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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2009
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1819-1825
Copyright © 2006 by The Endocrine Society

Second Primary Cancers in Thyroid Cancer Patients: A Multinational Record Linkage Study

Thekkepat C. Sandeep, Mark W. J. Strachan, Rebecca M. Reynolds, David H. Brewster, Ghislaine Scélo, Eero Pukkala, Kari Hemminki, Aage Anderson, Elizabeth Tracey, Søren Friis, Mary L. McBride, Chia Kee-Seng, Vera Pompe-Kirn, Erich V. Kliewer, Jon M. Tonita, Jon G. Jonasson, Carmen Martos, Paolo Boffetta and Paul Brennan

Metabolic Unit (T.C.S., M.W.J.S., R.M.R.), Western General Hospital, Edinburgh EH4 2XU, United Kingdom; Scottish Cancer Registry (D.H.B.), Edinburgh EH12 9EB, United Kingdom; International Agency for Research on Cancer (G.S., P.Bo., P.Br.), 69372 Lyon, France; Finnish Cancer Registry (E.P.), Institute for Statistical and Epidemiological Cancer Research, FIN-00170 Helsinki, Finland; Division of Molecular Genetic Epidemiology (K.H.), German Cancer Research Center, 69120 Heidelberg, Germany; Department of Biosciences at Novum (K.H.), Karolinska Institute, SE-171 77 Hudinge, Sweden; Institute of Population-Based Cancer Research (A.A.), 0310 Oslo, Norway; Central Cancer Registry (E.T.), Woolloomooloo, New South Wales 2011, Australia; Institute of Cancer Epidemiology (S.F.), Danish Cancer Society, DK-2100 Copenhagen, Denmark; Cancer Control Research Programme (M.L.M.), British Columbia Cancer Agency, Vancouver, British Columbia, Canada V5Z 4E6; Center for Molecular Epidemiology (C.K.-S.), Singapore 6874 4971; Cancer Registry of Slovenia (V.P.-K.), Institute of Oncology, Ljubljana, Slovenia SI-1000; Epidemiology and Cancer Registry (E.V.K.), CancerCare Manitoba, Winnipeg, Canada R3E 0V9; Community Health Sciences (E.V.K.), University of Manitoba, Winnipeg, Canada R3T 2N2; School of Public Health (E.V.K.), University of Sydney, Sydney 2006, Australia; Program Evaluation and Surveillance (J.M.T.), Saskatchewan Cancer Agency, Regina, Saskatchewan, Canada S7N 4H4; Icelandic Cancer Registry (J.G.J.), Icelandic Cancer Society, IS-125 Reykjavik, Iceland; The Medical Faculty (J.G.J.), University of Iceland, 101 Reykjavik, Iceland; and Cancer Registry of Zaragoza (C.M.), Health Department of Aragon Government, 50004 Zaragoza, Spain

Address all correspondence and requests for reprints to: Dr. Mark W. J. Strachan, Metabolic Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. E-mail: mark.strachan{at}luht.scot.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Increasing incidence and improved prognosis of thyroid cancer have led to concern about the development of second primary cancers, especially after radioiodine treatment. Thyroid cancer can also arise as a second primary neoplasm after other cancers.

Objective: The objective of the study was to assess the risk of second primary cancer after thyroid cancer and vice versa.

Design: This was a multinational record linkage study.

Setting: The study was conducted at 13 population-based cancer registries in Europe, Canada, Australia, and Singapore.

Patients or Other Participants: A cohort of 39,002 people (356,035 person-yr of follow-up) with primary thyroid cancer were followed up for SPN for up to 25 yr, and 1,990 cases of thyroid cancer were diagnosed after another primary cancer.

Main Outcome Measures: To assess any possible excess of second primary neoplasms after thyroid cancer, the observed numbers of neoplasms were compared with expected numbers derived from age-, sex-, and calendar period-specific cancer incidence rates from each of the cancer registries, yielding standardized incidence ratios (SIRs). The SIR of second primary thyroid cancer after various types of cancer was also calculated.

Results: During the observation period, there were 2821 second primary cancers (all sites combined) after initial diagnosis of thyroid cancer, SIR of 1.31 (95% confidence interval 1.26–1.36) with significantly elevated risks for many specific cancers. Significantly elevated risks of second primary thyroid cancer were also seen after many types of cancer.

