Familial Risks for Nonmedullary Thyroid Cancer

0021-972X/05/$15.00/0 Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 90(10):5747–5753 Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2005-0935

Familial Risks for Nonmedullary Thyroid Cancer Kari Hemminki, Charis Eng, and Bowang Chen Division of Molecular Genetic Epidemiology (K.H., B.C.), German Cancer Research Center, 69120 Heidelberg, Germany; Department of Biosciences at Novum (K.H.), Karolinska Institute, 141 57 Huddinge, Sweden; and Clinical Cancer Genetics Program (C.E.), Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210 Context: Reliable data on familial risks are important for clinical counseling and cancer genetics. Objective: We wanted to define familial risks for histopathologyspecific nonmedullary thyroid cancers through parental and sibling probands. Setting: The study examines the nationwide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. Patients: Cancer data were retrieved from the Swedish Cancer Registry from years 1958 to 2002, including 3292 patients with thyroid adenocarcinoma. The Systematized Nomenclature of Medicine histology was available from 1993 onward, with 1449 papillary, 288 follicular, 148 anaplastic, and 68 Hurthle cell tumors. Main Outcome Measures: Familial risk for offspring was defined through standardized incidence ratio, adjusted for many variables.

N

Results: The familial risk for papillary carcinoma was 3.21 and 6.24 when a parent and a sibling, respectively, were diagnosed with thyroid cancers. There was an apparent gender preference, particularly among sisters, whose risk was 11.19. The risks were highest for early onset cancers. Thyroid adenocarcinoma was shown to be associated with melanoma and connective tissue tumors, and probably also with neurinomas (schwannomas). Associations found in single comparisons with papillary thyroid cancer and other sites included right-sided colon, breast, ovarian, and kidney cancers. Hurthle cell tumors were associated with Hodgkin’s and non-Hodgkin’s lymphoma, but the numbers of cases were small. Conclusions: The present findings were based on a limited number of cases, but they display a complex and heterogeneous pattern of familial nonmedullary thyroid cancer. The high risk for papillary carcinoma among women requires clinical attention, although the absolute risks for this rare cancer are still low. (J Clin Endocrinol Metab 90: 5747–5753, 2005)

ONMEDULLARY THYROID CANCER (NMTC) accounts for over 95% of all thyroid cancers, and four histological types can be distinguished: papillary (85%), follicular (10%), Hurthle cell, and anaplastic types (1, 2). Overall, the incidence of thyroid cancer is high in the developed countries and in the countries of East Asia (3). In Sweden, the incidence has remained relatively stable over the past decades, but in many European countries and the United States there has been an increase in incidence, particularly of papillary carcinoma (4, 5). The two-times higher rate in women than in men has persisted (4, 6). However, not much is known about the epidemiology of the rare histological types (7). Some established risk factors for thyroid cancer are ionizing radiation, which causes papillary carcinoma, and iodine deficiency or imbalance, which predisposes to the follicular and anaplastic forms (3, 8); goiter also appears to be a risk factor for papillary tumors, particularly in men (9, 10). NMTC of distinct histological types can be a component in some heritable cancer syndromes such as familial adenomatous polyposis, Cowden syndrome, Werner syndrome, and Carney complex, and probably also in Peutz-Jeghers syndrome and

tuberous sclerosis (11, 12). The gene defects predisposing to these hereditary thyroid cancers are known (12, 13). Many of these syndromes are uncommon and they probably account for a small proportion of familial NMTC, and other susceptibility genes are to be expected (14 –16). Although several studies have described familial NMTC (17–19), only a few provide data on specific histology (15, 20, 21). Several types of associated tumors have been described in families with hereditary thyroid cancers, but population-based studies on histology-specific NMTCs and associated tumors in families have been limited (1, 15, 21, 22). In this study, we use the 2004 update of the nationwide Swedish Family-Cancer Database to address the questions about the age and gender effects in histology-specific NMTCs and their association with other familial cancers (23). Medullary thyroid cancer received a specific code in the Swedish Cancer Registry in 1985, which limited our previous study in sample size and follow-up time (22). In the present analysis, we have the possibility of considering both parentoffspring and sibling effects in the offspring population aged up to 70 yr.

