- Email: [email protected]
Trends in thyroid cancer demographics and surgical therapy in the United States
Trends in thyroid cancer demographics and surgical therapy in the United States Ian Mitchell, MD,a Edward H. Livingston, MD,a Alice Y. Chang, MD,b Shelby Holt, MD,a William H. Snyder, III, MD,a Ildiko Lingvay, MD, MPH,b and Fiemu E. Nwariaku, MD,a Dallas, Tex
Background. The incidence of thyroid cancer is increasing. Our objective was to characterize the demographic pattern of this increase and to examine trends in surgical therapy for thyroid cancer. Methods. Analysis of the SEER and NHDS databases was performed from 1974 to 2000 and from 1979 to 2004, respectively. Thyroid-related diagnoses were extracted, and thyroid cancer (ICD 193.X) were analyzed using the SAS statistical package. We compared the population-adjusted incidence of thyroid cancer and examined regional variations in the operative therapy for thyroid cancer. Results. The incidence of thyroid cancer has increased during the past 26 years. This increase occurred predominantly in women and in the Northeastern and Southern United States, whereas there has been a decrease in thyroid cancers in the Midwest. Papillary cancer accounts for most of this increase. Total thyroidectomy (TT) is now the most common operation for thyroid cancer. No differences in the use of TT were observed based on hospital size or insurance status. Conclusion. The increasing incidence of thyroid cancer in the United States is predominantly in women. These results suggest that women are a high-risk group for developing thyroid cancer although men have higher stage disease. (Surgery 2007;142:823-8.) From the Division of Gastrointestinal and Endocrine Surgery, Department of Surgery,a and the Division of Endocrinology and Metabolism, Department of Internal Medicine,b University of Texas Southwestern Medical Center, Dallas
Thyroid cancer occurs in an estimated 33,500 people in the United States and remains the most common cancer of endocrine organs, save ovarian cancer. The incidence has continued to increase over the past 3 decades and is also 1 of 4 cancer sites with an increasing death rate, showing a 13.5% increase between 1990 and 2003.1 Although the increase in thyroid cancer rates is well described, few studies have examined the nature of this increase and its effect on surgical therapy. Mangano2 documented an increase in thyroid cancer in Connecticut, and others have documented similar increases in other regions of the United States.3-5 Some regions, however, show no increase in the rate of thyroid cancer.6 This differ-
Accepted for publication September 6, 2007. Reprint requests: Fiemu Nwariaku, MD, FACS, Department of Surgery, UTSWMC, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9156. E-mail: [email protected]. 0039-6060/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.09.011
ence may be important to determine the appropriate allocation of resources in different regions. Few studies have examined the effect of this increase in thyroid cancer on operative therapy for the disease. If indeed a true increase occurs in the incidence of thyroid cancer, then thyroidectomy—as the primary therapy—should also increase during the same period. Our objective was to characterize the demographic trends in the incidence of thyroid cancer, including sex, racial, and regional differences. We also examined the use of partial or total thyroidectomy for the treatment of thyroid cancer. METHODS Data sources. Data on surgical therapy were obtained from the National Hospital Discharge Survey (NHDS). The NHDS databases for January 1979 to December 2004 were acquired from the Centers for Disease Control and Prevention website (http://www.cdc.gov/nchs/about/major/hdasd/ nhds.htm) and the Inter-University Consortium for Political and Social Research website (http:// www.icpsr.umich.edu/index-medium.html). The NHDS describes characteristics of inpatients disSURGERY 823
824 Nwariaku et al
charged from non-Federal short-stay hospitals in the United States and collects annually approximately 270,000 inpatient records acquired from a national sample of about 500 hospitals. Only hospitals with an average duration of stay of fewer than 30 days for all patients, general hospitals, or children’s general hospitals are included in the survey. Outpatient facilities, federal, correctional, military, and Department of Veterans Affairs hospitals, as well as hospitals with fewer than 6 beds staffed for patient use, are excluded. The NHDS uses a complex multistage design to ensure that the database is representative of the U.S. population. By using information from the U.S. census, the Centers for Disease Control and Prevention provide statistical weighting factors for each patient entry in the NHDS database that accounts for the survey’s design facilitating disease and procedure incidence estimates. These weighting factors were used to determine the national incidence of thyroid operations. Estimates of disease and procedure incidence are only valid when more than 60 cases are in the database. For disease or procedures that had fewer than 60 cases a year, the 5-year aggregate data were evaluated. All thyroid-related diagnoses were extracted using the ICD-9-CM codes, and thyroid cancer codes (ICD 193.X) were analyzed. We excluded benign thyroid diagnosis codes (226.x). We examined the rates of surgical therapy using codes for complete thyroidectomy (06.4) and partial thyroidectomy (06.3) among patients found to have thyroid cancer. We also examined differences in the use of partial or complete thyroidectomy among small (⬍99 beds) or large (⬎500) hospitals, and insurance type (HMO, Bluecross, Medicaid, Medicare, and Self-Pay). SEER. Data on incidence of thyroid cancer, histology, neoplasm size, extent, nodal involvement, mortality, and survival were obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Result program, version 9 (SEER 9). SEER 9 collects information from incident cancer registries in 5 states (Connecticut, Iowa, Hawaii, New Mexico, and Utah) as well as from 4 metropolitan areas (Detroit, Atlanta, San Francisco, and Seattle) and represents approximately 10% of the U.S. population. We compared thyroid cancer rates between black and white groups and both male and female gender by extracting using ICD-9-CM codes for thyroid cancer as above. Analyses. Incidences of new cases of thyroid cancer were adjusted to the appropriate U.S. population segment per year in the denominator and standardized per 100,000 people. Negative bino-
Surgery December 2007
Fig 1. Incidence of thyroid cancer over time (SEER).
