Hashimoto’s thyroiditis and papillary thyroid carcinoma
There has long been a controversy in the literature about a possible link between HT and PTC. Conflicting reports continue to emerge. Some suggest a positive correlation between the two, and even a cause-and-effect relationship, whereby the activated inflammatory response present in HT creates a favorable setting for malignant transformation. The inflammatory response may cause DNA damage through formation of reactive oxygen species, resulting in mutations that eventually lead to the development of PTC. Nevertheless, it remains unclear whether: (1) HT predisposes patients to develop PTC, (2) HT is an incidental finding with concurrent PTC, or (3)HT is a part of the host tumor response system. A meta-analysis done by Jankovic (McLeod, Watters et al. 2012, Jankovic, Le et al. 2013) revealed significant differences in the prevalence and the risk ratio of PTC in HT specimens obtained via FNAB vs thyroidectomy.
In population based studies where the specimens were obtained from FNAB, the average prevalence of PTC in patients with HT was 1.20%, with an average risk ratio of 0.69. Conversely, in studies from archival thyroidectomy specimens, the average prevalence and risk ratio were as high as 27.56% and 1.59, respectively. This variability could be a result of different methods of obtaining specimens and heterogeneity in the population under investigation in terms of ethnic, geographic, and gender differences.
The prevalence and the risk ratio of PTC in patients with HT compared to those without HT are significantly higher in studies of thyroidectomy specimens, compared to studies of patients undergoing FNAB. In studies that mentioned the indications, thyroidectomy was reserved for patients not responding to thyroid suppression therapy, those with symptoms of compression, worrisome or inconclusive FNA cytology, and historic or physical findings warranting further workup and treatment (e.g., irradiation, nerve paralysis, pain, or cervical lymph node enlargement). It should be noted that the vast majority of patients with HT do not require surgery. Hence, the patients who require thyroidectomy are already at higher risk for malignancy compared to the general population with HT.
There have been a number of proposed hypotheses to explain the linkage between the two diseases. From a histological perspective, Tamimi (Tamimi 2002) assessed the prevalence and severity of thyroiditis among three types of surgically resected thyroid tumors and found a significantly higher rate of lymphocytic infiltrate in patients with PTC. However, PTC with concurrent HT is associated with female gender, young age, less aggressive disease such as small tumor size, less frequent capsular invasion and nodal metastasis, and better prognosis. Furthermore, these patients are also less likely to develop recurrence and have a higher survival rate In the study by Eisenberg et al(Eisenberg and Hensley 1989), none of the patients with a thyroid carcinoma and HT developed relapse or metastases after 74 months of follow-up. Kebebew (Kebebew, Treseler et al. 2001) demonstrated that CLT correlates with improved survival in patients with PTC but is not an independent prognostic factor. Boi et al investigated the relationship between thyroid autoimmunity and thyroid cancer in a series of FNAB of unselected and consecutive thyroid nodules. This study revealed that the positive predictive values for thyroid carcinoma in antithyroid antibody-positive and –negative nodules are not statistically significant for class III (indeterminate risk) and class IV (suspected malignancy) cytology. It should be noted that it is important to distinguish between diffuse vs focal lymphocytic infiltration around the tumor. In the studies that described the histological findings, HT was defined as diffuse lymphocytic infiltration, rather than peritumoral lymphocytic infiltration alone. The significance of this is that HT does not represent a reaction to tumor alone but is an independent chronic process. In chronic inflammation, there are reactive alterations of stroma brought on by injury from chemokines, cytokines, and growth factors that cause damage to stromal cells. This in turn may cause malignant transformation in epithelial cells, thereby resulting in tumor development. In contrast, the lymphocytic infiltrate of HT may be an immunological response with a cancer-retarding effect, contributing to a favorable outcome of PTC compared to other thyroid cancers. Moreover, the relatively high prevalence of PTC in autopsy series may represent host immune control. Interestingly, lymphocytic infiltration within or surrounding the tumor was found to correlate with the existence of CLT. This may explain the “protective” effect of CLT in PTC.
Another hypothesis for the causal relationship between HT and PTC is that elevated levels of TSH found in hypothyroid patients with HT stimulate follicular epithelial proliferation, thereby promoting the development of papillary carcinoma (Jankovic, Le et al. 2013). McLeod et al (McLeod, Watters et al. 2012) conducted a systemic review that included 5786 thyroid cancer cases in 43 032 subjects and found that serum TSH confers a greater likelihood of development of thyroid cancer (odds ratio 1.87–2.83, depending on the level of TSH). A subset of studies that was adjusted for autoimmune thyroiditis did not find this relationship between TSH and heightened odds ratio for thyroid cancer. Conversely, several authors identified a few biomolecular markers, including RET/PTC rearrangements, p63 protein, and loss of heterozygosity of hOGG1, that are potentially involved in neoplastic transformation from HT to PTC. So far, no causal genetic linkage has been confirmed.
In conclusion, the existing data provide inconsistent evidence favoring a causal relationship between HT and PTC. Population-based studies using FNAC show no significant increase of PTC in patients with HT, whereas surgical series using thyroidectomy show a heightened risk for coexistent PTC, possibly related to selection bias. Prospective studies involving a large number of subjects and long-term follow-up are needed to further elucidate the relationship. Several studies also suggest that HT appears to confer a better prognosis in patients with PTC, but more research is necessary to further investigate this. At the present time, there is no valid established criterion to identify those patients with HT at a higher risk of developing PTC. Careful observation and follow-up of HT patients is recommended, especially those with nodular variants.