First Published Online July 19, 2005 Abbreviations: CI, Confidence interval; ICD, International Classification of Diseases; NMTC, nonmedullary thyroid cancer; O, observed; SIR, standardized incidence ratio; SNOMED, Systematized Nomenclature of Medicine. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Subjects and Methods Statistics Sweden maintains a “Multigeneration Register” where individuals (called children or offspring in this study) born in Sweden in 1932 and later are registered with their parents (those pleading parenthood at birth) and are organized in families (24). Practically, only the two oldest generations, parents and offspring, contributed cases to family studies. Information on the Database is also available at the Nature Genetics website as supplementary information (25), and the current

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update (2004) of the Database has recently been described (23). The data on families and cancers have a complete coverage, barring some groups of deceased offspring, which affect those born in the 1930s and who died before 1991. This small group of offspring with missing links to parents has a negligible effect on the estimates of familial risk (26). The Multigeneration Register was linked by the individually unique national registration number to the Cancer Registry from years 1958 –2002. Cancer registration is considered to be close to 100% currently (6). The site of cancer is registered based on a four-digit diagnostic code according to the seventh revision of the International Classification of Diseases (ICD-7). We have subdivided thyroid cancers according to histological types as coded in the Cancer Registry. Before 1985, thyroid cancers were subdivided into two histopathological categories: adenocarcinoma (code 096), including papillary and follicular thyroid cancer, and undifferentiated cancer, (code 196) which included anaplastic tumors. Most medullary cancers were classified as undifferentiated. A separate code for medullary cancer (186) was introduced in 1985, and thus the present follow-up was started in 1986. The following ICD-7 codes were pooled: “upper aerodigestive tract” cancer codes 161 (larynx) and 140 –148 (lip, mouth, pharynx), except for code 142 (salivary glands), and “leukemia” codes 204 –207 (leukemias), 208 (polycytemia vera), and 209 (myelofibrosis). Rectal cancer, ICD-7 code 154, was subdivided into anus (squamous cell carcinoma, 154.1) and mucosal rectum (154.0). In some analysis, leukemias were divided into subtypes. Only squamous cell carcinomas of the skin, but not basal cell carcinomas, are registered in the Cancer Registry. From year 1993 onward, ICD-O-2/ICD with histopathological data according to the Systematized Nomenclature of Medicine (SNOMED; http://snomed.org) was used; we refer to this classification as “SNOMED”. According to this classification, it was possible to distinguish papillary, follicular, anaplastic, and Hurthle histologies. Standardized incidence ratios (SIRs) were used to measure thyroid cancer risks for offspring when their parents, siblings, or both were diagnosed with specific cancers (i.e. using parents and siblings as probands). The reference rate was calculated for offspring whose parents/ siblings had no specified cancer, as the number of cases divided by person-years at risk. SIR was the ratio of the observed (O) to expected number of cases. The expected numbers were calculated from 5-yr-age-, sex-, period-, area (county)-, socioeconomic status-standardized rates for offspring whose parents were not diagnosed with thyroid cancer. This is an indirect standardization for the listed possible intervening variables. Confidence intervals (95% CI or 99% CI) were calculated assuming a Poisson distribution (27). Follow-up was started for each offspring at birth, immigration, or January 1, 1986, whichever came latest. When the SNOMED histology was used, follow-up was started January 1, 1993. Follow-up was terminated on diagnosis of first cancer, death, emigration, or the closing date of the study, December 31, 2002. Risks for siblings were calculated using the cohort method, considering dependence between the pairs in the assessment of 95% CIs, as described elsewhere (28). Some analyses were carried out in “reverse order”, using family members with thyroid cancer as probands and calculating SIRs for any cancer among offspring.

