The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1513-1517
Copyright © 2000 by The Endocrine Society
The Changing Incidence and Spectrum of Thyroid Carcinoma in Tasmania (1978–1998) during a Transition from Iodine Sufficiency to Iodine Deficiency1
John R. Burgess,
Terrence Dwyer,
Kathryn McArdle,
Paul Tucker and
Dace Shugg
Departments of Diabetes and Endocrine Services (J.R.B.) and
Anatomical Pathology (K.M.), Royal Hobart Hospital; Tasmanian Cancer
Registry (D.S.), Menzies Centre for Population Health Research (T.D.),
University of Tasmania; Hobart Pathology (P.T.), Tasmania, Hobart 7001,
Australia
Address all correspondence and requests for reprints to: Dr. John R Burgess, M.D., FRACP, Department of Diabetes and Endocrine Services, Royal Hobart Hospital, GPO Box 1061L, Hobart 7001, Australia. E-mail:
jburges{at}postoffice.utas.edu.au
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Abstract
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Exposure to ionizing radiation, changing levels of iodine nutrition,
and increased pathologic diagnosis of clinically unimportant thyroid
neoplasia have all been proposed as explanations for a worldwide rise
in the incidence of thyroid carcinoma (TC) over the past 6 decades.
Tasmania is geographically an area of endemic iodine deficiency. In
this report, we describe the spectrum of TC in a population averaging
450,000 persons during a 21-yr period that spans the communities
transition from iodine sufficiency to iodine deficiency after
discontinuation of universal iodine prophylaxis in the mid 1980s.
The Tasmanian Cancer Register was used to ascertain all cases of TC
diagnosed in Tasmania between 1978 and 1998. Histopathological and
demographic data were reviewed.
A total of 289 cases of TC were identified. Papillary TC (PTC),
follicular TC, medullary TC, and other species accounted for 62%,
23%, 4%, and 11% of cases, respectively. The age standardized
incidence rate for total TC increased from 2.45 to 5.33 per 100,000 for
females and 0.75 to 1.76 per 100,000 for males between 1978 and 1984
and 1992 and 1998, respectively. A rise in the incidence of PTC by
4.5-fold (P < 0.05) in females and 2.1-fold in
males (not significant) was the dominant change over this
period. In parallel, the proportion of follicular TC relative to PTC
fell from 0.35 to 0.17 during these years (P <
0.05). The rise in PTC incidence was, in part, due to an increase in
the occurrence of tumors 1cm or less in diameter. Nonetheless, a 3-fold
rise in incidence of larger lesions was also observed during the study
period. Forty-three (24%) PTC cases had multifocal disease, 17 (40%)
of whom had bilateral tumors. Familial (autosomal dominant) PTC was
identified in nine (5%) total PTC cases.
Prior studies have linked iodine prophylaxis to a rise in the
proportion of differentiated TC, particularly PTC. Our data suggest a
complex relationship between iodine nutrition and thyroid
tumorigenesis. Factors such as a long latency between changes in iodine
nutrition and thyroid tumorigenesis, a dose threshold for the effect of
iodine nutrition on thyroid tumorigenesis, and an interaction between
iodine nutrition and thyroidal sensitivity to ionizing radiation may
all play a role.
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Introduction
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THYROID CARCINOMA (TC) is the most
frequently diagnosed endocrine malignancy (1). Globally, age
standardized incidence rates have increased by up to 5-fold during the
past 60 yr (2, 3, 4). This increase has largely resulted from a rise in
the incidence of differentiated carcinoma, particularly, papillary TC
(PTC) (5, 6). The rise in incidence of TC has been observed across
regions of disparate geography and ethnicity (2). The cause remains
unclear. Increased exposure to ionizing radiation, changes in iodine
nutrition, and greater recognition of prevalent, yet clinically
irrelevant, thyroid neoplasia have all been postulated as contributory
(7, 8, 9, 10, 11).
Studies documenting the spectrum of TC in iodine-deficient communities
commencing iodine prophylaxis have noted a rise in incidence of PTC
relative to the other tumor types (12, 13). Although some authors have
reported a rise in the overall incidence of TC after correction of
iodine deficiency (ID), the increment in TC is, in general,
similar to that occurring contemporaneously in populations with stable
iodine nutrition (1, 3).
Additional studies are required to clarify the relationship between
iodine nutrition and thyroid tumorigenesis. In particular, longitudinal
data spanning transition from iodine sufficiency to deficiency should
establish the contributions of improved diagnostic practice,
environmental carcinogens, and iodine nutrition, to the observed
changes in the spectrum of TC.