Conclusion: Pooled data from 13 cancer registries show a 30% increased risk of second primary cancer after thyroid cancer and increased risks of thyroid cancer after various primary cancers. Although bias (detection, surveillance, misclassification) and chance may contribute to some of these observations, it seems likely that shared risk factors and treatment effects are implicated in many. When following up patients who have been treated for primary thyroid cancer, clinicians should maintain a high index of suspicion for second primary cancers.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID CANCER ACCOUNTS for 1% of all cancers. The incidence is increasing in most populations (1, 2, 3, 4, 5). This increase may be due to evolution in clinical practice (5, 6) and/or changes in histological criteria (5) but may also be due to changing environmental and hormonal factors (7). Although thyroid cancer is more common overall in females, the risk of familial thyroid cancer seems to be higher in males (8).

Depending on histology and extent of disease, thyroid cancer can be treated by a range of modalities, including surgery, radioiodine, external beam radiotherapy, and suppressive thyroid hormone therapy (9). In most cases, the disease, when treated, has a very good prognosis, and survival rates have increased steadily (5, 10). With more and more cancers diagnosed early, survivors of this cancer live longer and hence are at risk of second primary cancers. There have been several studies looking at the risk of second primary cancers after thyroid cancer, including multicenter studies from Europe (11) and the United States (12), but most of them report experiences from one center or data from one cancer registry (13, 14, 15, 16, 17, 18, 19, 20, 21, 22). These studies have shown an increase in incidence of second cancers after thyroid cancer. Thyroid cancer can also arise as a second primary neoplasm after other cancers (12, 13, 14, 15, 19).

The present investigation is a multicenter study including data from 13 population-based cancer registries in Europe, Canada, Australia, and Singapore. The large data set provided a unique opportunity to assess risks with some precision. Examining the differing patterns of second cancers after thyroid cancer and thyroid as a second primary cancer may help to shed light on common etiological factors and illustrate the contribution of treatment for a primary tumor on the incidence of subsequent primary cancers.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
To conduct a systematic analysis of second primary cancers, an international multicenter study was initiated incorporating large cancer registries that have been in operation for at least 25 yr. Nineteen cancer registries that consistently reported cancer incidence figures in Cancer Incidence in Five Continents (23) were invited to participate. Publication in consecutive editions of this monograph was taken as a proxy measure of data quality of the cancer registry, including high levels of microscopic verification and low levels of cancers identified only through death certificates. A low proportion of registrations from death certificates suggests a high degree of completeness of ascertainment. Of an initial group of 19 contacted registries, 15 confirmed that the project was feasible and provided all necessary data. Two registries were subsequently excluded because of discrepancies in the observed rates of second primaries, leaving 13 registries in the current analysis. These registries were New South Wales (Australia); British Columbia, Manitoba, and Saskatchewan (Canada); Denmark; Finland; Iceland; Norway; Singapore; Slovenia; Zaragoza (Spain); Sweden; and Scotland (United Kingdom).

Data were provided from each cancer registry on all initial primary cancers, including age and sex of the subject, and date and diagnosis of the first primary [International Classification of Diseases, ninth revision (ICD-9)], follow-up for mortality and date and diagnosis of the second primary (ICD-9), if any. Information was also obtained from each cancer registry on the set of rules used for defining a second primary cancer. Because these differed between cancer registries and also over time, the International Association of Cancer Registries/International Agency for Research on Cancer rules on second primary cancers were adopted as a common set of rules (24). This was possible because all participating cancer registries currently use the International Association of Cancer Registries/International Agency for Research on Cancer rules or a local set of more extensive or detailed rules. Note that there is some overlap between the data set assembled for this study and data used for some previously published, single-registry studies (14, 15, 16, 18, 21).