Results

Some relevant numbers from the Database are shown in Table 1. The number of parents was 6.59 million and the number of offspring was 6.99 million. Thyroid adenocarcinoma was recorded in 2893 parents and 1863 offspring between 1986 –2002. The specific SNOMED histology was available from 1993 onward, resulting in 1592 parental and 1104 offspring tumors. Because the offspring population was younger (0 –70 yr) than the parental population (any age), the proportion of relatively early onset papillary tumors was higher among the offspring (83.0%) compared with the parents (72.5%). The opposite was true for anaplastic tumors, which present at a relatively old age. The distribution of follicular and Hurthle cell tumors did not differ much between the two generations. Figure 1 shows age-incidence relationships for the specific histologies. Papillary cancer

Hemminki et al. • Familial Thyroid Cancers

TABLE 1. Numbers of individuals and cancers covered in the analyses

No. of persons Patients with thyroid adenocarcinoma (1986 –2002) SNOMED histology (1993–2002) Papillary Follicular Hurthle Anaplastic

Parents [n (%)]

Offspring [n (%)]

6,590,250 2893

6,994,345 1863

1681 (100.0)

1162 (100.0)

1218 (72.5) 256 (15.2) 62 (3.7) 145 (8.6)

965 (83.0) 139 (12.0) 36 (3.1) 22 (1.9)

showed a large difference for female and male rates; the female rates reached a maximum in the age group of 40 – 49 yr, preceding the male maximum by a decade. Note that the y-scale is different for papillary and the three other tumor types. Follicular and anaplastic tumors showed prominent old-age components in the 70- to 79-yr age group. For Hurthle cell tumors, the age-incidence curves were relatively flat between ages 40 –79 yr. Familial risks for thyroid adenocarcinoma in offspring are shown in Table 2 when parents (without affected siblings) and siblings (without affected parents) were used as probands. Only one family was found with more than two individuals diagnosed with thyroid cancer: the mother was diagnosed with follicular cancer at age 70, the father was diagnosed with an unspecified adenocarcinoma at age 43, and both of their male offspring were diagnosed with papillary cancer at ages 45 and 64. The SIR for thyroid adenocarcinoma was 3.83 or 5.15 when parents and siblings, or siblings, respectively, were diagnosed with any thyroid cancer; both of these SIRs were significant even at the 0.01 level, as shown by underling in the tables. The risk was significant (SIR 4.50) when the mother was the proband; however, from an affected mother, the risk was equally high (data not shown) for sons (SIR 4.37, n ⫽ 5, 95% CI 1.38 –10.28) and for daughters (SIR 4.54, n ⫽ 15, 95% CI 2.53–7.51). When either parent was diagnosed with thyroid cancer, the risk for sons was 4.98 (n ⫽ 8, 95% CI 2.13–9.86) and for daughters 3.44 (n ⫽ 16, 95% CI 1.96 –5.60). The SIR for thyroid adenocarcinoma for siblings was 5.15 (Table 2), and only women showed an excess risk (6.36). Among the 14 affected sibling pairs, all were women, except for one brother-sister pair. At discordant cancer sites, only maternal breast (1.22) and kidney (1.70) cancers and parental connective tissue tumors (2.18) were associated with an increased risk of thyroid adenocarcinoma. In one family, a father was diagnosed with fibrosarcoma and his two daughters were diagnosed with thyroid adenocarcinoma, of which one was papillary cancer. An association with connective tissue tumors was also noted among siblings (5.50 for men) but they were of diverse histological types. The association with kidney cancer among siblings was of borderline significance (2.32). Right-sided colon cancer (2.92) and ovarian cancer (2.52) were other significant tumors. We carried out analyses of thyroid adenocarcinoma in reverse order by calculating SIR for any cancer in offspring using parents and siblings diagnosed with thyroid adeno-



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FIG. 1. Age-incidence relationships for histology-specific thyroid cancers in the Family-Cancer Database.