Tasmania is an island with a population of relatively stable size and
structure. Geographically, Tasmania is also an area of endemic ID (14, 15). A number of distinct phases of iodine prophylaxis can be
identified. Potassium iodide tablets were provided to school age
children between 1950 and 1965, whereas in 1966 universal iodine
supplementation via the addition of potassium iodate to bread commenced
(14, 15). A well-documented increase in the incidence of thyrotoxicosis
occurred within months of introducing this measure (16).
Contemporaneous iodine contamination of milk supplies by iodine
residues from a newly introduced dairy disinfectant was subsequently
identified as the additional source of dietary iodine. Thereafter,
regulation of milk iodine content in conjunction with ongoing bread
supplementation provided an effective method for ensuring adequate
iodine nutrition in Tasmania (14, 15).
In 1974, iodine supplementation of bread was discontinued and,
thereafter, milk provided the primary method of community iodine
repletion. For commercial reasons, the use of iodine containing dairy
disinfectants declined in the early 1980s. Community iodine monitoring
programs documented a fall in median urinary iodine levels. Surveys of
urinary iodine excretion subsequent to 1981 have confirmed the return
of mild-moderate ID in Tasmania. During the period 1969–1981 only 4%
of school children surveyed had urinary iodine to creatinine ratios
less than 75 µg/g, whereas, during the years 1982–1985 the
percentage below 75 µg/g increased to 26% (14). Persistence of
mild-moderate ID has been confirmed by subsequent public health
studies, including a 1996 analysis in which a median urinary iodine
excretion of 42 µg/L was documented. More recently, studies have
indicated the possible emergence of ID in the other Australian states
(17).
In this report, we describe the changing incidence and spectrum of TC
in Tasmania during the years 1978–1998. This period spans the
transition of the Tasmanian population from iodine sufficiency to
ID.
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Patients and Methods
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Tasmania is an island state of the Commonwealth of Australia.
There are three major population centers located in the south, north,
and northwest of Tasmania where three quarters of the population
reside. The remainder of the population lives in a semirural setting.
Data provided by the Australian Bureau of Statistics show that during
the period 1978–1998 Tasmania’s population increased by 15% (62,000
persons) from a 1978 population of 413,538 persons. The male to female
ratio remained stable during this period, ranging between 0.98 and
1.00. Inpatient medical services are provided by one tertiary referral
hospital and eight smaller hospitals distributed throughout the
island.
All pathology services in Tasmania provide data to the Tasmanian Cancer
Registry. By statutory regulation the Registry receives notification of
all cases of cancer (excluding nonmelanoma skin cancer) diagnosed in
the Tasmanian population. Case registration has been shown to be at
least 98% complete (18). In the current study, all cases of thyroid
cancer diagnosed during the period 1978–1998 were identified by
examining the records of the Tasmanian Cancer Registry. This study has
received approval from the Data Release Committee of the Tasmanian
Cancer Registry.
A total of 298 cases of TC were registered in Tasmania between 1978 and
1998. Histopathological evaluation of tissue specimens was
predominantly undertaken by four pathology services. Review of
histopathology reports and/or allied clinical details resulted in
exclusion of nine (3%) cases that did not satisfy diagnostic criteria
for a primary TC. The remaining 289 cases of primary TC were assigned
to one of four diagnostic categories: papillary (PTC), follicular
(FTC), medullary (MTC), and other TC. To determine the comparability of
diagnoses recorded by archival reports with contemporary diagnostic
standards, original histology slides for all cases (n = 134) of
PTC and FTC diagnosed during even numbered years commencing 1978 were
sought for review by two histopathologists blinded to the original
diagnosis.
Age standardized incidence rates were estimated using the world
standard population age and gender weights (4). All incidence rates are
per 100,000 of population. Data were analyzed using the Student’s
t test for normally distributed variables and the
2 test for nonparametric data. Where
appropriate, numerical data is presented as mean ±
SEM.
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Results
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A total of 289 incident cases of TC were identified in Tasmania
during the 21-yr period spanning 1978–1998. PTC, FTC, MTC, and other
TC accounted for 180 (62%), 67 (23%), 12 (4%), and 30 (11%) cases,
respectively (Table 1
). Of the 30 cases
of other TC, 21 (70%) were classified as either anaplastic or
undifferentiated thyroid cancer. The mean age at diagnosis was
50.8 ± 1.0 yr, and the male to female ratio was 1:2.8 (Table 1).
