratios (IRR) by type and racial/ethnic group, SEER-13.Data points shown for IRRs with female and male rates each based on 10 or more cases.



Database (1992–2006) by Type, Racial/Ethnic Group, and Registry for Women and Men Combined

Papillary Follicular Medullary Anaplastic

Registry n Rate SE n Rate SE n Rate SE n Rate SE

WhitesSan Francisco–Oakland SMSA 1867 5.37 0.13 214 0.61 0.04 61 0.17 0.02 32 0.09 0.02Connecticut 3295 7.70 0.14 378 0.85 0.04 101 0.23 0.02 69 0.14 0.02Detroit (Metropolitan) 3028 6.89 0.13 428 0.97 0.05 101 0.23 0.02 59 0.13 0.02Hawaii 279 5.96 0.36 49 1.05 0.15 9 — — 4 — —Iowa 2684 6.51 0.13 439 1.02 0.05 73 0.17 0.02 36 0.07 0.01New Mexico 1248 9.24 0.27 136 0.96 0.08 26 0.19 0.04 15 0.10 0.03Seattle (Puget Sound) 3464 6.81 0.12 449 0.89 0.04 87 0.17 0.02 46 0.09 0.01Utah 2132 8.51 0.19 214 0.89 0.06 41 0.17 0.03 22 0.10 0.02Atlanta (Metropolitan) 1687 6.91 0.17 232 1.00 0.07 43 0.19 0.03 17 0.09 0.02San Jose–Monterey 1156 6.22 0.18 141 0.76 0.06 32 0.17 0.03 18 0.09 0.02Los Angeles 3860 7.27 0.12 435 0.80 0.04 113 0.21 0.02 74 0.12 0.01Rural Georgia 41 3.92 0.63 14 1.41 0.39 3 — — 1 — —

HispanicsSan Francisco–Oakland SMSA 465 5.63 0.28 51 0.72 0.11 11 0.16 0.05 5 — —Connecticut 277 8.98 0.60 31 1.27 0.25 8 — — 2 — —Detroit (Metropolitan) 53 4.92 0.74 6 — — 1 — — 0 — —Hawaii 23 5.39 1.19 4 — — 0 — — 0 — —Iowa 36 5.20 1.05 1 — — 0 — — 0 — —New Mexico 720 7.79 0.30 66 0.75 0.10 12 0.13 0.04 13 0.17 0.05Seattle (Puget Sound) 132 6.70 0.72 15 0.94 0.26 4 — — 1 — —Utah 148 8.45 0.79 14 0.64 0.21 3 — — 0 — —Atlanta (Metropolitan) 102 5.22 0.66 23 1.12 0.27 4 — — 1 — —San Jose–Monterey 393 5.54 0.32 35 0.57 0.11 10 0.21 0.08 9 — —Los Angeles 2524 5.80 0.13 230 0.61 0.05 78 0.21 0.03 20 0.10 0.02

AsiansSan Francisco–Oakland SMSA 824 6.33 0.22 92 0.74 0.08 16 0.12 0.03 13 0.12 0.03Connecticut 72 5.31 0.66 5 — — 4 — — 1 — —Detroit (Metropolitan) 81 5.83 0.71 6 — — 2 — — 2 — —Hawaii 1128 8.71 0.26 121 0.93 0.09 19 0.14 0.03 13 0.09 0.03Iowa 39 9.53 1.81 6 — — 1 — — 1 — —New Mexico 25 8.53 1.83 1 — — 0 — — 0 — —Seattle (Puget Sound) 353 7.47 0.41 37 0.85 0.15 3 — — 2 — —Utah 43 6.11 0.97 3 — — 0 — — 1 — —Atlanta (Metropolitan) 98 6.02 0.72 12 0.95 0.31 2 — — 1 — —San Jose–Monterey 457 6.65 0.32 57 0.91 0.13 8 — — 12 0.26 0.08Los Angeles 1381 7.44 0.20 115 0.65 0.06 18 0.10 0.03 16 0.11 0.03