carcinoma as probands, which, for any discordant site, is a completely independent analysis for the parent-offspring comparison. However, because the offspring population has fewer cancers than the parental population, the power was decreased (the total number of offspring-parent pairs diagnosed with any cancer decreased from 623 in Table 2 to 158, data not shown). With the exception of thyroid cancer, none of the significant increases in Table 2 were found in the reverse analyses. However, the SIR for melanoma was increased from parental (SIR 1.69, n ⫽ 19, 95% CI 1.02–2.65) and sibling probands (SIR in brothers 2.55, n ⫽ 7, 95% CI 1.01– 5.28). The SIR for nervous system tumors was also increased (SIR 1.78, n ⫽ 20, 95% CI 1.08 –2.75) when parents were diagnosed with thyroid adenocarcinoma. The increase was particularly for neurinoma (synonymous to schwannoma and neurilemoma), the SIR being 4.27 (n ⫽ 6, 95% CI 1.54 –9.35). Familial risks were analyzed by the specific SNOMED histology; data for papillary cancer with the largest numbers of cases are shown in Table 3. For papillary thyroid cancer, the SIR was 3.21 from parents and 6.24 from siblings diagnosed with any thyroid cancer. The risk in offspring was 3.60 (n ⫽ 8, 95% CI 1.54 –7.13) when the mother was diagnosed with thyroid cancer, and it was 2.23 (n ⫽ 2, 95% CI 0.21– 8.20) when the father was affected (data not shown); the mother was a proband only to one son with papillary cancer, giving an SIR of 1.50 (95% CI 0 – 8.57), and to seven daughters, giving

an SIR of 4.21 (95% CI 1.67– 8.53). Among siblings, only females were diagnosed with papillary cancer, giving an SIR of 11.19 (n ⫽ 8, 95% CI 4.78 –22.16) (data not shown). Maternal breast cancer (SIR 1.37) and sibling right-sided colon (SIR 3.70, borderline significance), ovarian (SIR 3.17), and kidney (SIR 3.71) cancers were associated with a risk of papillary tumors. Among the 10 offspring with papillary thyroid cancers (Table 2), all but one were diagnosed before age 50 yr. For ages less than 40 yr, the SIR was 4.64 (n ⫽ 5, 95% CI 1.46 – 10.91); for ages 40 to 49 yr, the SIR was 4.43 (n ⫽ 4, 95% CI 1.15–11.15). The mean age of onset of papillary cancer was 41.4 yr (median 43 yr). When a parent was diagnosed with thyroid cancer, the mean age for papillary cancer was 39.4 yr (median 41 yr). For sibling pairs (all sisters) the mean was 37.9 yr (median 35 yr). The cumulative risks for papillary thyroid cancers up to age 70 yr were 0.03% for men and 0.09% for women. No single significant associations were observed for follicular, Hurthle, and anaplastic cancers (data not shown), with some exceptions. The risk for prostate cancer was increased (SIR 4.52, n ⫽ 4, 95% CI 1.18 –11.70) when a sibling was diagnosed with follicular thyroid cancer. However, three of the prostate cancers came from one family. Another exception was an increase in follicular thyroid cancer to 4.25 when fathers were diagnosed with leukemia (n ⫽ 4, 95% CI 1.11–10.99); two of these were acute myeloid leukemia and

0.95 1.17 1.02 0.91 0.57 1.28 1.04 0.96 1.41 0.53 0.86 1.21 0.77 1.42 1.13 1.11 1.13 1.24 0.82 1.30 0.95 1.16 3.83 1.04 2.18 1.22

1.62 1.30 0.94 1.04

6 15 20 623

95% CI

0.58–3.56 0.73–2.15 0.58–1.46 0.96–1.12

0.55–1.53 0.46–2.42 0.71–1.41 0.68–1.20 0.32– 0.95 0.85–1.87 0.72–1.46 0.77–1.19 0.97–2.00 0.27– 0.93 0.63–1.14 0.99–1.47 0.41–1.33 0.96–2.04 0.70–1.73 0.92–1.33 0.11– 4.17 0.84–1.77 0.55–1.17 0.85–1.89 0.62–1.41 0.75–1.70 2.45–5.71 0.57–1.76 1.08–3.92 0.81–1.78