Fig 2. Trends in thyroid cancer histology (SEER).
mial regression was performed with the populationadjusted thyroid cancer incidence rates from 1979 to 2004 from the NHDS database in the analysis of regional differences in thyroid cancer. Statistical analyses were performed using SAS software (version 9.1; SAS Institute, Inc., Cary, NC). RESULTS The overall incidence of thyroid cancer has increased by 2.4-fold since 1979 according to the SEER database (Fig 1). The increase in rates of thyroid cancer by cancer type is attributable to the rise in papillary thyroid cancer (Fig 2). When examined as a proportion of all thyroid cancer, papillary thyroid cancer (PTC) comprised an increasing percentage, whereas the incidence of follicular cancers decreased (data not shown). Sex and racial distribution trends. Because PTC accounted for most of the increased incidence of thyroid cancer, we examined the incidence of PTC in sex and racial subgroups in the SEER database. The increased incidence of PTC was observed more
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Fig 3. Differences in incidence rates according to (A) sex for PTC and (B) size distribution for thyroid cancer. Fig 4. Racial differences in thyroid cancer over time (SEER) in (A) incidence and (B) size distribution.
often in women (Fig 3, A). Although PTC reported in SEER increased 7.8-fold in women over the 2-year period, only a 6.6-fold increase occurred in men. In the SEER database, although both racial groups had an increase in rates of thyroid cancer, the increase in blacks was much less than in whites (Fig 4, A). Similar to our overall population findings, PTC accounted for most of the increase (data not shown). As a result, the number of patients with PTC as a percentage of all thyroid cancers was greater in whites compared with blacks. Disease stage. Secular changes in disease stage were assessed by examining sex and racial trends in neoplasm size, extent of invasion, and nodal involvement. Most neoplasms were small; 58% of neoplasms measured less than 2 cm in largest diameter, 29% were 2 cm to 4 cm, and 13% of
neoplasms were larger than 4 cm. Women had smaller neoplasms than men (Fig 3, B). Fifty-one percent of neoplasms less than 2 cm in size occurred in women compared with 36% in men. In contrast, men were more likely than women to have neoplasms greater than 4 cm. Women had a greater percentage of neoplasms confined to the thyroid and were less likely to have lymph node involvement (data not shown). White patients were more likely to have neoplasms smaller than 2 cm, whereas black patients had larger neoplasms (⬎4 cm) (Fig 4, B). No racial differences were found in the extent of neoplasm or nodal involvement (data not shown). Mortality and survival. The overall mortality from thyroid cancer was 4.6%. Mortality was
826 Nwariaku et al
Surgery December 2007
Fig 5. Mortality (percent) and median survival (months) expressed as a function of histologic subtype (SEER).
Fig 6. The ratio of partial to total thyroidectomy for cancer in the United States (NHDS).
greater in men compared with women, 7.1% versus 3.5% (all subtypes). No differences were found in mortality between blacks and whites. As expected, mortality was less and survival was greater for patients with small neoplasms confined to the thyroid gland (data not shown). The overall mortality rate was 0.5% for patients with a neoplasm less than 2 cm, 2% for those between 2 cm and 4 cm, and 15% for those greater than 4 cm. No differences were observed in mortality or survival between patients with or without lymph node involvement (data not shown). Papillary and follicular histologies were associated with greater survival and less mortality compared with medullary and undifferentiated cancers (Fig 5). Surgical therapy. The ratio of partial thyroidectomy for total thyroidectomy thyroid cancer decreased from 1979 to 2004 (Fig 6). Initially, twice as many partial thyroidectomies were performed compared with total thyroidectomy, but this trend reversed after 2004. After adjusting for the respective changes in the incidence of thyroid cancer, the male-to-female ratio for type of operation was nearly equal and remained constant over the years (data not shown). No differences in the use of TT were observed based on hospital size or insurance status. Regional differences. Evaluating by region in NHDS, the Northeast had a significant increase in thyroid cancer over time, with a smaller (although still significant) increase observed in the South (Fig 7, A). Incidence of thyroid cancer in the West remained stable, whereas it decreased in the Midwest. Regional trends in operative resection are described in Fig 7, B. Operations for thyroid cancer in the Northeast, Midwest, and West seemed to mirror their respective regional changes in inci-
dence as well as the national trend, which showed increased use of total thyroidectomy over partial thyroidectomy. Total thyroidectomy was also more common in the Southern United States, but overall the use of thyroidectomy for thyroid cancer remained stable over time. DISCUSSION In this study, we found that the increasing rates of thyroid cancer occur predominantly in women and in the Northeastern and Southern areas of the United States. Papillary thyroid cancer accounted for the bulk of this increase. Furthermore, a generalized increase occurred in the use of total thyroidectomy as the primary operative treatment for thyroid cancer. Thyroid cancer, although relatively uncommon (18th in incidence), is the most common endocrine cancer except for ovarian cancer. Prior reports confirm that the incidence of thyroid cancer increased over the past 3 decades.7 Davies and Welch also found a preponderance of thyroid cancer in women compared with men by a ratio of 2.7. This predilection for women is poorly understood and represents a major unanswered question in the epidemiology of thyroid cancer. Understanding the reason for the increased rates of thyroid cancer in women will be important as we attempt to identify high-risk groups for screening. Some investigators postulated that increased circulating estrogens may predispose to thyroid proliferation and neoplasia.8 Chan et al9 demonstrated an association between increased estrogen metabolites and proliferative thyroid disease. Lee et al10 showed that estradiol promotes proliferation in thyroid cancer cell when compared with cells treated with testosterone, and the growth-promoting effect of estradiol was attenuated by tamoxifen. Although these studies sug-
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Fig 7. Regional differences in thyroid cancer. Incidence (A) based on a binomial regression model (asterisks denote P ⬍ .5) and comparison (B) of regional differences in surgery per 100,000 (NHDS).