BlacksSan Francisco–Oakland SMSA 158 2.62 0.21 28 0.48 0.09 5 — — 7 — —Connecticut 156 3.65 0.30 29 0.72 0.14 2 — — 3 — —Detroit (Metropolitan) 516 3.88 0.17 122 0.94 0.09 14 0.10 0.03 13 0.12 0.03Hawaii 19 4.15 1.29 5 — — 1 — — 0 — —Iowa 26 3.50 0.72 10 1.59 0.53 0 — — 1 0.17 0.17New Mexico 14 2.74 0.76 6 — — 2 — — 0 — —Seattle (Puget Sound) 91 3.98 0.45 22 0.95 0.21 5 — — 0 — —Atlanta (Metropolitan) 403 3.14 0.17 89 0.76 0.09 17 0.14 0.04 5 — —San Jose–Monterey 27 2.72 0.57 5 — — 0 — — 3 — —Los Angeles 430 3.18 0.16 96 0.75 0.08 14 0.10 0.03 13 0.12 0.03Rural Georgia 26 3.72 0.73 7 — — 1 — — 0 — —

AIs/ANsNew Mexico 100 5.03 0.53 9 — — 1 — — 1 — —Seattle (Puget Sound) 53 7.33 1.19 7 — — 3 — — 0 — —Utah 14 7.75 2.18 2 — — 0 — — 1 — —ANs 71 5.43 0.67 10 0.89 0.32 0 — — 1 — —

Whites include non-Hispanic only, Hispanics include whites only, and AI/ANs include CHSDA counties only.—, not applicable; SMSA, standard metropolitan statistical area.



Database (1992–2006) by Gender, Type, and Tumor Stage Among Whites

Women Men Female/male 95% CI

Stage n Rate SE n Rate SE IRR LL UL

PapillaryLocalized 12,349 6.91 0.06 3316 1.90 0.03 3.63 3.50 3.78Regional 5381 3.04 0.04 2421 1.40 0.03 2.18 2.08 2.29Distant 493 0.27 0.01 363 0.22 0.01 1.26 1.09 1.44Unstaged 300 0.16 0.01 118 0.07 0.01 2.34 1.88 2.92

FollicularLocalized 1197 0.66 0.02 475 0.28 0.01 2.39 2.15 2.66Regional 751 0.41 0.02 422 0.25 0.01 1.64 1.45 1.85Distant 120 0.06 0.01 75 0.05 0.01 1.26 0.93 1.71Unstaged 69 0.04 0.00 20 0.01 0.00 2.95 1.76 5.17

MedullaryLocalized 220 0.12 0.01 115 0.07 0.01 1.77 1.41 2.24Regional 130 0.07 0.01 114 0.07 0.01 1.07 0.82 1.39Distant 43 0.02 0.00 52 0.03 0.00 0.75 0.49 1.16Unstaged 7 — — — — — — — —

AnaplasticLocalized 16 0.01 0.00 11 0.01 0.00 1.07 0.46 2.61Regional 95 0.04 0.00 49 0.03 0.00 1.44 1.01 2.09Distant 96 0.04 0.01 95 0.06 0.01 0.76 0.56 1.02Unstaged 18 0.01 0.00 13 0.01 0.00 0.97 0.44 2.19

Whites include non-Hispanics only.—, not calculated and/or not applicable.


Database (1992–2006) by Gender, Type, and Tumor Size Among Whites

Women Men Female/male 95% CI

Tumor size n Rate SE n Rate SE IRR LL UL

Papillary<1 cm 5551 3.09 0.04 1470 0.84 0.02 3.67 3.46 3.891 to <2.0 cm 5199 2.95 0.04 1426 0.82 0.02 3.60 3.40 3.832.0 to <4.0 cm 3849 2.18 0.04 1506 0.87 0.02 2.51 2.36 2.664.0þ cm 907 0.50 0.02 651 0.38 0.02 1.32 1.19 1.46Unknown 2931 1.63 0.03 1141 0.67 0.02 2.44 2.28 2.62