The median year for diagnosis was 1992. The age standardized incidence
of TC (male and female) increased by 2.3-fold (from 0.75 to 1.76 per
100,000) and 2.2-fold (from 2.45 to 5.33 per 100,000), respectively,
between 1978–1984 and 1992–1998 (Fig. 1) (P < 0.05). Between
these two intervals, the Tasmanian population increased by 45,800
persons (10.7%).
The overall increase in incidence for TC resulted predominantly from a
rise in the incidence for PTC by 4.5- and 2.1-fold in females
(P < 0.05) and males (not significant),
respectively, between the periods 1978–1984 and 1992–1998 (Fig. 2). During this time, the overall FTC/PTC
ratio decreased from 0.74 to 0.24 (P < 0.005). The
rise in incidence of PTC was observed in all Tasmanian population
regions, spanning all pathology services. The increase in incidence of
TC was dominated by the rise in PTC, whereas the incidence of other
categories of thyroid cancer did not change significantly (Table 1
).
The rise in PTC incidence was, in part, due to an increase in tumors of
1 cm or less in diameter; however, a 3-fold rise in incidence of larger
lesions also occurred during the study period (Table 2).
Histopathological material from 108 patients was available for
prospective reexamination by two histopathologists blinded to original
diagnoses. This sample represented 47% of all PTCs and 34% of all
FTCs. Diagnostic reclassification occurred for five (6%) PTCs and four
(17%) FTCs (Table 3). Of the
reclassified PTCs, three were considered to be FTC and two were
classified as papillary oncocytic neoplasms. Of the reclassified FTCs,
two were considered to be PTC and one each an adenoma and anaplastic
carcinoma. Reclassifications did not alter the temporal trends observed
at the a priori examination of original pathology
reports.
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Table 3. Comparison of original and contemporary
histolopathological diagnoses for 108 cases of differentiated TC
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Nine (5%) patients with PTC had an immediate familial history of PTC
in which at least one first-degree relative was affected. This included
two pairs of monozygotic twins with concordant development of PTC.
Multifocal and metastatic PTCs were identified in 43 (24%) and 33
(18%) patients, respectively (Table 2). Seventeen (40%) patients with
multifocal PTC had bilateral tumors.
Diagnoses of PTCs were made at autopsy in eight (4%) cases. For
non-PTC carcinoma, the presence of multinodular histopathology as a
copathology in thyroid specimens remained stable during the study
period (20% vs. 21%) between 1978–1984 and 1992–1998,
respectively. During this time, the prevalence of multinodular change
occurring in association with PTC increased from 11% to 36%
(P < 0.05).
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Discussion
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There was a significant rise in the incidence of TC during the
study period. This largely resulted from an increasing incidence of PTC
in women. Although the FTC/PTC ratio diminished over this period, there
was a nonsignificant rise in the overall incidence of FTC. Changes in
pathological classification are unlikely to account for the observed
changes in TC incidence and spectrum. We have been unable to identify
any substantial modification of pathological classification to account
for our observations. This is evident from the low rate of discordance
between original and contemporary diagnoses (Table 3). Similarly,
whereas other studies have documented high rates of PTC at autopsy,
only 4% of the patients in our series had tumors found at postmortem
examination (11).
It is not possible to exclude subtle changes in clinical practice,
such as increased use of ultrasonography and fine-needle biopsy, as
contributory to the rise in PTC incidence. However, on the basis of
available anecdotal information, we believe this unlikely to fully
account for the observed increase in PTC. By way of example, despite a
rise during recent years of multinodular goiter occurring in
association with PTC, the majority of patients with combined PTC and
multinodular goiter had evidence of clinically relevant TC. Of the 39
cases of PTC associated with multinodular goiter diagnosed during the
1992–1998 period, in 8 (21%) cases the PTC was more than 3 cm in
diameter, in 11 (33%) cases it was multifocal, and in 2 (6%) cases it
was metastatic. Furthermore, even when lesions of 1 cm or less in
diameter are excluded, a 3-fold rise in the incidence of larger PTC was
evident (Table 2).
The role of iodine nutrition in the pathogenesis of TC is both complex
and controversial (7, 9, 19, 20). Comparison of incidence rates between
iodine-deficient and iodine-sufficient communities yields conflicting
results (1, 7). Relative to iodine-sufficient populations, high rates
of TC have been found in a number of iodine-deficient communities (1, 7, 19). Conversely, the populations of Hawaii and Iceland both have
high rates of TC, as well as diets rich in iodine (1, 19, 21, 22).