To assess any possible excess of second primary neoplasms after thyroid cancer, the observed numbers of neoplasms were compared with the expected numbers derived from the age-, sex-, and calendar period-specific cancer incidence rates in each of the cancer registries. Standardized incidence ratios (SIRs) were calculated overall and after stratifying for age at diagnosis of first cancer, sex, follow-up period, and calendar period of diagnosis. In addition, specific histological subtypes of most interest (papillary, medullary, and follicular) were analyzed separately. Exact 95% confidence intervals (CIs) around the SIR were calculated assuming a Poisson distribution for the observed number of neoplasms. The same methodology was adopted for thyroid cancer as a second primary after other cancers as the first primary. However, SIRs of second primary thyroid cancer were not stratified by histological subtype because the process of achieving a comparable classification of thyroid cancer morphology across all registries and time periods was laborious, the background reference rates supplied by registries were not morphology specific, and the number of second primary cancers was generally lower in this analysis than in the analysis of second primaries arising after a primary thyroid cancer.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A total of 39,002 people with primary thyroid cancer were followed up for a second primary cancer, representing 356,035 person-yr of follow-up. At the time of thyroid cancer diagnosis, 29,030 (74.4%) were female, 22,188 (56.9%) were younger than 56 yr of age, and 15,523 (39.8%) had a histological diagnosis of papillary carcinoma (Table 1Go). The majority of cases were from Europe (73%), whereas a smaller number were from Canada (12%), Australia (11%), and Singapore (4%). After other primary cancers, 1990 thyroid cancers were diagnosed. Compared with the cohort of persons with a first primary thyroid cancer, the thyroid cancers after other primary cancers had a similar distribution by sex, histology, and registry but were older (Table 1Go).


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  		TABLE 1. Distribution of thyroid cancer patients as first and second cancer by sex, age at diagnosis, calendar period of diagnosis, follow-up period, morphological group, and registry

 
Second primary cancer after first thyroid cancer

During the observation period, there were 2821 second primary cancers (all cancers combined). The risk of second primary cancer after a first primary thyroid cancer was 1.31 (95% CI 1.26–1.36). The SIRs of second primary cancers by duration of follow-up are shown in Table 2Go for cancers with at least 10 cases included, in either this analysis or the analysis of second primary thyroid cancer after selected types of first primary cancer. For the total period of follow-up, significantly elevated risks were seen for many specific cancers, including salivary gland (SIR 3.15), pharynx (1.72), stomach (1.22), small intestine (2.11), colon (1.30), rectum (1.23), bone (3.62), soft tissue sarcoma (3.63), nonmelanoma skin (1.42), female breast (1.31), prostate (1.52), kidney (2.33), brain (1.39), adrenal gland (8.34), non-Hodgkin’s lymphoma (1.68), and leukemia (2.26). The overall risk of parathyroid gland cancer was also increased after primary thyroid cancer (SIR 15.8, 95% CI 1.91–56.9), but this result was based on only two cases. Concentrating on those cancers with significantly elevated risks for the total period of follow-up, it was evident that for all cancers combined and some specific cancers (e.g. nonmelanoma skin, prostate, kidney, adrenal gland, and non-Hodgkin’s lymphoma), statistically significant risks of a second cancer were highest within a year of diagnosis of the primary thyroid cancer; for others, such as small intestine, colon, rectum, and female breast, risks seemed to increase with duration of follow-up. Disregarding the first year of follow-up, which may reflect detection or surveillance bias, there was also evidence of increasing risk with duration of follow-up for all cancers combined; soft tissue sarcoma; nonmelanoma skin cancers (marginal); prostate, kidney, brain, and adrenal cancers; and non-Hodgkin’s lymphoma. No substantial differences in risk were evident by age at diagnosis of thyroid cancer, sex, or calendar period of diagnosis (data not shown).


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  		TABLE 2. SIRs of second primary cancers after thyroid cancer by follow-up duration

 
The increased incidence of second primary cancer after papillary and follicular carcinoma followed a similar pattern to all thyroid cancers combined (data not shown). After medullary carcinoma of thyroid, the only cancer with a significantly increased risk was of the adrenal gland (five of 11 cases of adrenal cancer were recorded as after a medullary carcinoma of thyroid: SIR 147, 95% CI 47.4–343.0).