Follicular<1 cm 105 0.06 0.01 38 0.02 0.00 2.66 1.82 3.971 to <2.0 cm 457 0.26 0.01 99 0.06 0.01 4.48 3.59 5.632.0 to <4.0 cm 849 0.47 0.02 300 0.18 0.01 2.67 2.34 3.064.0þ cm 375 0.19 0.01 397 0.24 0.01 0.83 0.72 0.96Unknown 350 0.18 0.01 158 0.09 0.01 1.97 1.62 2.39

Medullary<1 cm 63 0.03 0.00 42 0.03 0.00 1.39 0.92 2.111 to <2.0 cm 104 0.06 0.01 46 0.03 0.00 2.18 1.52 3.152.0 to <4.0 cm 129 0.07 0.01 85 0.05 0.01 1.43 1.08 1.914.0þ cm 50 0.03 0.00 60 0.04 0.01 0.74 0.50 1.10Unknown 54 0.03 0.00 57 0.03 0.01 0.85 0.58 1.27

Anaplastic<1 cm 2 — — 1 — — — — —1 to <2.0 cm 9 — — 2 — — — — —2.0 to <4.0 cm 22 0.01 0.00 17 0.01 0.00 1.01 0.51 2.064.0þ cm 93 0.04 0.00 80 0.05 0.01 0.83 0.61 1.14Unknown 99 0.05 0.01 68 0.04 0.01 1.10 0.80 1.53

Whites include non-Hispanics only.—, not calculated and/or not applicable.


follicular types and generally smaller IRRs for medullary andanaplastic types. Although a gender disparity was observedacross all SEER racial/ethnic groups for the follicular type, theexcess during reproductive years was not as pronounced asobserved for the papillary type. A notable lack of genderdisparity was noted for the medullary and anaplastic typeswith the incidence among both women and men generallyincreasing with age. The female-to-male IRRs subsequentlydecreased with age for all SEER racial/ethnic groups for bothpapillary and follicular thyroid cancer, and a similar patternwas observed for medullary thyroid cancer among whites,but the female-to-male IRR increased with age among whitesfor the anaplastic type.

Our findings build upon previous reports of racial/ethnicpatterns in SEER (4,8). The results of our study are relevant asa principal concern in thyroid cancer research is whether therising incidence over the past decades reflects a true increasein disease incidence or an artificial inflation in disease ratesdue to improvements and increased access to technologiessuch as ultrasonography. If detection plays a substantial rolein diagnosis, we would expect to see racial differences indisease incidence and potentially different age-specific inci-dence patterns as those in lower socioeconomic groups wouldlikely be diagnosed later in life once they are eligible forMedicare. We might also expect to see similar patterns acrossSEER racial/ethnic groups during reproductive years amongwomen even if detection is an important factor, as women inlower socioeconomic groups would potentially qualify forreproductive health services (16,17). However, we observedsimilar racial/ethnic patterns across the lifespan. In addition,if the rising incidence was mostly due to diagnosis, we mightalso expect to see different patterns for SEER racial/ethnicgroups by registry. However, our evaluation of thyroid cancerincidence by tumor registries did not reveal clear patterns ofdifferential diagnosis.

When we looked at the IRRs within each type of thyroidcancer, comparing rates among SEER racial/ethnic groups towhites separately by gender, we found variation by histologictype. The similarity of follicular thyroid cancer rates amongwomen of the other SEER racial/ethnic groups compared towhite women was particularly notable. Thyroid cancer inci-dence may reflect a socioeconomic marker, as not all segmentsof the population may benefit equally from screening efforts,and these differences are often related to lack of access tohealthcare. Given that health insurance status is associatedwith race/ethnicity, as blacks, Hispanics, Asian/Pacific Is-landers, and American Indian/Alaska Natives are more likelyto be uninsured than non-Hispanic whites (18), similarities indisease rates for a cancer that is thought to be increasinglydiagnosed in asymptomatic persons are striking (including alltypes except anaplastic). Further support for this point is ob-served in the age-specific figure of female-to-male IRRs. Thesimilarity in disease patterns (including gender disparities)across SEER racial/ethnic groups is notable and unexpected.Previous research by the U.S. Centers for Disease Control andPrevention has shown that Hispanics are twice as likely asnon-Hispanic blacks and three times as likely as non-Hispanicwhites to lack a regular healthcare provider (18). In short,these patterns argue against the notion that access to careaccounts for the majority of incidence differences.

