Both HT and PTC have a high prevalence worldwide, and these conditions may have a close relationship. Thus, there may be many patients who have both diseases simultaneously. Whether PTC represents a reactive response to HT or HT is a prerequisite tumourigenic event still remains to be determined.
In our population, 653 patients suffered from HT during the period from 2008 to 2010. Of these patients, 58.3% had co-occurring PTC, which was a higher rate than in previous reports
[8–19]. If the patients were subdivided by gender, the result was statistically significant for the females with HT. Compared with the females without HT, the women with HT were found to be approximately 30% more likely to have co-occurring PTC. Our findings in this patient population support the previous studies linking HT with PTC
[10, 13, 20].
At the molecular level, the evidence shows that HT may be a precursor of PTC. It is well known that RET was the first activated receptor-tyrosine kinase to be identified in papillary thyroid cancer. The proto-oncogene, located on chromosome 10q11.2, encodes a transmembrane receptor-tyrosine kinase with four cadherin-related motifs in the extracellular domain
. The reported overall prevalence of RET/PTC rearrangements in papillary carcinomas varies from 3% to as high as 85%, depending on the detection methods and geographical location of the patients; a reasonable range is 13–43%
[22–27]. Moreover, RET/PTC rearrangements have also been reported in the thyroids of patients with the autoimmune inflammatory condition known as Hashimoto’s thyroiditis
[28–31]. However, these findings are controversial and might reflect either PCR contamination or the presence of microscopic nodules of papillary carcinoma, as studies that have excluded these possibilities do not confirm the data
[32, 33]. Whether RET/PTC rearrangements induce HT to PTC remains unknown. The connection of RET/PTC rearrangements in HT and PTC requires further investigation.
However, several retrospective and prospective studies have found no correlation between these two diseases. Interestingly, our univariate analysis found that HT is a risk factor for PTC, whereas HT played a protective role in the multivariate analysis, which is consistent with previous reports. It is difficult to explain this phenomenon. It has been hypothesised that serum TSH levels may play an important role. Since Boalart et al. found that elevated serum TSH can be a risk factor for PTC
, many studies have replicated their results
[15, 35–41]. Thus, when considering whether HT is a risk factor for PTC, it is important to evaluate the serum TSH level. In our study, most of the patients’ serum TSH levels were evaluated before their surgeries. As Table 2 and Table 3 show, the HT patients had higher TSH levels than the patients without HT. Moreover, the patients with co-occurring HT and PTC had the highest serum TSH levels among all of the sub-groups.
It is well known that serum TSH has a trophic effect on follicular-cell-derived thyroid cancer growth. Unfortunately, the present study could not provide evidence concerning the malignant transformation of thyroid follicular cells in the TSH-cAMP pathway. Recently, genome-wide association studies (GWAS) and carefully designed candidate gene approaches have determined that the FOXE1 genetic variant, which is downstream of the TSH-cAMP pathway, is the suspected risk factor for follicular-cell-derived thyroid cancer
[42–44]. In the future, genetic studies may provide stronger evidence supporting the theory that high TSH levels cause thyroid cancer. When considering HT, it should be recognised that long-term HT can cause hypothyroidism, which elevates the serum TSH level. In China, where iodine intake is increasing, there is a high prevalence of HT and hypothyroidism in subjects with euthyroidism
. In our study, the rates of co-occurring PTC in the HT patients were higher than those in previous reports
[8–19]. Considering these results, we hypothesise that long-term HT causes elevated serum TSH, which is the real thyroid cancer risk factor. This hypothesis may explain why HT was a risk factor in the univariate analysis, whereas in the multivariate analysis, which controlled for TSH levels, HT became a protective factor. Furthermore, this hypothesis may explain why several of the prospective studies that have examined the association between HT and thyroid cancer have found negative results (i.e., because the HT patients in these studies did not have high serum TSH levels for a long period). Since TSH is a growth factor for PTC, the serum TSH could be an individual marker for each HT patient. In clinic, doctors could control the serum TSH level under a lower level in the normal range of TSH for HT patients
With regard to the clinical course, thyroid tumours associated with HT do not appear to be any more aggressive than those not associated with HT
[20, 46]. In our series of studies, we found that PTC patients with HT had less aggressive tumours than the patients with PTC only. Interestingly, the PTC patients with HT had less CLNM than those without HT (Table
3). This result conflicts with those of a previous report
. In Table
5, TSH is not a factor associated with an increased risk of central lymph node metastases in patients with PTC, which is not in agreement with Kim’s study
. The Kim’s study included only 554 patients, which was less than our patients. This might cause our different result. Furthermore, we take TSH as a constants variable, while Kim’s study considered TSH as a dichotomous variable.
Recently, Hanahan et al. proposed a new hallmark of cancer genesis: “Tumor-Promoting Inflammation.”
 This new hallmark could play an important role in the pathogenic process of co-occurring PTC and HT. In certain cases, it is evident that inflammation is present at the earliest stages of neoplastic progression and capable of fostering the development of incipient neoplasia into cancer and causing the invasion and metastasis of existing cancer
[49, 50]. It is certain that in the near future, the relationship between inflammation and cancer invasion or metastasis will be further elucidated.
Consistent with previous reports
[14, 15], our study also found that a nodule >1 cm plays a protective role in our study population (Table 4). This finding may have been due to the selection of patients for surgery. Patients with the small benign nodules are typically not sent to surgery, whereas patients with larger benign nodules, especially >4 cm, are more likely to be candidates for surgical treatment. However, in PTC patients, a primary tumour > 1 cm is a risk factor for neck metastasis (Table 5). Also, there was an interesting phenomenon that the cancer size of “PTC with benign disease” is larger than “PTC only” or “ PTC with HT”, while “PTC with benign diseas” shows less or similar invasion. This might be due to the different genetic origin of different types of PTC. The genesis of "PTC with benign nodule" might come from the benign nodule, which is less invasion
. The genesis of “PTC only” might come from the somatic mutation, which is more invasion.
In the morphological examination, an extensive relationship was shown between HT and PTC (Additional file 1: Figure S1-S4). Thus, based on the histomorphological features, laboratory findings and clinical data, the co-occurrence of PTC and HT is an interesting topic concerning thyroid cancer research and cancer hallmarks.
We also have some limitations in this study. Since our study is a retrospective cross-section study, there could be a selection bias in the incidence of PTC in HT. The number of HT patients who develop nodules was not given. Next, we could not estimate the mean time for the HT patient who would suffer from PTC. It is necessary that the basic research on raised TSH causing PTC in HT patients should be done in the future, which could provide more powerful evidence for the correlation of HT and PTC.