gest an association between female hormones and thyroid cell proliferation, elucidation of the mechanisms of development of thyroid cancer in women is still underway. Furthermore, no specific studies have implicated estrogens and thyroid neoplasia. Interestingly, although women had more cancers, their neoplasms were smaller compared with men. Similarly, the mortality was greater in men. Therefore the elucidation of mechanisms involved in the genesis of papillary thyroid cancers in women will be crucial if we are to provide better risk stratification for women. Men with large neoplasms represent a high-risk subgroup for poor outcomes after therapy and may require clinical studies to determine the benefits of adjuvant therapy. As with other studies, we found that papillary thyroid cancer accounted for the bulk of the increased rate of cancer, whereas some other subtypes decreased in incidence. Davies and Welch7 reported that most papillary thyroid cancers are smaller (⬍1 cm), thus suggesting that the increased rate is an artifact of additional screening, Although we are not aware of any dedicated screen-
Nwariaku et al 827
ing programs in thyroid cancer, it is possible that the greater use of health care services by women (especially younger women) with a concomitant increase in neck imaging, could lead to the increased identification of thyroid incidentalomas and subsequently to small thyroid cancers in women. Others11 hypothesize that the increased rates of thyroid cancer may be caused by the pathologic reclassification of papillary thyroid cancer in 1988.12 Nevertheless, we observed no changes in the rate of increase after 1988 compared with the pre-1988 period. Analysis of trends in the use of cytopathology for thyroid nodules may help elucidate the role of screening and fine-needle aspiration biopsy on the observed increased rates of thyroid cancer. Racial trends suggest that black patients had increased rates of thyroid cancer. Although black patients were more likely to harbor larger neoplasms, the mortality and survival in blacks was not different from white patients; however, a major weakness of the SEER database is the relatively poor representation of minority populations. The 9 cancer registries from which data are collected represent approximately 10% of the U.S. population. Therefore, this small sample may not reflect accurately the incidence of cancer in minority populations in the United States. There have been regional increases in the incidence of thyroid cancer reported previously in the United States11; however, these trends are not uniform as shown by the report by Burke et al6 who found no increase in the rates of thyroid cancer in a small, but well-controlled, Minnesota county since 1965. Interestingly the study by Hodgson et al11 was performed in Florida which is in the Southern United States, strengthening even more our observation of increased incidence of thyroid cancer in the Southern United States but lesser rates in the Midwest. Because the data showing regional variations in thyroid cancer rates and surgery are derived from the National Hospital Discharge Database, the lower rates of thyroidectomy for thyroid cancer in the Midwest and unchanged rates in the South may represent a greater rate of same-day operative resection for thyroid cancer. Regional variation is important because the genesis of thyroid cancer may be subject to environmental influences, not the least of which is ionizing radiation. A few examples include the stable incidence rates of thyroid cancer reported over a 6-decade period in Olmsted County, Minnesota, and a low prevalence in Guatemala.6,13 This observation may have implications for utilization of regional resources and screening programs. Although many factors influ-
828 Nwariaku et al
ence thyroid cancer rates and reporting, these regional variations should temper the urge to use national figures for prevalence when designing screening programs or identifying high-risk groups. Examination of upcoming SEER versions with greater regional and minority representation as well as other databases will help establish whether these regional trends are consistent. In addition to the well-described limitations of using large, population-based databases, our study is limited by the poor minority sample sizes in SEER. Our observations may be supported by the relatively low event rates among black patients compared with whites; however, the addition of NHDS data showing similarly increased rates of thyroid cancer suggests that overall rates of thyroid cancer are truly increasing. SEER is also limited by variable follow-up; therefore, some cumulative rates may not reflect the variable follow-up. Our study was not designed to identify the complication rates associated with thyroidectomy or the cost of increased total thyroidectomy. REFERENCES 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43-66. 2. Mangano JJ. A post-Chernobyl rise in thyroid cancer in Connecticut, USA. Eur J Cancer Prev 1996;5:75-81. 3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments]. Cancer 1998;83:2638-48.
