The incidence of thyroid cancer is increasing in several countries. However, the issue of whether this applies to all different histological types and related variants is poorly addressed.
The incidence of thyroid cancer is increasing in several countries. However, the issue of whether this applies to all different histological types and related variants is poorly addressed.
All incident thyroid cancers diagnosed between 1998 and 2009 in a mildly iodine-deficient area in northern Italy were derived from a population-based tumor registry. Stage of disease, size of the tumor, focality, and histological variants were recorded from a review of pathology reports and slides. The mean annual increase (MAI) of the standardized incidence rate was calculated over the entire 12-year period of observation and a standardized rate ratio was evaluated to compare the mean standardized incidence between 2 periods of 6 years each (1998-2003 vs 2004-2009).
In total, 980 cases were considered. An increase in the incidence trend for all thyroid tumors was demonstrated; the increase was found to be continuous from 1998 to 2002 but not afterward. The cancer incidence increased in both male and female subjects. Papillary thyroid carcinoma (PTC), the follicular variant of PTC, the tall cell variant of PTC (TCV-PTC), and Hurthle cell carcinoma (HC) showed the most relevant changes in incidence whereas follicular carcinoma was not found to be significantly affected. TCV-PTC was the only histological type to demonstrated a significant (P < .01) proportional increase in the second 6-year period of observation. Only TCV-PTC and HC were found to display a significant MAI after 2002.
The incidence of thyroid cancer has increased within the last decade, an increase that is accounted for mostly by differentiated tumors. The most significant increases were documented for aggressive variants of basic histotypes. Cancer 2012. © 2012 American Cancer Society.
An increase in the incidence of thyroid cancer has been reported over the past 30 years worldwide.1-7 In the United States, the incidence of thyroid cancer is rising more than that of other cancers3, 8 and by the end of 2011 this tumor was expected to be the fifth most common cancer among women.9 The incidence of thyroid cancer is also increasing in Europe, where the average incidence, estimated in a 2004 survey, has been reported to be 5.0 and 12.9 cases per 100,000 residents per year among men and women, respectively.10 The average incidence of thyroid cancer in Italy has been calculated at 5.2 and 15.5 cases per 100,000 residents per year among men and women, respectively.11
Many authors have attributed the increasing incidence of thyroid cancer to improved diagnostic procedures to detect thyroid nodules.3, 12 However, there are several arguments against this hypothesis. First, thyroid cancer mortality has reportedly remained unchanged3, 10 or even increased9, 13, 14 in recent years. If earlier diagnosis were the only explanation for the increased incidence, the mortality rate for thyroid cancer would be expected to be reduced. Second, studies from the United States indicate that the increase in the incidence of thyroid cancer between 1988 and 2005 occurred across tumors of all sizes.15 An increase in the frequency of small tumors would be expected if the increased incidence rates were because of an earlier diagnosis. Third, the diagnostic approach to thyroid nodules has not significantly changed over the last 10 years.
It has been reported that the increase in the incidence of thyroid cancer is for the most part accounted for by well-differentiated (WD) tumors,3, 4, 16 which generally have a good prognosis. However, among WD tumors, some histological variants are characterized by a more aggressive behavior. To the best of our knowledge, it is unknown whether changes in the frequency of aggressive variants of WD thyroid cancer have occurred over time.
In the current study, we evaluated the incidence of thyroid cancer in the general population of the province of Parma, a geographical area with a moderate iodine deficiency that is located in Northern Italy, from January 1, 1998 through December 31, 2009. To this aim, we retrospectively retrieved incidence data from the local tumor registry, which has been active since 1978 with an estimated total population coverage. The incidence data were integrated with information regarding tumor stage, histotype, and focality that was derived from a review of the pathological reports.
The province of Parma is a 3449-km2 area with a population of 393,963 inhabitants reported in 1998 and 437,308 inhabitants reported in 2009, according to the Italian Institute for Statistics (available at http//www.istat.it/sanita/Health/). In previous studies, the levels of iodine intake in this area were evaluated by measuring urinary iodine excretion in a sample of the population. On the basis of these results, a mild-to-moderate iodine deficiency was demonstrated.17, 18
All cases of thyroid cancer diagnosed between January 1, 1998 and December 31, 2009 were retrieved from the tumor registry of Parma. Only patients identified by code C73.9 (indicating malignancy) in the third edition of the International Classification of Diseases for Oncology were included. Of 980 total thyroid cancers, original pathological reports were available for 936 cases. Original slides available at the surgical pathology unit of the Regional Hospital of Parma (approximately 85% of overall cases) were reviewed for the purpose of the study by one of the authors (L.C.). In 4 cases, WD thyroid cancers were reclassified according to different variants.