Second primary thyroid cancer after selected types of first primary cancer

Table 3Go shows the SIRs of thyroid cancer after the cancers listed in Table 2Go. For the total period of follow-up, significantly elevated risks of second primary thyroid cancer were seen after many specific cancers, including salivary gland (SIR 3.77), esophagus (2.65), stomach (1.66), colon (1.57), rectum (1.43), liver (6.68), pancreas (3.91), larynx (3.09), lung (2.51), bone (3.36), soft tissue sarcoma (2.94), melanoma (1.84), nonmelanoma skin cancer (1.44), female breast (1.62), cervix uteri (1.29), corpus uteri (1.41), ovary (1.59), testis (2.73), kidney (2.91), brain (2.57), adrenal gland (13.0), Hodgkin’s disease (4.77), non-Hodgkin’s lymphoma (2.26), and leukemia (2.49). Although not statistically significant for the total period of follow-up, the risks of thyroid cancer after a primary cancer of mouth, pharynx, and gallbladder or biliary tract were significantly increased within 12 months of diagnosis of the first cancer. Focusing on those cancers with significantly elevated risks for the total period of follow-up, it was evident that for some cancers [e.g. oral cavity and pharynx, salivary gland, esophagus, colorectal (colon only), liver, pancreas, larynx, lung, testis, brain, other endocrine gland, and adrenal gland], statistically significant risks of a subsequent thyroid cancer were highest within a year of diagnosis of the original primary cancer; for others, such as nonmelanoma skin (marginal) and kidney cancer, risks seemed to increase with duration of follow-up. Disregarding the first year of follow-up, there was also evidence of increasing risk of thyroid cancer with duration of follow-up after cancers of oral cavity and pharynx; salivary gland; colorectum (colon only); pancreas; larynx; melanoma; female breast; cervix; ovary; testis; other endocrine gland; adrenal gland; and after Hodgkin’s disease, non-Hodgkin’s lymphoma and leukemia. Again, no obvious differences in risk were evident by age at diagnosis of the primary cancer, sex, or calendar period of diagnosis (data not shown).


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  		TABLE 3. SIRs of thyroid cancer after selected first primary cancers by follow-up duration

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study has shown that in people with a primary thyroid cancer, there is a 30% increased risk of developing a second primary cancer in comparison with the general population. In addition, there is an increased risk of thyroid cancer developing after many other types of primary cancers.

It is important to consider the possibility of misclassification of recurrences or metastases as primary tumors (and vice versa) or one primary cancer as another. For example, the increased risk of bone cancer after thyroid cancer could reflect metastatic disease misclassified as primary bone cancer. Against this, the risk was not elevated during the first year of follow-up, and a sustained higher risk of thyroid cancer was also observed to follow primary bone cancer. However, it is not possible to exclude the possibility that some pharyngeal, stomach, and small bowel lymphomas may have been recorded incorrectly (according to ICD-9) as pharyngeal, stomach, and small intestine cancers.

When one cancer is followed by another, the possibility of detection and/or surveillance bias arises, especially if the second cancer is diagnosed soon after the diagnosis of the first cancer, and is followed by a lower-than-expected risk emerging later during the course of follow-up. There is evidence suggestive of detection or surveillance bias in this study, especially for thyroid cancer occurring as a second primary.

Bidirectional associations between cancers raise the possibility of shared genetic or environmental risk factors or, when potentially carcinogenic therapies are used for both cancers, a treatment effect. Such reciprocal associations were observed for cancers of the oral cavity and pharynx (combined); salivary glands; stomach; colorectum; bone; skin (nonmelanoma); female breast; kidney; brain; adrenal gland; and for soft tissue sarcoma, non-Hodgkin’s lymphoma, and leukemia; and possibly small intestine cancer (borderline). In contrast, unidirectional associations are more likely to indicate an effect of treatment. Such an association was seen for prostate cancer arising after thyroid cancer. For thyroid cancers arising after other primary cancers, unidirectional associations were less definite but may exist for cancers of esophagus, liver, pancreas, larynx, lung, skin (melanoma), cervix uteri, corpus uteri, ovary, testis, and Hodgkin’s disease.

Despite our large study population, the relative rarity of thyroid cancer and some apparently associated cancers, combined with stratification into subgroups for analysis, reduces the precision of some risk estimates. In the context of effectively very large numbers of tests of statistical significance, it is important to interpret the results with caution and not to draw unwarranted conclusions. However, a similar, recently published study from the United States has reported findings that are, in many respects, consistent with the results of our study (12). Specifically, elevated risks of cancers of salivary gland, breast, prostate, kidney, brain, adrenal gland, scrotum, and leukemia were reported to follow primary thyroid cancer. The risk of thyroid cancer was also found to be increased after most of the cancer sites studied, a phenomenon that has previously been well documented for survivors of several forms of childhood cancer (25).

The traditional risk factors associated with thyroid cancer include ionizing radiation and hormonal and genetic factors (26, 27, 28). Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways and also abnormalities in tumor suppressor genes and cell cycle proteins (29). Ras is the most frequently altered gene in spontaneous thyroid cancers and Ret in radiation-induced thyroid cancers (29). Activation of the Akt/protein kinase B signaling pathway also appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression (30). Akt is activated in Cowden’s syndrome (an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers). More recently CHEK2 gene has been identified as a multisite cancer susceptibility gene. A positive association was seen between mutations in CHEK2 and cancers of thyroid, breast, and colon (31). These genetic alterations may help to explain some of the results in our study. The strikingly increased incidence of adrenal cancers after thyroid cancer (especially medullary type) and the reverse have been reported previously in a Swedish study (32) and, of course, reflect the shared susceptibility to multiple endocrine tumors of multiple endocrine neoplasia type 2 arising from mutations in Ret oncogene (33).