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4. Hundahl SA. Perspective: National Cancer Institute summary report about estimated exposures and thyroid doses received from iodine 131 in fallout after Nevada atmospheric nuclear bomb tests. CA Cancer J Clin 1998;48:285-98. 5. Zheng T, Holford TR, Chen Y, Ma JZ, Flannery J, Liu W, et al. Time trend and age-period-cohort effect on incidence of thyroid cancer in Connecticut, 1935-1992. Int J Cancer 1996;67:504-9. 6. Burke JP, Hay ID, Dignan F, Goellner JR, Achenbach SJ, Oberg AL, et al. Long-term trends in thyroid carcinoma: a population-based study in Olmsted County, Minnesota, 1935-1999. Mayo Clin Proc 2005;80:753-8. 7. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006;295:2164-7. 8. Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A, et al. 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol 2006;70:1414-23. 9. Chan EK, Sepkovic DW, Yoo Bowne HJ, Yu GP, Schantz SP. A hormonal association between estrogen metabolism and proliferative thyroid disease. Otolaryngol Head Neck Surg 2006;134:893-900. 10. Lee ML, Chen GG, Vlantis AC, Tse GM, Leung BC, van Hasselt CA. Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL. Cancer J 2005;11:113-21. 11. Hodgson NC, Button J, Solorzano CC. Thyroid cancer: is the incidence still increasing? Ann Surg Oncol 2004;11:1093-7. 12. Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 1989;63:908-11. 13. Solares CA, Penalonzo MA, Xu M, Orellana E. Occult papillary thyroid carcinoma in postmortem species: prevalence at autopsy. Am J Otolaryngol 2005;26:87-90.
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DISCUSSION Dr Herbert Chen (Madison, Wisconsin): Great presentation. I just have two questions for you. One is, looking at your data from the discharge database, it includes only inpatient admissions. And I am wondering, some of us who do lobectomies would probably send those patients home the same day, so you might be overestimating the number of total thyroidectomies performed because those patients tend to stay overnight. Perhaps you can comment on that. Secondly, when you showed your incidence of thyroid cancer, the Midwest is very different from every place else, and I am wondering, maybe we are doing something right in preventing thyroid cancer in the Midwest or maybe there is another reason for it that you can shed some light on. Dr Ian C. Mitchell (Dallas, Texas): There is some discrepancy between the incidence rates between NHDS and SEER. NHDS is going to be missing some of the outpatient surgeries that occur, and that may underestimate the total number of operations in this database. As far as for regional differences, we intend to examine the newest versions of the SEER database to confirm that these differences exist. For example if you look at the SEER 9, the overall population representation for the Midwest is not very big. So we need to look at other longitudinal data to confirm that these differences do exist. If they do exist, are these environmental or practice pattern differences? Dr Rebecca S. Sippel (San Francisco, California): You have some gender differences and racial differences in the size of the tumor. I am wondering if you controlled for tumor size or stage of the tumor when you looked at the subsequent invasiveness and metastatic disease that was higher in both the racial and the gender differences. Also, I was wondering if you think that this is just the fact that we are detecting these tumors earlier and hence they are behaving a little differently clinically, or do you think these tumors are actually behaving differently in men versus women and in different races? Dr Ian C. Mitchell (Dallas, Texas): To answer your first question, we did not control for the size of the tumor or the invasiveness. But I do think that we are catching a lot of these tumors earlier and performing more operations for them. Then the next question for us to determine is; are we actually affecting mortality rates by doing so? Dr Electron Kebebew (San Francisco, California): My question is really similar to Dr Sippel’s in that
Nwariaku et al 828.e1
most of these cancers that are being reported are called papillary thyroid cancer and in fact may not be even diagnosed preoperatively. And I was interested in the data that you showed it was more common in women and then the disparity, if you actually eliminated all of the papillary thyroid cancers that were 1 centimeter or less and have actually seen any difference in their presentation. Dr Ian C. Mitchell (Dallas, Texas): At this point we have not. Dr Electron Kebebew (San Francisco, California): I think it is very important to do the analysis excluding the papillary thyroid cancer, because most of these are found by the pathologist in a patient that has had a thyroidectomy for hyperthyroidism or for a multinodular goiter. So I think you would need to do that before suggesting there is any difference or disparity in the presentation. Dr Jeffrey A. Van Lier Ribbink (Scottsdale, Arizona): Do you think the explanation for the increased frequency of these lesions seen in women and the lower apparent, and these lesions found earlier in women could be simply related to the fact that in the United States the primary individual of the American family to pursue medical care is the woman and she may be getting this earlier than men? And then relative to the black population, could very well simply be related to changes, the differences you see could be related to socioeconomic situations and clearly documented fact that the black population do not receive medical care and screening earlier, as compared to the white population. Dr Ian C. Mitchell (Dallas, Texas): I agree with both of your points, though interestingly we also examined the NHDS trends in surgery with respect to insurance status. No significant difference in surgery rates were found among the groups. Dr Robert Udelsman (New Haven, Connecticut): I would like to challenge you for a question I think you may not be able to answer. And I would also like to challenge the group here. I think all of us recognize that endocrine in general, thyroid and parathyroid, is perhaps three times more common in women than men. I want to know the explanation for that, please. Dr Ian C. Mitchell (Dallas, Texas): There have been some recent studies that have questioned whether increased estrogen levels in vitro may increase thyroid follicle proliferation, but I think it is very presumptive to say that that is the case. Beyond that, I don’t have an answer.