Primary tumors were classified as follows: 1) papillary carcinoma (PTC) (code 8260/3); 2) follicular carcinoma (FTC) (code 8330/3); 3) medullary carcinoma (code 8510/3); and 4) undifferentiated/anaplastic thyroid carcinoma (codes 8020/3 and 8021/3). Some variants of these basic histological types were also recorded: Hurthle cell carcinoma (code 8290/3); follicular variant of PTC (FV-PTC) (code 8340/3); and tall cell variant of PTC (TCV-PTC). The histological diagnosis of TCV-PTC was based on published criteria.19 The few cases of columnar variant of PTC (5 cases) were included in the TCV-PTC group. Other primary malignant tumors or tumors not otherwise specified(19 cases) were categorized as a separate group (“other”). Tumor staging was performed according to the TNM classification.20 The number of tumor nodules (focality) and the presence or absence of angioinvasion were also recorded. On the basis of previous reports,21 we distinguished between single (unifocal) and multiple (multifocal) lesions; the latter were further subdivided in contralateral, ipsilateral, and bilateral tumors.
Statistical analysis was performed based on age at diagnosis (all ages, aged < 45 years, or aged ≥ 45 years), sex (male vs female), tumor size (≤ 10 mm, 11 mm-20 mm, 21 mm-40 mm, or > 40 mm), stage of disease (pT1N0/Nx, pT2N0/Nx, pT3-pT4-N+, or M), angioinvasion (yes vs no), and focality (unifocal vs multifocal, including subclasses of multifocal lesions).
The overall incidence of thyroid tumors over the entire period of observation was evaluated as the number of new cases per 100,000 residents per year (standard was the European population/100,000 residents) and the mean annual increase (MAI) of the standardized incidence rate was calculated. Cases were divided into 2 periods of 6 years each according to the year of diagnosis; the first period was comprised of 1998 through 2003 and the second period encompassed 2004 through 2009. The frequency distribution of tumor features between these 2 periods was compared using a 2-sided chi-square test. Adjusted chi-square (Mantel-Haenszel) odds ratios and their 95% confidence intervals (95% CIs) were calculated to compare groups. The 2-sided P value as determined using the Fisher exact test and exact confidence limits were used when appropriate. The standardized rate ratio (SRR) was used to compare the mean standardized incidence between the 2 periods. Statistical calculations were performed using the Epi Info software 3.5.1 database (Centers for Disease Control and Prevention, Atlanta, Ga) and statistics software for public health professionals. Statistical significance was set at P ≤ .05.
Overall, 980 new thyroid cancers were recorded from January 1998 through December 2009. The majority of cases occurred in women (n = 745; 76%) with a female to male ratio of 3.1. The age distribution at the time of diagnosis is reported in Table 1. The sex-related composition of the data set changed with age. In subjects aged < 45 years, men were proportionally more represented for the years 2004 through 2009 compared with the years 1998 through 2003 (Table 2). An opposite trend was found for subjects aged ≥ 45 years (Table 2).
|Age, Years||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi-Square P .65731||OR||−95%||+95%|
|Age, Years||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi- Square P||OR||−95%||+95%|
|Birth to 44||24||28.2%||49||32.7%||73||31.1%||0.81||0.43||1.51|
|Birth to 44||105||39.3%||155||32.4%||260||34.9%||1.35||0.98||1.97|
The overall and sex-related distributions of incidence rates over the period of observation are reported in Figure 1. The overall incidence progressively increased from 1998 to 2002 followed by a plateau from 2002 to 2009. When the 2 periods of observation were compared, a significant increase (P < .01) in the incidence of both total (second period vs first period: SRR 99% CI, 1.40-1.99) and sex-related cases (second period vs first period: SRR 99% CI, 1.15-2.33 and 1.37-2.05 for males and females, respectively) was found in more recent years (Table 3).
|1998-2003||2004-2009||99% CI SRR||MAI 1998-2009a||P||MAI 2002-2009b||P|
The MAI values increased significantly over the entire period (P < .01), whereas they were stable or slightly decreased both for total and sex-related cases when calculated from 2002 to 2009.
pT1N0/Nx tumors represented the majority of cases in both time periods (Tables 4 and 5). No significant changes were found with regard to pathologic TNM stage distribution over time, although the frequency of distant metastases was lower in the second period (P = .035). In patients aged ≥ 45 years, the percentage of pT1N0/Nx tumors was significantly higher between 2004 and 2009 compared with the previous period (P < .04) (Tables 4 and 5).
|1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi- square P .16168||OR||−95%||+95 %|
|Patients Aged <45 Years||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi- Square P .69754||OR||−95%||+95%|
|Patients Aged ≥45 Years||.06861|
The overall distribution of nodule sizes between the 2 periods demonstrated a significant (P < .04) decrease only for those tumors measuring between 21 mm and 40 mm (Table 6). No significant changes were observed for other size categories. More specifically, no changes in tumor size within the pT1N0/Nx stage were recorded (data not shown).