Further, if most or all of the rising incidence was due toimproved disease detection, a more rapid increase in small

early stage tumors than larger late stage would be expected.An increase across all histologic types would also be expectedwith the exception of the anaplastic type due to its symp-tomatic presentation and more aggressive progression.Recent reports (1,4) showed that the most rapid increases inthyroid cancer among both men and women were observedfor larger size tumors (4.0þ cm) as well as microcarcinomas(<1 cm), and substantial increases in recent decades wereobserved for regional and distant stage tumors in addition tolocalized tumors (1). Our findings for papillary thyroid canceramong whites in a more recent study period showed that thehighest rates for women were observed for the smallest sizetumors but not men. For the other tumor types, we generallyobserved the lowest rates for the smallest tumors. Our resultssupport the previous research showing the highest rates forlocalized papillary tumors, and we found that this is true forthe follicular and medullary thyroid cancers as well.

It is unlikely that differences in clinical methods of tumordetection bias the rates of the papillary type compared to thefollicular and medullary types. Patients presenting with thy-roid cancer are typically asymptomatic with the exception ofoccasional neck swelling (19). Those with papillary tumors arenot more likely to experience pain or discomfort than thosewith follicular or medullary thyroid cancer. In general, pa-tients present for workup of nodular goiter, based on symp-toms (such as neck mass, hoarseness, difficulty and or pain onswallowing) or most likely the tumor is incidentally found onroutine imaging (20). Upon discovery of thyroid nodules byphysical examination, a neck ultrasonography is typicallyobtained to assess characteristics of nodules. This is followedby fine-needle aspiration biopsies of suspicious nodules.There are no distinctive features by ultrasonography that canseparate papillary from follicular or medullary thyroid can-cer. Further, the ease of obtaining a biopsy is also similar forthe different types (21).

However, once the biopsied specimen is sent to pathologyfor disease diagnosis, opportunities for biases in disease diag-noses may occur between specific types, which may be ofconcern in the interpretation of incidence patterns. There isgreat variability (up to 40%) between pathologists in how theyread a fine-needle aspiration biopsy and subsequently deter-mine the thyroid cancer tumor type (21). There are differencesin the ease of tumor type identification by cell type; specifically,the detection of a papillary thyroid cancer is simple if papillaryformations are present. However, papillary tumors are a mix-ture of thyroid follicles and neoplastic papillae. In the papillaeof a thyroid tumor, cells are usually larger than normal, withlarge nuclei that appear crowded and overlapping and maycontain hypodense chromatin, cytoplasmic pseudoinclusions,and/or nuclear grooves that are typically obvious to a pa-thologist. In contrast, follicular tumors can be more difficult toidentify as follicular tumors are characterized with solidgrowth of small to medium-sized follicles, absence of colloid,and presence of vascular and/or capsular invasion, which canmake it difficult to distinguish a follicular benign lesion from afollicular carcinoma. As such, it is possible that more papil-lary tumors are classified as malignant compared to folliculartumors, which are more likely to be classified as benign.

The female-to-male IRRs varied substantially by thyroidcancer histology, posing questions related to disparities bygender in diagnosis or incidence. It is known that women aremore frequent users of healthcare services, particularly during