High dietary iodine intake is also typical in Japan, yet similarly high
rates for TC to those occurring in Hawaii and Iceland are not observed
in this population (1, 23). Ethnic Japanese living in Hawaii, however,
have incidence rates for thyroid cancer up to 2-fold higher than those
occurring in Japan (1). Factors other than iodine nutrition have been
proposed to explain these inconsistencies (7, 24). For example, it has
been proposed that the high levels of TC in Hawaii and Iceland relate
to volcanic activity rather than iodine nutrition (24).
Case control studies have also produced contradictory findings,
iodine-rich diets having been associated with both a heightened and an
attenuated risk of TC (25, 26). Despite these conflicting results, a
relatively consistent association has been the link between iodine
nutrition and tumor histology (7, 9, 10). The incidence of FTC and
anaplastic TC is greatest in iodine-deficient populations, whereas the
converse is true in regions of iodine sufficiency (9, 12, 19, 20).
Consistent with this observation, iodine prophylaxis is associated with
a rise in the proportion of differentiated TC; so called
"papillarization" of TC (9, 12, 19, 20, 27). This is evidenced
by a rise in the proportion PTC relative to FTC (12, 13).
The observed increase in PTC incidence in Tasmania has occurred despite
the recurrence of mild ID. A complex interaction between iodine
nutrition and thyroid tumorigenesis may account for our findings. A
study by Galanti et al. (10) indicated a possible
differential effect for iodine prophylaxis on the spectrum of TC,
depending on an individual’s age at the time of iodine exposure. The
increasing incidence and predominance of PTC despite the fall in
contemporary iodine nutrition may reflect either a dose threshold for
iodine nutrition and modulation of tumorigenesis, or a latency between
changes in iodine intake and the clinical expression of neoplastic
disease.
The rise in the incidence of PTC in recent years has been most evident
in females (4.5-fold). Studies have linked TC to female reproductive
patterns, increased risk associated with increasing parity (28).
Tobacco smoking has inconsistently been associated with a raised
relative risk (29). The role of such risk factors warrants further
evaluation given the relatively gender-specific increase in PTC
incidence observed in Tasmania.
Superimposed on the steady rise in incidence of TC during the past 2
decades, there has also occurred a relatively abrupt rise in PTC during
the last 5 yr. It is possible that the current rise in PTC incidence
relates to a delayed impact of the iodine over-replacement occurring
during the late 1960s and early 1970s (14, 15). Whereas this was
associated with an acute increase in the incidence of thyrotoxicosis at
the time, it may also have primed susceptible individuals, then in
their 2nd decade of life, for subsequent development of PTC (16).
Preliminary examination of cohorts based on birth year (not presented
here) indicates possible case clustering in the 1949–1951 birth years.
Individuals born in these years would have reached adolescence during
the period when the Tasmanian community was exposed to excessive levels
of dietary iodine. We speculate that a 15- to 20-yr latency following
exposure of susceptible individuals to iodine excess during adolescence
might account for the current pattern of thyroid disease. If this
speculation is correct, a fall in the incidence of PTC is to be
expected over the next 5 yr.
Exposure to fallout from nuclear weapon testing is an alternate
explanation for a birth cohort effect for TC incidence (30).
Atmospheric nuclear weapon testing occurred both in Australia and
elsewhere in the South Pacific between 1950 and 1962 (31). The highest
predicted susceptibility to TC following exposure to this fallout maps
to birth years 1945–1962. Children born during this period were
potentially exposed to fallout at a time when community iodine
nutrition was suboptimal, enhancing the risk of thyroidal exposure to
ionizing radiation. The latency for TC developing in this context may
be many decades (30). Medical uses of ionizing radiation also warrant
consideration as an etiological factor in the Tasmanian population,
although available case data do not indicate this to be the explanation
for the observed rise in PTC.
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Conclusion
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The increased incidence of PTC observed in this study has occurred
despite a fall in iodine nutrition and recurrence of mild ID. Possible
explanations include a long latency for the impact of changes in iodine
nutrition on thyroid tumorigenesis and a dose threshold for the effect
of iodine nutrition on thyroid neoplasia. Additional factors, such as
exposure to ionizing radiation and subtle changes in clinical and
diagnostic practice, may also have influenced the observed change in
the spectrum of TC.
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Acknowledgments
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We gratefully acknowledge the assistance of Sr. Rachel Saunders
in data collation.
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Footnotes
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1 Research grants from the State government of Tasmania and the
Cancer Council of Tasmania have supported this project. This work was
presented in part at the 42nd meeting of The Endocrine Society of
Australia, Melbourne, Australia, 1999. 
Received June 10, 1999.
Accepted January 6, 2000.
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Abstract
Introduction