Parent

SIR

17 7 35 51 15 27 34 84 32 12 48 107 13 30 21 121 2 31 30 27 25 26 24 14 11 27

O

0.90 1.07 1.14 0.95

1.11 1.13 0.90 0.73 1.04 0.79 1.02 2.21 1.27 2.50 1.22

121 2 13 21 11 13 11 4 5 7 15 2 7 14 342

1.09 1.33 1.03 0.88 0.55 1.17 1.13 0.97 1.17 0.57 0.77

95% CI

0.08–3.30 0.42–2.22 0.62–1.92 0.85–1.05

0.92–1.33 0.11– 4.17 0.48–1.54 0.45–1.11 0.52–1.87 0.42–1.35 0.51–1.84 0.57–5.70 0.40–2.99 0.99–5.19 0.68–2.01

0.61–1.81 0.48–2.92 0.66–1.53 0.57–1.31 0.22–1.14 0.62–2.01 0.71–1.71 0.71–1.29 0.60–2.05 0.23–1.19 0.52–1.10

Father SIR

15 6 24 25 7 13 22 46 12 7 31

O

4 8 6 372

18 9 16 12 15 20 10 4 12

2 1 11 26 8 14 12 38 20 5 17 107 13 30 21

O

2.72 1.60 0.67 1.18

1.70 1.15 1.55 1.22 1.27 4.50 1.05 1.78 1.22

0.48 0.67 0.97 0.93 0.59 1.40 0.91 0.93 1.60 0.48 1.06 1.22 0.77 1.42 1.13

0.71–7.05 0.68–3.17 0.24–1.46 1.07–1.31

1.01–2.70 0.52–2.19 0.89–2.53 0.63–2.13 0.71–2.09 2.74– 6.96 0.50–1.95 0.46– 4.61 0.63–2.15

0.05–1.78 0.00–3.85 0.48–1.74 0.61–1.36 0.25–1.17 0.77–2.36 0.47–1.59 0.66–1.27 0.98–2.48 0.15–1.13 0.61–1.69 1.00–1.48 0.41–1.33 0.96–2.04 0.70–1.73

95% CI

Mother SIR

1.61 1.12 1.08

5 79

1.31 1.34 1.81 1.48 2.92 0.44 1.63 1.40 1.61 0.52 1.10 0.82 0.99 1.02 2.52 1.07 1.33 2.32 0.88 1.11 0.76 1.01 5.15 0.71 2.80 1.51

0.35–2.64 0.85–1.34

0.30– 4.75

0.34–3.40 0.00–7.66 0.47– 4.68 0.63–2.93 1.16– 6.05 0.00–2.53 0.59–3.57 0.72–2.45 0.30– 4.78 0.00–2.99 0.47–2.18 0.52–1.23 0.31–2.33 0.26–2.62 1.30– 4.42 0.46–2.12 0.35–3.43 0.99– 4.59 0.23–2.27 0.55–1.99 0.07–2.79 0.46–1.93 2.80– 8.66 0.13–2.12 0.73–7.23 0.65–2.99

95% CI

Sibling SIR

3

4 1 4 8 7 1 6 12 3 1 8 23 5 4 12 8 4 8 4 11 2 9 14 3 4 8

O

3 33

1.17 1.07

2.66

5.50 1.85

4 6 3

1.07 1.33 2.34 0.89 0.91 0.63 0.91 1.48

0.93 1.63 1.49 1.83 3.40 0.85 1.41 1.75 1.08 0.97 0.78 10.52

0.22–3.45 0.74–1.51

0.50–7.87

1.43–14.22 0.67– 4.06

0.46–2.12 0.35–3.43 0.74–5.51 0.17–2.64 0.24–2.35 0.00–3.63 0.24–2.37 0.00– 8.47

0.09–3.42 0.00–9.36 0.14–5.49 0.58– 4.31 0.88– 8.79 0.00– 4.84 0.27– 4.17 0.75–3.46 0.00– 6.21 0.00–5.57 0.15–2.30 0.00– 60.32