|Diameter||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi- square P .06663||OR||−95%||+95%|
Data regarding focality are reported in Table 7. The rate for unifocality was 67% and that for multifocality was 33%. A significant increase in multifocal lesions regardless of tumor site (P < .02) was found in the second compared with the first period (Table 7). When multifocal lesions were stratified further, a significant increase in the prevalence of contralateral tumors was found in the second compared with the first period (P < .01), with no significant changes noted for the other groups (Table 7). All major histotypes were found to have an increase in multifocality during the second period, although the statistical significance was only reached by TCV-PTC (8.3% compared with 43.4% for the first vs second period, respectively; P < .05) (data not shown).
|Focality||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||P .03431||OR||−95%||+95%|
A slight, although not significant, increase in angioinvasion was found in the period between 2004 and 2009 (9.82% compared with 11.55% for the first vs second period, respectively) (data not shown).
A higher incidence of all major histotypes was found over the entire period with the exclusion of FTC and anaplastic/undifferentiated carcinomas. The most significant increases were found for TCV-PTC (SRR 99% CI, 1.93-8.70) and Hurthle cell carcinoma (SRR 99% CI, 1.17-8.14) (Table 8). When incidence rates were evaluated after 2002, only TCV-PTC and Hurthle cell carcinoma demonstrated a significant increase (Table 8).
|Average Annual Age-Standardized Incidence Rate (European Population)||99% CI of Standardized Rate Ratio (B)/(A)||Average Annual Increase in the Age-Standardized Incidence Rate and Significance of Trend (Critical Values of the t Distribution With n-2 df)|
|Hurtle cell carcinoma||0.27||0.84||1.17-8.14||0.075||.009||0.124||.020|
When the percentage of histotypes was calculated and compared between the 2 periods, only TCV-PTC was found to be significantly (P < .01) increased in more recent years (Table 9).
|Histotype||1998- 2003, No.||1998- 2003, %||2004- 2009, No.||2004- 2009, %||Total||% Total||Chi- square P .00532||OR||−95%||+95%|
No changes in T or N classification according to histotypes were noted between the 2 periods of observation (data not shown).
This population-based study, performed in a high-incidence area with a moderate iodine deficiency over a 12-year period (1998-2009), confirms previous reports from several countries that the incidence of thyroid cancer has recently increased. In the province of Parma, thyroid cancer incidence continuously increased from 1998 through 2002 and stopped afterward with a nonsignificant MAI of standardized incidence rates from 2002 to 2009. Overall standardized incidence rates over each 6-year period (1998-2003 vs 2004-2009) were 12.6 and 21.3, respectively, with similar proportional increases noted in men and women. These figures are higher than those recently reported for the Italian population in a survey of the period between 1991 to 200522 and nearly twice as high as those reported in a previous study from the period between 1998 and 2002.11
The majority of tumors were classified as pT1N0/Nx, with no significant differences noted between time periods. However, in patients aged ≥ 45 years, the percentage of pT1N0/Nx tumors significantly increased in more recent years. According to the TNM classification, age 45 years is a critical cutoff point for staging thyroid tumors because tumor aggressiveness is generally considered to be higher in older patients.23 The finding that the incidence of pT1N0/Nx tumors increased during the period between 2004 and 2009 in older subjects suggests that, despite an increased incidence, tumors are diagnosed earlier or are characterized by a less advanced stage of disease at the time of diagnosis. These data are in agreement with those recently reported by Elisei and et al, who reached the same conclusions in a larger series of cases and using a different staging system.24
Approximately 52% of cancers measured ≤ 10 mm, with no differences noted between the periods of observation. Variations in tumor size over time may indicate that higher incidences reflect time bias detection rather than a true increase in the number of cases. Some authors have suggested that the increase in incidence is limited to small tumors,3, 24 an observation that has not been confirmed by other studies and by the current study data.15
The vast majority of cases in the current study were unifocal, with a 33% prevalence of multiple tumors and a 22% frequency of contralateral disease. The number of multifocal tumors increased between 2004 and 2009. These figures are within the range reported in the literature,21 although a high variability has been documented among studies, most likely because of differences in populations, including genetics and environmental factors. The increase in multifocal lesions was found to be statistically significant for TCV-PTC only, although a positive trend was documented for other histotypes, especially FV-PTC. It remains controversial whether multifocal thyroid tumors are clonally related25, 26; nonetheless, they are usually considered to be an indication of intraglandular spread and to represent a risk factor for local recurrence or metastases, with the exclusion of multifocal papillary microcarcinoma.23 Data regarding the size of multifocal foci were not available in all cases and therefore, we cannot assess whether an increase in multifocality corresponds to more severe disease.
