Association between benign thyroid disease and breast cancer: a single center experience

Breast cancer (BC) is the most common malignancy in women and the second most common cancer overall. Over 2 million new cases were diagnosed in 2018, accounting for almost 25% of cancer cases among women [1]. Although hereditary and genetic factors account for 5–10% of BCs, nonhereditary factors are more commonly involved in geographical and ethnic differences in incidence [2‐6]. In this context, the relationship of BC with thyroid disease (TD) has been widely investigated. However, data are still controversial and, although almost every form of TD, including autoimmunity disorders and thyroid cancer, has been identified in association with BC, no convincing evidence exists of a causal role for TD in BC [2‐6].

A recent meta-analysis performed by Hardefeldt et al. [7] found that patients with autoimmune thyroiditis presented an increased risk of BC (OR 2.92) and subgroup analysis identified a significant association with both anti-TPO and anti-TG thyroid antibodies. Although the exact mechanism linking BC and TD has not been found yet, several hypotheses have been postulated. The possible interactions between thyroid gland and breast tissue may be based on the common property of both epithelial tissues to concentrate iodine by means of a sodium/iodine symporter (NIS), as well as on the presence of TSH receptors in fatty tissue, which is abundant in mammary glands [6]. Alternatively, since estrogen receptors have been identified in abnormal thyroid tissue cells, a reversal in the relationship with BC acting as a trigger for thyroid dysfunction cannot be excluded [3‐6]. Additionally, some endocrine stimuli may exert a simultaneous action on both breast and thyroid gland, determining the coincidence of mammary and thyroid disorders [2‐7].

Aim of this study was to evaluate the prevalence of TD in a consecutive series of patients treated for primary BC in order to assess any possible association in terms of clinical presentation, management, and oncologic outcome.

Between January 2014 and December 2016, 823 patients were treated for BC at the Breast Unit of Trieste University Hospital. Clinical data and information recorded from patients charts as well as radiology and pathology reports were retrospectively reviewed to assess for the following inclusion criteria:

Patients with recurrent BC, patients with metastatic BC, and patients with histopathological diagnosis of lymphoma or sarcoma of the breast were excluded from the analysis.

According to these inclusion criteria, the study population consisted of 793 patients.

Between January 2014 and December 2016, 823 patients were referred for BC at the Breast Unit of Trieste University Hospital. Of these, 793 patients were eligible for the purposes of this study.

The cohort consisted of 786 (99%) women (mean age 66 ± 14 years), and 7 (1%) men (mean age 71 ± 12 years). Among the female population, 30 patients presented bilateral BC. Overall, 716 (87%) patients underwent breast surgery and 107 (13%) patients were not considered for surgery because of severe comorbidities and thus medically treated with hormonal therapy. BC molecular profile was reported in 754 (95%) patients, while no information were available in 39 (5%) cases because BC diagnosis was made by on FNA cytology.

Information about thyroid function was recorded in 779 (98%) BC patients. Of these, 161 (21%, 160 women and 1 man) presented both BC and TD, 151 (93.8%) of them showed a benign TD and 10 (6.2%) presented malignant TD. Concerning data for thyroid cancer, mean age at the time of diagnosis was 65 ± 13 years and tumor subtypes were classified as follows: 8 papillary thyroid carcinomas, 1 follicular thyroid carcinoma, and 1 medullary thyroid carcinoma.

Among the 161 BC patients with concurrent TD, 88 (55%) patients had hypothyroidism, 19 (12%) patients showed hyperthyroidism, and 54 (33%) patients had normal thyroid function.

Thyroid autoimmunity was identified in 51 (32%) patients out of 161 cases of BC with concurrent TD. Table 1 shows the distribution of different TDs according to thyroid function.

BC and TD have a well known epidemiological impact among the world population. Both pathologies have greater incidence in women than in men and an increasing number of cases has been diagnosed in recent years. The possible correlation between BC and TD has been widely discussed in literature, but data remain still controversial [5, 7]. Some studies have shown an increased prevalence of BC in patients with benign TD [4], but a clear relationship between hormonal status and serum thyroid antibodies has not been demonstrated yet [5].

Several hypotheses have been postulated on the mechanism linking TD and BC. Some Authors showed that the absorption and oxidation of iodine may play an important role in the development of BC, which is known having a greater incidence in iodine-deficient geographic areas [11‐14]. Another possible interaction may be based on the presence of a sodium/iodine symporter in both the thyroid and breast tissue [15]. In this context, Tazebay et al. [16] demonstrated that there is an increased sodium/iodine symporter expression in thyroid and breast cancer tissues compared to healthy breast tissues. Consequently, this overexpression may play a role in the development of targeted therapies and screening programs for BC. The possible interaction between thyroid and mammary glands can also be explained by the presence of TSH receptors in the adipose tissue of mammary gland. In 2006, Conde et al. [17] showed that pathological samples of non-invasive BCs there were many more thyroid receptors α (TR-α) than in pathological samples of invasive BCs. Furthermore, Jerzak et al. [18] found that BC patients overexpressing this type of receptors showed a better outcome.