95% CI

Brother SIR

8 4 5 3 4 1 4 1

2 1 2 5 4 1 3 8 1 1 3 1

O

Sibling only

1.92 1.23 2.14 1.46 0.79 0.99 1.02 2.52

3 5 2 5 22 5 4 12

2 50

2

1.06 1.11

0.97

2.26 0.84 1.26 0.94 1.10 6.36 1.15

2.31 1.11 2.44

2 3 3

3 1 7 1 5 13 3

2.23

95% CI

0.10–3.90 0.83–1.47

0.09–3.58

0.43– 6.68 0.00– 4.82 0.50–2.61 0.00–5.39 0.35–2.58 3.37–10.90 0.22–3.39

0.48–3.44 0.49–1.19 0.31–2.33 0.26–2.62 1.30– 4.42

0.36–5.68 0.39–2.89 0.20–7.86

0.22– 8.48 0.21–3.28 0.46–7.21

0.21– 8.19

Sister SIR

2

O


Bold type, 95% CI does not include 1.00; underline, 99% CI does not include 1.00.

Upper aerodigestive tract Esophagus Stomach Colon Right-sided Left-sided Rectum Colorectum Liver Pancreas Lung Breast Cervix Endometrium Ovary Prostate Testis Kidney Urinary bladder Melanoma Skin Nervous system Thyroid gland Endocrine glands Connective tissue Non-Hodgkin’s lymphoma Hodgkin’s disease Myeloma Leukemia Any

Familial site

Parent only

TABLE 2. SIR for adenocarcinoma of the thyroid gland in offspring by familial cancer

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TABLE 3. SIR for familial papillary thyroid in offspring by familial cancer Papillary Familial site

Parent O

Upper aerodigestive 7 tract Esophagus 5 Stomach 18 Colon 24 Right-sided 6 Left-sided 15 Rectum 17 Colorectum 40 Liver 16 Pancreas 7 Lung 28 Breast 60 Cervix 4 Endometrium 17 Ovary 13 Prostate 63 Kidney 16 Urinary bladder 17 Melanoma 11 Skin 14 Nervous system 17 Thyroid gland 10 Endocrine glands 7 Connective tissue 6 Non-Hodgkin’s 12 lymphoma Hodgkin’s disease 2 Myeloma 10 Leukemia 6 Any 326

SIR

95% CI

0.81 0.32–1.69

Sibling O

SIR

95% CI

2 1.42 0.13–5.22

1.74 1.13 0.91 0.49 1.51 1.10 0.97 1.50 0.56 1.04 1.37 0.48 1.68 1.44 1.22 1.35 0.97 1.03 1.14 1.52 3.21 1.05 2.44 1.11

0.55– 4.10 0.67–1.78 3 2.97 0.56– 8.79 0.58–1.36 4 1.63 0.42– 4.22 0.18–1.07 4 3.70 0.96–9.58 0.84–2.50 0.64–1.76 2 1.20 0.11– 4.41 0.69–1.32 5 1.28 0.41–3.02 0.86–2.44 2 2.32 0.22– 8.53 0.26–1.37 0.69–1.50 6 1.81 0.65–3.97 1.05–1.77 13 1.01 0.54–1.73 0.12–1.24 1 0.41 0.00–2.35 0.98–2.70 1 0.56 0.00–3.22 0.76–2.47 7 3.17 1.26– 6.56 0.94–1.56 3 0.91 0.17–2.69 0.77–2.19 6 3.71 1.34– 8.13 0.57–1.56 1 0.48 0.00–2.78 0.51–1.86 5 1.07 0.34–2.52 0.62–1.92 1 0.83 0.00– 4.75 0.88–2.44 5 1.15 0.36–2.70 1.53–5.92 8 6.24 2.67–12.36 0.42–2.18 1 0.51 0.00–2.90 0.88–5.34 1 1.45 0.00– 8.28 0.57–1.95 2 0.81 0.08–2.97

