The epidemiology and aetiology of a rising incidence of papillary thyroid carcinoma in Tasmania

Thyroid carcinoma (TC) is the most prevalent endocrine malignancy. Four main subtypes are recognised - papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, medullary thyroid carcinoma and anaplastic thyroid carcinoma. PTC accounts the majority of diagnoses. As is typical of most thyroid disorders, women are affected approximately four times more frequently than men. The absolute incidence of PTC varies significantly between geographic locations and racial groups, suggesting an important interaction between environmental and genetic risk factors. Aside from relative differences in absolute PTC incidence between different communities, a significant increase in PTC incidence has also been observed within many populations over recent decades. In some jurisdictions the incidence of PTC has increased more than two fold. Industrialised as well as developing nations have been affected. Possible explanations include artifact due to changes in both medical practice and tumour registration by Cancer Registries. However, a true biological change in PTC pathogenesis and incidence is also possible. Family history and exposure to ionizing radiation are the most clearly established risk factors. Iodine nutrition may also influence the risk of thyroid malignancy, both by modulating thyroidal radioiodine uptake as well as by directly influencing the pathogenesis of benign and malignant thyroid disease. My research reviewed Australian national TC incidence trends during the 1980's and 1990's, identifying a rise of between 4.0% and 24.7% per annum in the incidence of PTC across the Australian states. This rise was most obvious in the eastern seaboard states, mapping to those states with the lowest historical levels of iodine nutrition. The greatest rise in PTC incidence was observed in Tasmania, an island State of the Australian Commonwealth, where PTC incidence increased by 24.7% per annum. Tasmania has a well-characterised history of iodine deficiency and a stable demographic structure with a centralised health care system and established Cancer Registry. These characteristics provided an opportunity for evaluating in detail the basis for the more widely observed rise in PTC incidence. A detailed evaluation of Tasmanian Cancer Registry data over the 21-year period 1978-98, confirmed that the incidence of PTC had increased by 450% in females and 210% in males. Furthermore, validation of Cancer Registry case ascertainment by de novo reconstruction of a Tasmanian TC data-set (using source pathology and hospital documentation), confirmed 93.9% completeness for existing PTC case ascertainment by the Cancer Registry over the study period. Similarly, a review of histopathological diagnoses did not demonstrate any significant change in the morphological classification of TC during this time. These findings exclude changes in either case reporting or tumour classification as the primary cause for observed PTC incidence trends. The key trend underlying observed changes in PTC incidence was an increase in diagnosis of small (‚Äöv¢¬ß1cm) PTC that were asymptomatic at the time of resection. Further studies evaluated the prevalence of both clinical and subclinical (by ultrasonography) nodular thyroid disease in the Tasmanian population. Thyroid ultrasonography revealed nodules in 43.4% of individuals evaluated, the majority (88%) of whom had no previously recognised history of thyroid disease. Non-specific neck imaging therefore had the potential to identify clinically inapparent thyroid nodules. Contemporary evaluation protocols for asymptomatic and incidentally discovered thyroid nodules promote the use of fine needle aspiration biopsy (FNAB) and specimen cytology. An assessment of trends for utilization of thyroid FNAB identified an increase of 17.6% per annum and 66.2% per annum for males and females respectively during the period 1988-98. As the prevalence of clinically silent PTC ‚Äöv¢¬ß1cm diameter (\occult\" PTC) is reported to be approximately 5% in thyroid nodules contemporary patterns of neck imaging and the subsequent FNAB evaluation of subclinical thyroid nodules might explain much of the recently observed rise in incidence of PTC. I further evaluated the relationship between iodine nutrition and PTC incidence. Comparison of documented changes in iodine nutrition in Tasmania during the past five decades against observed PTC incidence trends showed the increase in PTC incidence occurred during a period when the Tasmanian population was undergoing transition from iodine sufficiency to mild iodine deficiency (after the almost 30 years of optimal iodine nutrition that followed correction of endemic iodine deficiency in the mid-1960's). This observation was unexpected given much of the existing epidemiological evidence links poor iodine nutrition to a reduced proportion of PTC relative to other thyroid malignancies and a lower incidence of PTC compared to iodine replete populations. A study was undertaken to evaluate the impact of Tasmania (historically the most iodine deficient Australian state and the region with the greatest contemporary rise in PTC incidence) as a place of birth and residence on the likelihood of developing benign and malignant thyroid disease. There was a significant association for goitre and thyroidectomy with childhood lived in Tasmania. The association was non-significant for the development of TC. Therefore increased PTC incidence in Tasmania is potentially explicable on the basis of greater diagnosis of \"occult\" PTC most probably diagnosed at the time of investigation and management of benign iodine deficiency related thyroid disease. I also identified evidence to suggest an increase in the underlying incidence of clinically relevant PTC. Analysis of Tasmanian cancer registry data confirmed a 260% increase in large (>2.0cm) PTC between 1978 and 1998. Moreover it was notable that despite the rise in incidence of PTC versus FTC changes in two- five- and ten- year mortality rates for PTC remained parallel to those of FTC during the study period. As \"occult\" PTC usually exhibit a benign natural history an increase in PTC incidence solely due to greater recognition of \"occult\" PTC would be expected to produce a disproportionate improvement in survival for patients with PTC relative to FTC. Ionizing irradiation of thyroid tissue in childhood is the best characterized aetiologic factor for thyroid neoplasia. Both benign and malignant tumours are predisposed with PTC the most frequent malignant sequela. Studies suggest PTC arising after long latency following thyroid irradiation may exhibit a mutation (the RET/PTC1 rearrangement) with a prevalence higher than for PTC from non-irradiated populations. In the absence of objective radiation exposure data I attempted to use the RET/PTC1 mutation as surrogate marker for past exposure to ionizing radiation. Tasmanian PTC diagnosed between 1978 and 1998 were studied to determine the temporal trends for prevalence of RET/PTC1. However a clear relationship between PTC incidence trends and RET/PTC1 prevalence was not found. Despite this it was notable that the absolute prevalence of the RET/PTC1 rearrangement in Tasmanian PTC was greater than expected and was consistent with the prevalence in irradiated populations. Moreover a significant clinicopathological association for the RET/PTC1 rearrangement was identified. Tumours positive for the RET/PTC1 rearrangement were of larger size and more likely to exhibit lymph node metastases than those without the mutation. The role of heritable susceptibility to PTC and the potential for a founder effect influencing Tasmanian PTC incidence trends was also assessed. A family history of TC was described by 14.1% of Tasmanian patients diagnosed with PTC. Two large PTC kindreds demonstrating an autosomal dominant inheritance pattern for PTC accounted for the majority of familial cases. However the absolute contribution of autosomal dominant PTC to overall statewide incidence trends was small. A founder effect did not explain PTC incidence patterns in Tasmania. The research I have undertaken provides a useful insight into the genesis of Australian national PTC incidence trends. Whilst there is evidence to support a small increase in the underlying incidence of clinically relevant PTC the main cause for the observed rise in PTC incidence can be attributed to increased ascertainment of \"occult\" papillary microcarcinoma. The findings of my research highlight the potential adverse health consequences of inappropriate neck imaging and reinforce the importance of appropriate education for medical practitioners regarding the rational use of thyroid ultrasonography."