The present retrospective analysis aimed to assess the correlation between TD and BC with particular regard to different variables, namely menopausal status, BC molecular profile, and BC staging and grading. According to the results of this study, no differences were observed between pre- and post-menopausal women in terms of benign TD and/or altered thyroid functional status.

Differences was observed regarding autoimmune thyroiditis, with pre-menopausal BC patients being more frequently affected by this pathology than post-menopausal BC patients (45% vs. 29%, p = 0.05). Similar results have been recently published by Chiappa et al. [19], who described an association between chronic autoimmune thyroiditis and BC diagnosed in pre-menopausal state. However, these results may not be completely comparable, since for Chiappa and colleagues post-menopause was defined as women aged > = 45 years instead of 60 years. Anyway, several other studies have shown an association between BC and autoimmune TD [20], although the underlying reasons for this correlation are still unclear. In 2001, Gogas et al. [21] demonstrated a higher frequency of autoimmune thyroiditis in subjects with more advanced BC, therefore suggesting a possible correlation between thyroid autoimmunity and a worse BC prognosis. On the other hand, Smith et al. [22] published completely different data, giving evidence of a better prognosis in patients suffering from autoimmune TD. Giustarini et al. [23] evaluated thyroid autoimmunity in patients with malignant and benign breast diseases before surgery and observed a significantly higher presence of thyroid antibodies in BC patients compared to patients suffering from benign breast disease. Recently, Muller et al. [24] found no difference in terms of 10-year survival for BC patients with or without thyroid antibodies at blood tests analysis.

In the present series, the well-known aggressive TN and Her2 positive BC subtypes were more frequently observed in pre-menopausal women (p < 0.001), although no correlation was found with thyroid autoimmunity (p = 0.26). When considering thyroid functional status, in the current study 55% of patients presented with hypothyroidism, 12% with hyperthyroidism and 33% with normal thyroid function. At statistical analysis, no significant correlation was found with the menopausal status (p = 0.49). Regarding the possible relationship between BC staging and the presence of benign TD, this study found that patients with normal thyroid function presented predominantly AJCC stage I disease (67.5%), whereas patients with hypothyroidism presented more frequently AJCC stage II-III disease (12.2%). This could indicate that a reduced thyroid function might predispose to develop a more advanced stage of BC, while a condition of euthyroidism seems to correlate with lower BC stage. In this context, Sogaard et al. [25], in a case-control epidemiological study conducted on a large cohort of Danish women, showed an increased risk of BC in women with hyperthyroidism and a slightly increased risk of BC in women with hypothyroidism. On the other hand, Angelousi et al. [26] reported in their study a lower incidence of lymph node metastasis in hypothyroid patients suffering from BC, thus suggesting that hypothyroidism might represent a protective factor in BC outcome.

As far as the correlation between BC stage and the presence of autoimmune TD is concerned, the results of this study showed that there were no significant differences in the number of patients with autoimmune and non-autoimmune TD in BC stage 0, I and II. Conversely, BC stage III disease was significantly more common among women with autoimmune TD (14.6% vs. 4.5%, p = 0,05). This result is surprisingly in contrast with literature data, because several Authors have reported a higher prevalence of thyroid peroxidase antibodies (TPO-Abs) in BC patients, underlining their potentially protective role in terms of oncologic prognosis [27, 28]. Nevertheless, this result may reinforce the hypothesis that a reduced thyroid function, present in most cases of autoimmune thyroiditis, could predispose to develop more advanced stage of BC.

Regarding the concomitant occurrence of BC and thyroid cancer, the present series recorded only 10(1.3%) cases, all women and with a greater predominance of papillary thyroid carcinoma, reflecting the high epidemiological frequency of this type of thyroid cancer.

Last but not least, when assessing for a possible correlation between BC and benign TD, the present analysis showed that the vast majority (56.3%) of women with benign TD had G2 BC while G3 carcinomas were more represented among women with hyperthyroidism (52.9%), suggesting that an increased thyroid function may correlate with a higher grading of BC. Lastly, statistical analysis showed that BC grading is independent from the presence of autoimmune TD.

The present study has a number of limitation. Being a single-center experience based on retrospective non-randomized analysis, the possibility of generalizing the results is potentially limited. Additionally, the sample size is not very large and the observation period might not be long enough. However, the study managed to confirm that there is a relationship between BC and TD, although further studies with prospective analyses and extended follow-up are required in order to elucidate the nature of this relationship. Future research might investigate the precise pathological mechanisms that correlate the two pathologies also by checking the presence of estrogen and progesterone receptors on histologic specimens of thyroid carcinomas in order to possibly identify a subgroup of patients with higher risk of developing BC.