No statistically significant difference was found with regard to the prevalence of angioinvasion over the study period. Only a slight, nonsignificant, positive trend was found in recent years. Altogether, angioinvasion was detected in 11% of cases, a percentage that is higher than the 3% figure recently reported by Mete and Asa in a retrospective analysis of 4000 cases of thyroid carcinoma.27 Differences in the type of studies performed (ie, population-based vs non–population-based studies) and in the criteria used to define angioinvasion may explain this discrepancy.
In keeping with previous reports,3, 4, 16 we found that changes in incidence were accounted for by WD thyroid carcinomas. Among these tumors, PTC, but not FTC, was found to be increased, an observation that is in agreement with other reports.3, 28 The relative contribution of FTC and PTC to the determination of changes in the incidence of WD tumors is controversial and there appears to be no clear explanation of this phenomenon. It may depend on differences between studies, such as the number of cases, the genetics of the different populations, and the iodine content of the diet, which may affect the percentage of histotypes.
The relation between iodine intake and the pathogenesis of thyroid carcinoma is complex. Experimental animals who are fed an iodine-restricted diet are more likely to develop thyroid cancer.29, 30 On that basis, overstimulation by thyroid-stimulating hormone (TSH) was considered to play a major role in the tumorigenesis of thyroid carcinoma, especially FTC. However, recent studies have shown that the serum levels of TSH are in fact not increased or even lower in persons with mild-to-moderate iodine deficiency.31 Conversely, PTC is more prevalent in iodine-sufficient areas32 and its frequency increases after iodine prophylaxis,33 a phenomenon also accompanied by a decrease in PTC size and an attenuation of malignant phenotype.34-36 Iodine deficiency-associated thyroid cancer has been associated with a specific molecular basis; RAS mutation in particular was found to be more frequently present in FTC from iodine-deficient areas than that diagnosed in regions with sufficient iodine intake.37 It has also been suggested that iodine can prevent the progression of differentiated thyroid carcinoma to anaplastic carcinoma by interfering with oncogene expression or the mutation of tumor suppressor genes such as BRAF, ERK, RAS, and p53.38, 39 Although the geographic area of the current study is considered to be mildly to moderately iodine deficient, we did not measure urinary iodine concentrations and therefore we cannot address the role of iodine deficiency in the observed changes in tumor incidence.
Incidence reports of thyroid cancer mainly consider 4 principal classes (ie papillary, follicular, medullar, and anaplastic/undifferentiated). Data regarding the incidence of the so-called aggressive variants of WD thyroid cancer, such as TCV-PTC or Hurthle cell carcinoma, are scanty. These variants are not included in studies because of their small number; therefore, the question of their impact on the incidence of thyroid tumors remains to be elucidated. A novel finding of the current study was that the incidence of TCV-PTC and Hurthle cell carcinoma significantly increased over the entire study period. Furthermore, TCV-PTC and Hurthle cell carcinoma were the only histological types to demonstrate a significant annual increment after 2002.
TCV-PTC is considered an aggressive variant of PTC19 that initially was described in 197640 and gained wider recognition within the last decades after a large number of clinical, pathologic, and molecular studies.19 Some authors have suggested that TCV-PTC may be underdiagnosed, despite the vast amount of literature on the subject,19, 41-43 and this may have affected the relative frequency of this entity in several series. Hurthle cell carcinoma is classified by the World Health Organization as a variant of follicular carcinoma44 with a low prevalence.45 Although considered to be no more aggressive than usual FTC of a comparable stage,46, 47 a more severe clinical behavior has been reported with a higher rate of distant metastases compared with other differentiated cancers.44, 48, 49
A recent report on a large series of Italian patients diagnosed with differentiated thyroid cancer for whom long follow-up times were available has shown that the increased incidence observed in recent years was associated with an improved prognosis.24 In that study, an advanced stage of disease and older age at the time of diagnosis were found to be the most significant prognostic factors.24 However, no separate analysis was performed for TCV-PTC and Hurthle cell carcinoma and the study was not population based. At the current time, we cannot provide any evidence of the impact on mortality of the observed changes in the incidence of differentiated tumor variants. Nonetheless, it might be of interest to include these specific histotypes in future incidence studies given their clinical correlations and different genetic bases.
In the population examined in the current study, an increased incidence of thyroid tumors was noted to occur between 1998 and 2009 in both sexes, although stable standardized incidence rates have characterized the most recent years. Differentiated thyroid carcinomas accounted for this increased incidence; aggressive variants of basic histotypes demonstrated the highest increase.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.