1.10 1.84 0.59 1.12

0.10– 4.03 2 2.12 0.20–7.80 0.88–3.40 0.21–1.30 2 0.91 0.09–3.35 1.00–1.25 39 1.13 0.80–1.54

Bold type, 95% CI does not include 1.00; underline, 99% CI does not include 1.00.

the others were chronic myeloid leukemia and chronic lymphoid leukemia. No follicular or anaplastic cancers were found in offspring when parents were diagnosed with any thyroid cancer. For the rare Hurthle cell tumors, no familial thyroid cancers were observed; however, associations with parental Hodgkin’s disease (SIR 26.08, n ⫽ 2, 95% CI 2.46 – 95.91) and sibling non-Hodgkin’s lymphoma (SIR 15.13, n ⫽ 2, 95% CI 1.43–55.63) were significant, although encompassing only two sibling pairs each. Discussion

All thyroid cancer diagnoses reported to the Swedish Cancer Registry are histologically verified, and we can assume that the diagnostic accuracy is as good as it can be at a national level (6). The age-incidence curves in Fig. 1 showed characteristic features for the four histological types implying diagnostic consistency. Papillary thyroid cancer showed a large female excess and an early age of onset, the maximum incidence being 40 – 49 yr for women and 50 –59 yr for men. Follicular thyroid cancer also had a clear female excess but the age of onset peaked at ages 70 –79 yr. Anaplastic cancer was largely a disease of old age, whereas Hurthle cell tumors show a broad age-incidence maximum between ages 40 –79 yr. Although the present study was nationwide, the number of cases was small for a rare cancer, such as thyroid cancer.

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A further limitation was that the specific SNOMED histology was used beginning only in 1993. Thus we are unable to address time trends in the incidence of these histological types. Yet, the overall incidence of thyroid cancer and the female excess have remained stable throughout cancer registration in Sweden (6). The number of familial cases for follicular, anaplastic, and Hurtle cell cancers was so small that no definite associations could be found. The familial clustering of Hodgkin’s disease and non-Hodgkin’s lymphoma with Hurthle cell cancers may not be a coincidence, because Hodgkin’s disease and non-Hodgkin’s lymphoma share many etiological features, including familial risks and association with immunosuppression and infections by Epstein-Barr virus and HIV (3, 29 –31). Independent studies are necessary to confirm the association of Hurthle cell tumors with lymphomas. The association of follicular tumors with diverse types of leukemias was probably fortuitous. Papillary thyroid cancer showed a high familial risk when parents or siblings were diagnosed with thyroid cancer, SIRs being 3.21 and 6.24, respectively. Both of these SIRs were highly significant (⬍1% level) but they were not significantly different from each other (95% CIs overlapped). The underlying cause may be a medium-penetrant dominant gene or group of genes, and the excess risk in siblings could be a recessive effect. Mothers appeared to transmit the susceptibility more to daughters (SIR 4.32) than to sons (SIR 1.50, but one case only). The excess sibling risk was contributed entirely by females, whose SIR was as high as 11.19. All these SIRs were based on small numbers, implying wide CIs and discouraging strong conclusions. Also it should be pointed out that the absolute risks even for familial cases were low. The female cumulative risk of papillary cancer was 0.09% up to age 70, translating to a cumulative risk of 1% among affected sisters (11-fold risk). The high female excess incidence in papillary thyroid cancer has been associated with a response to estrogen stimulation or other hormonal factors, which could underlie the risks for sisters (32). However, the small number of male cases warrants caution. A review on families with papillary thyroid carcinoma makes no point about gender effects, as many families have affected individuals of both genders (10). In the collected families, there was an association with papillary cancer and multinodular goiter, and goiter appears to predispose men in particular to papillary thyroid cancer (9). Thus, in Sweden, where goiter has been rare during the past decades, this putative male contribution to papillary thyroid cancer may be small and hence, the female predominance. A female excess in familial cases of NMTC was noted also in a Canadian study (18), but in an Icelandic study, men were at a higher risk (19). In the present study, the mean and median ages of onset were 2 yr lower for papillary cancer in offspring of affected parents and some 5 yr lower for affected sisters, providing further support for a true familial risk. The associations of thyroid adenocarcinoma with discordant sites could largely be ascribed to papillary thyroid cancers, the most common subtype (cf. Tables 2 and 3). However, these kinds of exploratory analyses are complicated by problems of multiple comparisons. Because much of the existing literature cannot be used as a reference, we have to rely on