Background. The incidence of thyroid cancer is increasing. Our objective was to characterize the demographic pattern of this increase and to examine trends in surgical therapy for thyroid cancer. Methods. Analysis of the SEER and NHDS databases was performed from 1974 to 2000 and from 1979 to 2004, respectively. Thyroid-related diagnoses were extracted, and thyroid cancer (ICD 193.X) were analyzed using the SAS statistical package. We compared the population-adjusted incidence of thyroid cancer and examined regional variations in the operative therapy for thyroid cancer. Results. The incidence of thyroid cancer has increased during the past 26 years. This increase occurred predominantly in women and in the Northeastern and Southern United States, whereas there has been a decrease in thyroid cancers in the Midwest. Papillary cancer accounts for most of this increase. Total thyroidectomy (TT) is now the most common operation for thyroid cancer. No differences in the use of TT were observed based on hospital size or insurance status. Conclusion. The increasing incidence of thyroid cancer in the United States is predominantly in women. These results suggest that women are a high-risk group for developing thyroid cancer although men have higher stage disease. (Surgery 2007;142:823-8.) From the Division of Gastrointestinal and Endocrine Surgery, Department of Surgery,a and the Division of Endocrinology and Metabolism, Department of Internal Medicine,b University of Texas Southwestern Medical Center, Dallas
Thyroid cancer occurs in an estimated 33,500 people in the United States and remains the most common cancer of endocrine organs, save ovarian cancer. The incidence has continued to increase over the past 3 decades and is also 1 of 4 cancer sites with an increasing death rate, showing a 13.5% increase between 1990 and 2003.1 Although the increase in thyroid cancer rates is well described, few studies have examined the nature of this increase and its effect on surgical therapy. Mangano2 documented an increase in thyroid cancer in Connecticut, and others have documented similar increases in other regions of the United States.3-5 Some regions, however, show no increase in the rate of thyroid cancer.6 This differ-
Accepted for publication September 6, 2007. Reprint requests: Fiemu Nwariaku, MD, FACS, Department of Surgery, UTSWMC, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9156. E-mail: [email protected]. 0039-6060/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.09.011
ence may be important to determine the appropriate allocation of resources in different regions. Few studies have examined the effect of this increase in thyroid cancer on operative therapy for the disease. If indeed a true increase occurs in the incidence of thyroid cancer, then thyroidectomy—as the primary therapy—should also increase during the same period. Our objective was to characterize the demographic trends in the incidence of thyroid cancer, including sex, racial, and regional differences. We also examined the use of partial or total thyroidectomy for the treatment of thyroid cancer. METHODS Data sources. Data on surgical therapy were obtained from the National Hospital Discharge Survey (NHDS). The NHDS databases for January 1979 to December 2004 were acquired from the Centers for Disease Control and Prevention website (http://www.cdc.gov/nchs/about/major/hdasd/ nhds.htm) and the Inter-University Consortium for Political and Social Research website (http:// www.icpsr.umich.edu/index-medium.html). The NHDS describes characteristics of inpatients disSURGERY 823
824 Nwariaku et al
charged from non-Federal short-stay hospitals in the United States and collects annually approximately 270,000 inpatient records acquired from a national sample of about 500 hospitals. Only hospitals with an average duration of stay of fewer than 30 days for all patients, general hospitals, or children’s general hospitals are included in the survey. Outpatient facilities, federal, correctional, military, and Department of Veterans Affairs hospitals, as well as hospitals with fewer than 6 beds staffed for patient use, are excluded. The NHDS uses a complex multistage design to ensure that the database is representative of the U.S. population. By using information from the U.S. census, the Centers for Disease Control and Prevention provide statistical weighting factors for each patient entry in the NHDS database that accounts for the survey’s design facilitating disease and procedure incidence estimates. These weighting factors were used to determine the national incidence of thyroid operations. Estimates of disease and procedure incidence are only valid when more than 60 cases are in the database. For disease or procedures that had fewer than 60 cases a year, the 5-year aggregate data were evaluated. All thyroid-related diagnoses were extracted using the ICD-9-CM codes, and thyroid cancer codes (ICD 193.X) were analyzed. We excluded benign thyroid diagnosis codes (226.x). We examined the rates of surgical therapy using codes for complete thyroidectomy (06.4) and partial thyroidectomy (06.3) among patients found to have thyroid cancer. We also examined differences in the use of partial or complete thyroidectomy among small (⬍99 beds) or large (⬎500) hospitals, and insurance type (HMO, Bluecross, Medicaid, Medicare, and Self-Pay). SEER. Data on incidence of thyroid cancer, histology, neoplasm size, extent, nodal involvement, mortality, and survival were obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Result program, version 9 (SEER 9). SEER 9 collects information from incident cancer registries in 5 states (Connecticut, Iowa, Hawaii, New Mexico, and Utah) as well as from 4 metropolitan areas (Detroit, Atlanta, San Francisco, and Seattle) and represents approximately 10% of the U.S. population. We compared thyroid cancer rates between black and white groups and both male and female gender by extracting using ICD-9-CM codes for thyroid cancer as above. Analyses. Incidences of new cases of thyroid cancer were adjusted to the appropriate U.S. population segment per year in the denominator and standardized per 100,000 people. Negative bino-
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Fig 1. Incidence of thyroid cancer over time (SEER).