Radioiodine is frequently used in the treatment of thyroid cancer. It is eliminated from the body via the urinary tract, digestive tract, and salivary glands, thus potentially exposing a number of anatomical locations to ionizing radiation. Many studies have looked at the late effects of this modality of treatment. One follow-up study on 2968 people with thyroid cancer showed an increase in kidney, endocrine, and nervous system tumors (16), whereas another study noted an increase in the above sites plus small intestine, prostate, and leukemia (32). A recent study (11) showed an increased risk of both solid tumors (colorectal, salivary gland, bone and soft tissue) and leukemia with increasing cumulative dose of radioiodine (62% of patients received radioiodine and 17% external radiotherapy). Our study confirms the increased incidence of the above cancers and, in addition, in cancers of the pharynx, stomach, skin (nonmelanoma), female breast, and non-Hodgkin’s lymphoma. We do not have information about the treatment modalities used, but there is no reason to suspect that therapy will have deviated from accepted practice, i.e. most with papillary and follicular cancers should have received I-131 treatment.

In our study, the risk of breast cancer after thyroid cancer increased with duration of follow-up. Some studies have shown increased incidence after radioiodine treatment (34), but others have not (11, 16). Despite expression of sodium iodide symporter in breast tissue (35), breast tissue is rarely visualized on I-131 whole-body scanning. At the same time, there is no substantial evidence that treatment for breast cancer increases the risk of thyroid cancer (36). Therefore, the reciprocal association between breast cancer and thyroid cancer seems more likely to be explained by shared genetic factors (as discussed above) and/or shared environmental risk factors. Hormonal factors have been suspected to be relevant to the etiology of thyroid cancer as well as breast cancer because sporadic thyroid cancer is more common in women and because estrogen receptors have been found in thyroid tumors (26). However, associations between menstrual and reproductive factors and thyroid cancer are weak and not all in the same direction as for breast cancer (37).

The increased incidence of second primary kidney cancer has been shown previously in population-based cohort studies (12, 16, 19) but does not appear to be related to I-131 exposure (11). This observation and the increased incidence of second primary thyroid cancer after kidney cancer suggests a shared risk factor. Although the sustained, unidirectional increase in risk of prostate cancer after thyroid cancer observed in our study would be consistent with an effect of treatment with I-131, a reciprocal association between prostate cancer and thyroid cancer was found in the recent study in the United States (12).

Treatment effects might explain the increased incidence of second primary thyroid cancer after cancers of lung, larynx, esophagus, and salivary gland. In these cancers the modalities of treatment include radiotherapy to fields that may include the thyroid gland, and, as noted above, ionizing radiation is a well-established risk factor for thyroid cancer. However, there is no evidence that risks increase with duration of follow-up. Most of the evidence that implicates ionizing radiation in the etiology of thyroid cancer relates to exposure during childhood rather than the older age groups typically receiving treatment for lung, laryngeal, esophageal, and salivary gland cancers (26).

Thus, it seems unlikely that carcinogenic effects of therapy can, in all cases, explain the increase in risk of thyroid cancer observed after so many different types of cancer. It is only possible to speculate on other potential explanations such as alterations in immune function or thyroid function, which might represent a response to tumor growth and/or other (not directly carcinogenic) effects of therapy.

To summarize, in common with several other studies, we have demonstrated associations between thyroid cancer and numerous other types of cancer. Although detection bias, surveillance bias, misclassification bias, and chance may contribute to some of these observations, it seems likely that shared risk factors and treatment effects are implicated in many cases. Thyroid cancer incidence is increasing, and it is being diagnosed in younger individuals who then have a higher risk of developing second primary cancers. Thus, clinicians should maintain a high index of suspicion, both for second primary cancers at a variety of sites when following up patients who have been treated for primary thyroid cancer and for second primary thyroid cancers, especially among survivors of childhood cancer.


   Footnotes
 
All authors have nothing to declare.

First Published Online February 14, 2006

Abbreviations: CI, Confidence interval; SIR, standardized incidence ratio.

Received September 8, 2005.

Accepted February 7, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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