EDITORIAL
THYROID Volume 20, Number 6, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2010.1647
Iodine and Anaplastic Thyroid Carcinoma Peter P.A. Smyth
A
s programs of iodine prophylaxis have been implemented in many European countries in the recent past, the report of Besic and colleagues (1) about associated alterations in the frequency of anaplastic thyroid cancer (ATC) is particularly timely. Alterations in dietary iodine supply have been shown to result in changes in the presentation of a variety of thyroid disorders (2). These include hyperthyroidism, which can present as toxic nodular goiter when the iodine supply is increased in a previously iodine-deficient population ( Jod Basedow), or hypothyroidism as a consequence of disruption of thyroid hormonogenesis when a significantly increased amount of iodine is ingested (Wolff–Chaikhoff effect). Even small changes in iodine supply have been shown by Laurberg and his colleagues (2) to alter the prevalence of disorders of thyroid function. These reported changes in the presentation of thyroid disorders do not only apply to altered thyroid function. Many studies have shown that the rate of differentiated thyroid cancer (DTC) presenting in the follicular (FTC) or anaplastic histologic form was relatively more frequent in areas of iodine deficiency, while the papillary form (PTC) predominated in iodine-replete populations (3). What is less clear is whether the overall rate of thyroid cancer is influenced by the dietary iodine status of a population (3,4). Although conclusive evidence exists showing that thyroid cancer rates are higher in animals fed an iodine-deficient diet and that carcinogen-induced thyroid carcinomas can be potentiated by iodine deficiency, proof of a direct causative role for iodine deficiency remains elusive (5–7). It has also been suggested that iodine administration can prevent the transformation of DTC to ATC (8). Many studies have shown an increase in the papillary form of thyroid cancer following iodine prophylaxis (5). Although the rate of ATC has been reported as being greater in areas of iodine deficiency, there have been few reports on the effect of iodine prophylaxis on ATC frequency. Besic et al. cite two conflicting reports on ATC rate from different regions of Austria (9,10). In Carinthia, the incidence was the same (9), and in Tyrol (10), the incidence was lower, when the iodization of salt was changed from 10 mg I/kg to 20 mg I/kg. The report of Besic and colleagues is in agreement with that from the Tyrol in that they noted a fall in the incidence of ATC from 3.25 per million (lower salt iodization 10 mg I/kg) to 1.9 per million (higher salt iodization 25 mg I/kg). There are always caveats, particularly relating to diagnostic methodology (5), which must be factored in when comparing epidemiological
findings for thyroid cancer incidence. However, this is probably less relevant when dealing with ATC, and Besic and colleagues detail how diagnostic criteria did not change over the two study periods in their study. While the debate continues as to the importance of iodine prophylaxis in altering the rate of all thyroid cancers, including ATC, the significance of the findings in terms of therapeutic possibilities that increasing iodine intake may diminish the frequency of ATC remains unclear. In practice, excess iodide, by inhibiting thyroid hormone production (Wolff–Chaikhoff effect), may stimulate thyroid growth via increased thyrotropin (TSH). However this effect is selflimiting because iodide is also known to suppress iodide transport via Naþ/I symporter inhibition (11). Iodide in vitro also exerts an inhibitory effect on cyclic adenosine monophosphate (cAMP) production in rat FRTL-5 cells, which in turn would limit thyroid cellular growth. Current concepts on the pathogenesis of ATC are that it derives from a goiter that evolves into a DTC such as FTC or PTC, which in turn undergoes further dedifferentiation to ATC (6). Iodine deficiency may be involved as an initial promoting factor or it may be necessary to complement the effects of some genetic factors involving gene amplifications, activations, or mutations of tumor suppressor genes such as, BRAF, RAS, ERK, or p53 (6). While there is little doubt that iodine deficiency resulting in increased serum TSH can contribute to initial thyroid tumor growth, excess iodide does not reverse the effect. It has been suggested that molecular iodine (I2) rather than I may inhibit cellular proliferation in both thyroid and breast cancer cell lines (12–14). This hypothesis is supported by evidence that inhibition of thyroid peroxidase generation of I2 from I abolished the antiproliferative effect (12). It has also been suggested that this I2–related growth inhibition may involve the action of iodolipids such as iodolactones (15). Whether these compounds in association with the systemic therapies outlined by Smallridge (16) have any in vivo therapeutic role remains an open question. The exact mechanism of action of I2 or iodinated compounds remains to be elucidated but may involve promotion of apoptosis (17). Besic and colleagues attribute the reduction in ATC incidence in Slovenia after higher iodination of salt to the longer duration of population exposure to the higher iodine levels. An interesting aspect of their report was the finding that patients diagnosed with ATC during the period of higher salt iodization were significantly younger 66.7 10.8 years
University College Dublin School of Medicine and Medical Science, Dublin, Ireland.
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582 vs. 72.2 8.7 years with lower iodization ( p ¼ 0.02). They hypothesized that the patients in the earlier (1972–1997) lower iodization grouping may have been iodine deficient for a longer time. This hypothesis remains to be confirmed because the distribution of serum TSH, at least in iodine-sufficient populations, appears to shift to higher values with increasing age (18). However, the opposite situation, TSH decrease with increasing age, has been demonstrated in iodine-deficient populations, presumably attributable to the presence of autonomous thyroid nodules. This discordance is compounded by the observation that increasing the dietary iodine supply can lead to mild increases in serum TSH (2). Despite its uncertain therapeutic provenance, there is little doubt that increasing dietary iodine intake will limit goiter and thyroid nodule formation, the formation of DTC, and possible further dedifferentiation to ATC. Promoting awareness of this fact as in the report of Besic and colleagues may stimulate further studies on a possible role for iodine in the natural history of thyroid cancer, in particular ATC, and advance efforts to improve outcome for this most aggressive malignancy.
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Address correspondence to: Peter P.A. Smyth UCD School of Medicine and Medical Science Health Sciences Building Lab C3.39 University College Dublin Belfield, Dublin 4 Ireland E-mail:
[email protected]