Fig 2. Trends in thyroid cancer histology (SEER).
mial regression was performed with the populationadjusted thyroid cancer incidence rates from 1979 to 2004 from the NHDS database in the analysis of regional differences in thyroid cancer. Statistical analyses were performed using SAS software (version 9.1; SAS Institute, Inc., Cary, NC). RESULTS The overall incidence of thyroid cancer has increased by 2.4-fold since 1979 according to the SEER database (Fig 1). The increase in rates of thyroid cancer by cancer type is attributable to the rise in papillary thyroid cancer (Fig 2). When examined as a proportion of all thyroid cancer, papillary thyroid cancer (PTC) comprised an increasing percentage, whereas the incidence of follicular cancers decreased (data not shown). Sex and racial distribution trends. Because PTC accounted for most of the increased incidence of thyroid cancer, we examined the incidence of PTC in sex and racial subgroups in the SEER database. The increased incidence of PTC was observed more
Surgery Volume 142, Number 6
Nwariaku et al 825
Fig 3. Differences in incidence rates according to (A) sex for PTC and (B) size distribution for thyroid cancer. Fig 4. Racial differences in thyroid cancer over time (SEER) in (A) incidence and (B) size distribution.
often in women (Fig 3, A). Although PTC reported in SEER increased 7.8-fold in women over the 2-year period, only a 6.6-fold increase occurred in men. In the SEER database, although both racial groups had an increase in rates of thyroid cancer, the increase in blacks was much less than in whites (Fig 4, A). Similar to our overall population findings, PTC accounted for most of the increase (data not shown). As a result, the number of patients with PTC as a percentage of all thyroid cancers was greater in whites compared with blacks. Disease stage. Secular changes in disease stage were assessed by examining sex and racial trends in neoplasm size, extent of invasion, and nodal involvement. Most neoplasms were small; 58% of neoplasms measured less than 2 cm in largest diameter, 29% were 2 cm to 4 cm, and 13% of
neoplasms were larger than 4 cm. Women had smaller neoplasms than men (Fig 3, B). Fifty-one percent of neoplasms less than 2 cm in size occurred in women compared with 36% in men. In contrast, men were more likely than women to have neoplasms greater than 4 cm. Women had a greater percentage of neoplasms confined to the thyroid and were less likely to have lymph node involvement (data not shown). White patients were more likely to have neoplasms smaller than 2 cm, whereas black patients had larger neoplasms (⬎4 cm) (Fig 4, B). No racial differences were found in the extent of neoplasm or nodal involvement (data not shown). Mortality and survival. The overall mortality from thyroid cancer was 4.6%. Mortality was
826 Nwariaku et al
Surgery December 2007
Fig 5. Mortality (percent) and median survival (months) expressed as a function of histologic subtype (SEER).
Fig 6. The ratio of partial to total thyroidectomy for cancer in the United States (NHDS).
greater in men compared with women, 7.1% versus 3.5% (all subtypes). No differences were found in mortality between blacks and whites. As expected, mortality was less and survival was greater for patients with small neoplasms confined to the thyroid gland (data not shown). The overall mortality rate was 0.5% for patients with a neoplasm less than 2 cm, 2% for those between 2 cm and 4 cm, and 15% for those greater than 4 cm. No differences were observed in mortality or survival between patients with or without lymph node involvement (data not shown). Papillary and follicular histologies were associated with greater survival and less mortality compared with medullary and undifferentiated cancers (Fig 5). Surgical therapy. The ratio of partial thyroidectomy for total thyroidectomy thyroid cancer decreased from 1979 to 2004 (Fig 6). Initially, twice as many partial thyroidectomies were performed compared with total thyroidectomy, but this trend reversed after 2004. After adjusting for the respective changes in the incidence of thyroid cancer, the male-to-female ratio for type of operation was nearly equal and remained constant over the years (data not shown). No differences in the use of TT were observed based on hospital size or insurance status. Regional differences. Evaluating by region in NHDS, the Northeast had a significant increase in thyroid cancer over time, with a smaller (although still significant) increase observed in the South (Fig 7, A). Incidence of thyroid cancer in the West remained stable, whereas it decreased in the Midwest. Regional trends in operative resection are described in Fig 7, B. Operations for thyroid cancer in the Northeast, Midwest, and West seemed to mirror their respective regional changes in inci-
dence as well as the national trend, which showed increased use of total thyroidectomy over partial thyroidectomy. Total thyroidectomy was also more common in the Southern United States, but overall the use of thyroidectomy for thyroid cancer remained stable over time. DISCUSSION In this study, we found that the increasing rates of thyroid cancer occur predominantly in women and in the Northeastern and Southern areas of the United States. Papillary thyroid cancer accounted for the bulk of this increase. Furthermore, a generalized increase occurred in the use of total thyroidectomy as the primary operative treatment for thyroid cancer. Thyroid cancer, although relatively uncommon (18th in incidence), is the most common endocrine cancer except for ovarian cancer. Prior reports confirm that the incidence of thyroid cancer increased over the past 3 decades.7 Davies and Welch also found a preponderance of thyroid cancer in women compared with men by a ratio of 2.7. This predilection for women is poorly understood and represents a major unanswered question in the epidemiology of thyroid cancer. Understanding the reason for the increased rates of thyroid cancer in women will be important as we attempt to identify high-risk groups for screening. Some investigators postulated that increased circulating estrogens may predispose to thyroid proliferation and neoplasia.8 Chan et al9 demonstrated an association between increased estrogen metabolites and proliferative thyroid disease. Lee et al10 showed that estradiol promotes proliferation in thyroid cancer cell when compared with cells treated with testosterone, and the growth-promoting effect of estradiol was attenuated by tamoxifen. Although these studies sug-
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Fig 7. Regional differences in thyroid cancer. Incidence (A) based on a binomial regression model (asterisks denote P ⬍ .5) and comparison (B) of regional differences in surgery per 100,000 (NHDS).