childbearing years (22). However, as noted above, if the inci-dence patterns were due to diagnostic inflation, one mightexpect that a consistent pattern of similar increases in risk forwomen would be observed across all types of thyroid cancerwith the possible exception the anaplastic type. When welooked at the age-specific incidence of the various types ofthyroid cancer, we noted an early age-at-onset predominancefor women for the papillary and follicular types, which isconsistent with previous reports for papillary thyroid cancer(1). It was previously reported and we show here that IRs roserapidly with increasing age among women, peaking at ages40–49 years and then declined at ages 80þ years. In contrast,age-specific rates among men rose more slowly, peaking atages 60–69 years and then declined at ages 80þ years (1). Such ahook pattern observed for women, particularly for the papil-lary type, is typically an indication of confounding by periodand/or cohort (23). This phenomenon is observed when thereis a progressive increase in cancer risk from one period and/orone generation to the next (23). This raises the question of whythere would be differential period or cohort effects by histologictype. On the basis of prior reports (1), there is clearly a periodand cohort effect affecting rates of papillary thyroid cancer;however, the different age-specific patterns by type indicatethat such effects are impacting the types differently, suggestingdifferent risk factors, different responses to exposure, or dif-ferent opportunities for diagnosis.

A major strength of this study was the ability to evaluatethyroid cancer patterns using SEER’s racially/ethnically di-verse sample. Extensive efforts have been made since theprogram’s inception to ensure that case ascertainment is ascomplete as possible and that data on all cancer patients are ofthe highest quality. However, our study was limited by theusual concerns related to analyses of registry data: nonreviewof histopathologic diagnoses, potential incomplete data col-lection, and inconsistencies in tumor classification over timedue to changing classification and staging systems. Despitethese limitations, our results are consistent with other popu-lation-based studies that have largely used SEER data.

In sum, through the examination of the SEER database andits racially/ethnically diverse national sample, we were ableto offer additional insights to what is currently known aboutthe distribution of thyroid cancer in the U.S. population. Wefurther suggest that there are etiologic clues and insights intothe possible role of increased detection conferred by ouranalysis. Specifically, the similar age-specific patterns andlack of geographical variation across the SEER racial/ethnicgroups indicate that a detection effect cannot completely ex-plain the observed increases in thyroid cancer incidence. Weconclude that the similar age-specific patterns and lack ofgeographical variation across the SEER racial/ethnic groupsindicate that a detection effect cannot completely explain theobserved increases in thyroid cancer incidence as variation inthe amount or quality of healthcare provided is a function ofSEER racial/ethnic groups, gender, and/or age. We suggestthat the variations in age-specific patterns by gender andacross histologic types are intriguing and recommend thatfuture etiologic investigation focus on exogenous or endoge-nous exposures that are experienced similarly by REGs, morestrongly among women, and distinctively by age.

Further investigation of the relationship between risk factorsknown to interfere with thyroid function that may be relevantin the development of thyroid cancer may be warranted.

Acknowledgment

This research was supported in part by the IntramuralResearch Program of the National Institutes of Health/Na-tional Cancer Institute.

Disclosure Statement

The authors declare that no competing financial interestsexist.

References

1. Kilfoy BA, Devesa SS, Ward MH, Zhang Y, Rosenberg PS,Holford TR, Anderson WF 2009 Gender is an age-specificeffect modifier for papillary cancers of the thyroid gland.Cancer Epidemiol Biomarkers Prev 18:1092–1100.

2. Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, SjodinA, Zhang Y, Bai Y, Zhu C, Guo GL, Rothman N, Zhang Y2009 International patterns and trends in thyroid cancer in-cidence, 1973–2002. Cancer Causes Control 20:525–531.

3. Davies L, Welch HG 2006 Increasing incidence of thyroidcancer in the United States, 1973–2002. JAMA 295:2164–2167.

4. Enewold L, Zhu K, Ron E, Marrogi AJ, Stojadinovic A, Peo-ples GE, Devesa SS 2009 Rising thyroid cancer incidence inthe United States by demographic and tumor characteristics,1980–2005. Cancer Epidemiol Biomarkers Prev 18:784–791.

5. Liu S, Semenciw R, Ugnat AM, Mao Y 2001 Increasingthyroid cancer incidence in Canada, 1970–1996: time trendsand age-period-cohort effects. Br J Cancer 85:1335–1339.

6. Reynolds RM, Weir J, Stockton DL, Brewster DH, Sandeep TC,Strachan MW 2005 Changing trends in incidence and mortal-ity of thyroid cancer in Scotland. Clin Endocrinol 62:156–162.

