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


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Burgess, John Richard (2007) The epidemiology and aetiology of a rising incidence of papillary thyroid carcinoma in Tasmania. PhD thesis, University of Tasmania.

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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 (≤1cm) 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 ≤1cm 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.

Item Type: Thesis (PhD)
Keywords: Thyroid gland
Copyright Holders: The Author
Copyright Information:

Copyright 2007 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
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Available for library use only and copying in accordance with the Copyright Act 1968, as amended. Available for library use only but NOT for copying until 21/6/09. After that date, available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2007. Includes bibliographical references

Date Deposited: 25 Nov 2014 00:56
Last Modified: 01 Jul 2017 17:00
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