gest an association between female hormones and thyroid cell proliferation, elucidation of the mechanisms of development of thyroid cancer in women is still underway. Furthermore, no specific studies have implicated estrogens and thyroid neoplasia. Interestingly, although women had more cancers, their neoplasms were smaller compared with men. Similarly, the mortality was greater in men. Therefore the elucidation of mechanisms involved in the genesis of papillary thyroid cancers in women will be crucial if we are to provide better risk stratification for women. Men with large neoplasms represent a high-risk subgroup for poor outcomes after therapy and may require clinical studies to determine the benefits of adjuvant therapy. As with other studies, we found that papillary thyroid cancer accounted for the bulk of the increased rate of cancer, whereas some other subtypes decreased in incidence. Davies and Welch7 reported that most papillary thyroid cancers are smaller (⬍1 cm), thus suggesting that the increased rate is an artifact of additional screening, Although we are not aware of any dedicated screen-
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ing programs in thyroid cancer, it is possible that the greater use of health care services by women (especially younger women) with a concomitant increase in neck imaging, could lead to the increased identification of thyroid incidentalomas and subsequently to small thyroid cancers in women. Others11 hypothesize that the increased rates of thyroid cancer may be caused by the pathologic reclassification of papillary thyroid cancer in 1988.12 Nevertheless, we observed no changes in the rate of increase after 1988 compared with the pre-1988 period. Analysis of trends in the use of cytopathology for thyroid nodules may help elucidate the role of screening and fine-needle aspiration biopsy on the observed increased rates of thyroid cancer. Racial trends suggest that black patients had increased rates of thyroid cancer. Although black patients were more likely to harbor larger neoplasms, the mortality and survival in blacks was not different from white patients; however, a major weakness of the SEER database is the relatively poor representation of minority populations. The 9 cancer registries from which data are collected represent approximately 10% of the U.S. population. Therefore, this small sample may not reflect accurately the incidence of cancer in minority populations in the United States. There have been regional increases in the incidence of thyroid cancer reported previously in the United States11; however, these trends are not uniform as shown by the report by Burke et al6 who found no increase in the rates of thyroid cancer in a small, but well-controlled, Minnesota county since 1965. Interestingly the study by Hodgson et al11 was performed in Florida which is in the Southern United States, strengthening even more our observation of increased incidence of thyroid cancer in the Southern United States but lesser rates in the Midwest. Because the data showing regional variations in thyroid cancer rates and surgery are derived from the National Hospital Discharge Database, the lower rates of thyroidectomy for thyroid cancer in the Midwest and unchanged rates in the South may represent a greater rate of same-day operative resection for thyroid cancer. Regional variation is important because the genesis of thyroid cancer may be subject to environmental influences, not the least of which is ionizing radiation. A few examples include the stable incidence rates of thyroid cancer reported over a 6-decade period in Olmsted County, Minnesota, and a low prevalence in Guatemala.6,13 This observation may have implications for utilization of regional resources and screening programs. Although many factors influ-
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ence thyroid cancer rates and reporting, these regional variations should temper the urge to use national figures for prevalence when designing screening programs or identifying high-risk groups. Examination of upcoming SEER versions with greater regional and minority representation as well as other databases will help establish whether these regional trends are consistent. In addition to the well-described limitations of using large, population-based databases, our study is limited by the poor minority sample sizes in SEER. Our observations may be supported by the relatively low event rates among black patients compared with whites; however, the addition of NHDS data showing similarly increased rates of thyroid cancer suggests that overall rates of thyroid cancer are truly increasing. SEER is also limited by variable follow-up; therefore, some cumulative rates may not reflect the variable follow-up. Our study was not designed to identify the complication rates associated with thyroidectomy or the cost of increased total thyroidectomy. REFERENCES 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43-66. 2. Mangano JJ. A post-Chernobyl rise in thyroid cancer in Connecticut, USA. Eur J Cancer Prev 1996;5:75-81. 3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments]. Cancer 1998;83:2638-48.