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the internal consistency of the present data. According to the above results, even the “reverse analysis”, which is a potential way to confirm associations between discordant sites, was not very helpful because of the reduction in the study population. Yet, the association of ovarian cancer with thyroid adenocarcinoma was found, but because it was among siblings, it was not an independent test. Finding a risk through both parental and sibling probands provides strong evidence for a true familial association. Using that criterion, the associations between thyroid adenocarcinoma and connective tissue tumors and melanoma (reverse analysis) were confirmed. The associations that remained unconfirmed in the present dataset were between papillary thyroid cancers and right-sided colon, breast, and kidney cancers. However, breast cancer was found to be increased in families of NMTC patients in Canada (18). A Utah study found an association between all thyroid tumors and breast, prostate, and soft tissue tumors and leukemia (33). Stoffer et al. (20) reported an association of papillary tumors with colon cancer. In reverse analysis, thyroid adenocarcinoma associated with nervous system cancers, particularly with neurinomas, showing a high SIR of 4.27. Papillary thyroid cancer is an uncommon component of in familial polyposis coli, which is, however, a dominant disease, not preferentially affecting the right side of the colon (12). Because the risks between papillary thyroid cancer and right-sided colon cancer were exclusively between siblings, this syndrome appears less likely. Although breast cancer is a well-documented component of Cowden syndrome (occurring in 28 –50% of affected women), where follicular thyroid carcinoma is the main thyroid cancer component tumor (occurring in 10% of affected people in a lifetime), it is unclear whether it could be identified in the present Database because of the relatively small numbers of follicular tumors in the Database, and because of the variable expressivity and pleiotropy of Cowden syndrome (12). Specifically, benign neoplasias of the thyroid and breast are more common than malignant neoplasias of these organs in Cowden syndrome. Because this Database does not store information on nonmalignant disease, it is almost certain that this syndromic association could not be uncovered. In summary, the present analysis from a national population-based Database showed a high risk of familiality for thyroid papillary carcinoma, with intriguing gender preferences particularly among sisters. Thyroid adenocarcinoma, of which papillary tumors formed the largest subgroup, were found to be associated with melanoma and connective tissue tumors, and probably also with neurinomas. Associations found in single comparisons with papillary thyroid cancer and other sites included right-sided colon, breast, ovarian, and kidney cancers. Hurthle cell tumors associated with Hodgkin’s and non-Hodgkin’s lymphoma, but the number of cases was small. The present findings display a complex and heterogeneous pattern of familial NMTC which will be a challenge to molecular dissection of the underlying mechanisms. Acknowledgments The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.


Received April 28, 2005. Accepted July 8, 2005. Address all correspondence and requests for reprints to: Kari Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. E-mail: [email protected]. This work was supported by Deutsche Krebshilfe, the Swedish Cancer Society, and Grant EU LSHC-CT-2004-503465.

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Socie´te´ Franc¸aise d’Endocrinologie JOURNEES INTERNATIONALES D’ENDOCRINOLOGIE CLINIQUE Henri-Pierre Klotz First announcement The 49th Journe´es Internationales d’Endocrinologie Clinique will be held in Paris on May 11–12, 2006 and will be devoted to: “Hormones, calcium and osteoporosis.” Program will include 20 state-of-the-art lectures and a limited number of selected free communications for oral or poster presentation. Deadline for submission of abstracts: January 5, 2006 Information: Dr. G. Copinschi Laboratory of Experimental Medicine Brussels Free University – CP 618 808 Route de Lennik B-1070 Brussels Belgium E-mail: [email protected] Website: http://www.endocrino.net

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