7. Albores-Saavedra J, Henson DE, Glazer E, Schwartz AM2007 Changing patterns in the incidence and survival ofthyroid cancer with follicular phenotype—papillary, follic-ular, and anaplastic: a morphological and epidemiologicalstudy. Endocr Pathol 18:1–7.

8. Yu G, Chun-Lun Li J, Branovan D, McCormick S, Schantz SP2010 Thyroid cancer incidence and survival in the NationalCancer Institute surveillance, epidemiology, and end resultsrace/ethnicity groups. Thyroid 20:465–473.

9. Howell E 2001 The impact of the Medicaid expansions forpregnant women: a synthesis of the evidence. Med Care ResRev 58:3–30.

10. Surveillance, Epidemiology, and End Results (SEER) Pro-gram. (November 2008 submission.) Public-Use Database(1973–2006), National Cancer Institute DCCPS, SurveillanceResearch Program, Cancer Statistics Branch, Released April2009, based on the November 2008 submission.

11. World Health Organization 2000 International Classificationof Diseases for Oncology. Third edition. WHO, Geneva.

12. Surveillance Research Program. 2009 National Cancer In-stitute SEER*Stat software. Available at www.seer.cancer.gov/seerstat, version 6.4.4.

13. Fay MP. Approximate confidence intervals for rate ratiosfrom directly standardized rates with sparse data. CommunStat Theory Methods 28:2141–2160.

14. Fay MP, Tiwari RC, Feuer EJ, Zou Z 2006 Estimating aver-age annual percent change for disease rates without as-suming constant change. Biometrics 62:847–854.

15. Devesa SS, Donaldson J, Fears T 1995 Graphical presentationof trends in rates. Am J Epidemiol 141:300–304.

16. Egerter S, Braveman P, Marchi K 2002 Timing of insuranceand use of prenatal care among low-income women. Am JPublic Health 92:423–427.


17. Braveman P, Marchi K, Sarnoff R, Egerter S, Rittenhouse D2003 Promoting Access to Prenatal Care: Lessons from theCalifornia Experience. The Henry J. Kaiser Family Founda-tion, Washington, DC.

18. Pleis JR, Lethbridge-Cejku M 2007 Summary Health Statis-tics for U.S. Adults: National Health Interview Survey, 2006.National Center for Health Statistics Vital and Health Sta-tistics Series 10, Atlanta, GA.

19. American Thyroid Association (ATA) Guidelines Taskforceon Thyroid Nodules and Differentiated Thyroid Cancer;Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL,Mandel SJ, Mazzaferri EL, McIver B, Pacini F, SchlumbergerM, Sherman SI, Steward DL, Tuttle RM 2009 RevisedAmerican Thyroid Association management guidelines forpatients with thyroid nodules and differentiated thyroidcancer. Thyroid 19:1167–1214.

20. Wartofsky L 2000 The thyroid nodule: pathogenesis, evalu-ation and risk of malignancy. In: Wartosfsky L (ed) ThyroidCancer: A Comprehensive Guide to Clinical Management,Humana Press, Totowa NJ. pp 3–9.

21. Oertel Y 2000 The thyroid nodule: fine needle aspiration. In:Wartosfsky L (ed) Thyroid Cancer: A Comprehensive Guide toClinical Management, Humana Press, Totowa NJ. pp 35–39.

22. Owens GM 2008 Gender differences in health care expen-ditures, resource utilization, and quality of care. J ManagCare Pharm 14:2–6.

23. Tarone RE, Chu KC 1996 Evaluation of birth cohort patternsin population disease rates. Am J Epidemiol 143:85–91.

Address correspondence to:Briseis Aschebrook-Kilfoy, PhD, MPH

Occupational and Environmental Epidemiology BranchDivision of Cancer Epidemiology and Genetics

Department of Health and Human ServicesNational Cancer Institute, National Institutes of Health

EPS, Room 8, 6120 Executive Blvd.Bethesda, MD 20852-7244

E-mail: [email protected]


thyroid cancer incidence patterns in the united states by histologic type, 1992–2006

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