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4. Hundahl SA. Perspective: National Cancer Institute summary report about estimated exposures and thyroid doses received from iodine 131 in fallout after Nevada atmospheric nuclear bomb tests. CA Cancer J Clin 1998;48:285-98. 5. Zheng T, Holford TR, Chen Y, Ma JZ, Flannery J, Liu W, et al. Time trend and age-period-cohort effect on incidence of thyroid cancer in Connecticut, 1935-1992. Int J Cancer 1996;67:504-9. 6. Burke JP, Hay ID, Dignan F, Goellner JR, Achenbach SJ, Oberg AL, et al. Long-term trends in thyroid carcinoma: a population-based study in Olmsted County, Minnesota, 1935-1999. Mayo Clin Proc 2005;80:753-8. 7. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006;295:2164-7. 8. Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A, et al. 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol 2006;70:1414-23. 9. Chan EK, Sepkovic DW, Yoo Bowne HJ, Yu GP, Schantz SP. A hormonal association between estrogen metabolism and proliferative thyroid disease. Otolaryngol Head Neck Surg 2006;134:893-900. 10. Lee ML, Chen GG, Vlantis AC, Tse GM, Leung BC, van Hasselt CA. Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL. Cancer J 2005;11:113-21. 11. Hodgson NC, Button J, Solorzano CC. Thyroid cancer: is the incidence still increasing? Ann Surg Oncol 2004;11:1093-7. 12. Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 1989;63:908-11. 13. Solares CA, Penalonzo MA, Xu M, Orellana E. Occult papillary thyroid carcinoma in postmortem species: prevalence at autopsy. Am J Otolaryngol 2005;26:87-90.
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DISCUSSION Dr Herbert Chen (Madison, Wisconsin): Great presentation. I just have two questions for you. One is, looking at your data from the discharge database, it includes only inpatient admissions. And I am wondering, some of us who do lobectomies would probably send those patients home the same day, so you might be overestimating the number of total thyroidectomies performed because those patients tend to stay overnight. Perhaps you can comment on that. Secondly, when you showed your incidence of thyroid cancer, the Midwest is very different from every place else, and I am wondering, maybe we are doing something right in preventing thyroid cancer in the Midwest or maybe there is another reason for it that you can shed some light on. Dr Ian C. Mitchell (Dallas, Texas): There is some discrepancy between the incidence rates between NHDS and SEER. NHDS is going to be missing some of the outpatient surgeries that occur, and that may underestimate the total number of operations in this database. As far as for regional differences, we intend to examine the newest versions of the SEER database to confirm that these differences exist. For example if you look at the SEER 9, the overall population representation for the Midwest is not very big. So we need to look at other longitudinal data to confirm that these differences do exist. If they do exist, are these environmental or practice pattern differences? Dr Rebecca S. Sippel (San Francisco, California): You have some gender differences and racial differences in the size of the tumor. I am wondering if you controlled for tumor size or stage of the tumor when you looked at the subsequent invasiveness and metastatic disease that was higher in both the racial and the gender differences. Also, I was wondering if you think that this is just the fact that we are detecting these tumors earlier and hence they are behaving a little differently clinically, or do you think these tumors are actually behaving differently in men versus women and in different races? Dr Ian C. Mitchell (Dallas, Texas): To answer your first question, we did not control for the size of the tumor or the invasiveness. But I do think that we are catching a lot of these tumors earlier and performing more operations for them. Then the next question for us to determine is; are we actually affecting mortality rates by doing so? Dr Electron Kebebew (San Francisco, California): My question is really similar to Dr Sippel’s in that
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most of these cancers that are being reported are called papillary thyroid cancer and in fact may not be even diagnosed preoperatively. And I was interested in the data that you showed it was more common in women and then the disparity, if you actually eliminated all of the papillary thyroid cancers that were 1 centimeter or less and have actually seen any difference in their presentation. Dr Ian C. Mitchell (Dallas, Texas): At this point we have not. Dr Electron Kebebew (San Francisco, California): I think it is very important to do the analysis excluding the papillary thyroid cancer, because most of these are found by the pathologist in a patient that has had a thyroidectomy for hyperthyroidism or for a multinodular goiter. So I think you would need to do that before suggesting there is any difference or disparity in the presentation. Dr Jeffrey A. Van Lier Ribbink (Scottsdale, Arizona): Do you think the explanation for the increased frequency of these lesions seen in women and the lower apparent, and these lesions found earlier in women could be simply related to the fact that in the United States the primary individual of the American family to pursue medical care is the woman and she may be getting this earlier than men? And then relative to the black population, could very well simply be related to changes, the differences you see could be related to socioeconomic situations and clearly documented fact that the black population do not receive medical care and screening earlier, as compared to the white population. Dr Ian C. Mitchell (Dallas, Texas): I agree with both of your points, though interestingly we also examined the NHDS trends in surgery with respect to insurance status. No significant difference in surgery rates were found among the groups. Dr Robert Udelsman (New Haven, Connecticut): I would like to challenge you for a question I think you may not be able to answer. And I would also like to challenge the group here. I think all of us recognize that endocrine in general, thyroid and parathyroid, is perhaps three times more common in women than men. I want to know the explanation for that, please. Dr Ian C. Mitchell (Dallas, Texas): There have been some recent studies that have questioned whether increased estrogen levels in vitro may increase thyroid follicle proliferation, but I think it is very presumptive to say that that is the case. Beyond that, I don’t have an answer.