Background: Previous studies have demonstrated a high prevalence of thyroperoxidase antibodies (TPOAb) and autoimmune hypothyroidism in breast cancer (BC). These studies have been performed in BC patients generally 20-30 days after mastectomy. It is known that stress may have an influence on the immune system and a relation between stressful events and the onset or worsening of autoimmune thyroid disorders has been reported by several authors. The aim of the study was to evaluate the prevalence of autoimmune thyroid disease in patients with nodular breast disease selected for surgery before any treatment. Our hypothesis was that the high prevalence of thyroid autoimmune disorders in BC is independent of stressful events represented by surgery and/or anaesthetic procedures. Methods: Our series included 61 consecutive women aged 52.8G10.2 yrs (mean ageGS.D.) with nodular breast disease selected for breast surgery: 36 out of 61 of them (59%) had BC and 25 out of 61 had benign breast disease (BBD). Controls included 100 healthy age-matched women. All patients and control subjects were submitted to clinical, ultrasound thyroid evaluation and serum-free thyroxine (FT4), serum-free tri-iodothyronine (FT3), TSH, TPOAb and thyroglobulin antibodies (TgAb) determination. Results: Mean FT3, FT4 and TSH concentration showed no differences between BC patients, BBD patients and controls. The prevalence of TPOAb in BC patients (12/36: 33.33%) was significantly higher than in BBD patients (5/25: 20%) (P!0.01) and in controls (8/100: 8%) (P!0.01). Similarly, the prevalence of TgAb in BC patients was 12 out of 36 (33.33%) significantly higher than that detected in BBD patients (4/25: 16%) (P!0.01) and in controls (12/100: 12%) (P!0.01). Of the 36 BC patients, 20 showed a diffuse hypoechogenicity of the thyroid gland to ultrasound evaluation, significantly higher than in BBD (7/25: 28%) (PZ0.03). Of the 20 BC patients who showed a hypoechogenic pattern of thyroid gland, 10 (50%) were associated with antithyroid antibodies positivity (TAb). This finding was present in two of seven BBD (28.57%) (P!0.0001). Only two controls showed focal hypoechogenicity of the thyroid gland. Generally, 24 out of 36 (66.7%) of BC and 9 out of 25 (36%) of BBD (PZ0.02) had signs of thyroid autoimmunity consistent with the hypoechogenic pattern of thyroid gland associated or not with TAb; 2 out of 36 (5.55%) of BC and 1 out of 25 (4%) of BBD patients had autoimmune hypothyroidism and no hypothyroidism was found in controls. Conclusions: The results of this study confirm the strong relation between thyroid autoimmunity and BC. This finding is independent of stressful events represented by surgery or anaesthetic procedures. The present data call attention to the usefulness of screening for autoimmune thyroid disorders in patients with nodular breast disease selected for surgery.

A high incidence of anti-thyroid antibodies (TAb) has been found in patients with breast cancer (BC). The aim of this study was to evaluate the prognostic value of TAb in a group of 47 women submitted to mastectomy for high malignancy degree BC. All patients were evaluated for thyroid disorders after breast surgery and before any anti-tumoral adjuvant therapy. Five yr after BC diagnosis 31/47 (65.9%) patients were alive (survivors group: SG) and 16/47 (34.1%) were dead (deaths group: DG). The overall prevalence of TAb was 15/47 (31.9%): 14/31 (45.1%) in SG and 1/16 (6.2%) in DG (p=0.008). Five-yr mortality was 15/32 (46.9%) in TAb- and 1/15 (6.7%) in TAb+ patients (p=0.01). Eight out of 47 (17.0%) patients had Hashimoto's thyroiditis and 7 of them (87.5%) were in SG. Estrogen receptor (ER) was measured in 43/47 (91.5%) BC specimens. ER was detected in 19/30 (63.0%) patients in SG and 3/13 (23.1%) in DG (p=0.01). Five-yr mortality was 10/21 (47.6%) in ER- and 3/22 (13.6%) in ER+ patients (p=0.008). Absence of ER expression [odds ratio (OR) 6.54; p=0.006] and absence of TAb (OR 9.37; p=0.03) were related to a higher mortality rate. TAb were detected in 8/21 (38.1%) ER- and in 7/22 (31.8%) ER+ patients; no relation was found between ER expression and TAb positivity (p=ns). Patients with ER+ and TAb+ have a better prognosis and the absence of a significant relationship between these two parameters suggests an independent prognostic role in high malignancy degree BC women.

Women with breast cancer (BC) and antithyroid peroxidase (TPO) autoantibodies (TPOAb) have a better prognosis than women lacking TPOAb. Sera from women with TPOAb displayed immunoreactivity to BC tissue by immunofluorescence that was not apparent in women without TPOAb. We hypothesize a BC/thyroid shared antigen that provides a target for humoral or cellmediated immune activity; candidates include the sodium/iodide symporter (expressed in thyroid and BC), cross-reacting epitopes in TPO and lactoperoxidase (LPO) or TPO itself. As the association is with TPOAb, we investigated TPO expression in BC, breast peritumoral tissue (PT), other tissues (tumoral and not) and thyroid as positive control. Transcripts for known and novel TPO isoforms were detected in BC (n 5 8) and PT (n 5 8) but at approximately 10 4 -fold lower than in thyroid while in non-BC tumors (n 5 5) they were at the limit of detection. TPO was expressed also in adipose tissue (n 5 17), 10 3 -fold lower than in thyroid. Full length TPO (Mr 105-110 kDa) was detected in Western blots in the majority of examined tissues; preabsorption of the TPO antibody with recombinant TPO (but not LPO) reduced the signal, indicating specificity. The same occurred with some lower molecular weight bands, which could correspond to smaller TPO transcript isoforms, present in all samples. In conclusion, TPO is weakly expressed in BC and other tissues; this could partly explain the high frequency and protective role of TPOAb in BC patients. Further studies will investigate tissue specificity, function and immunogenicity of the novel TPO variants (some BC-specific) identified.

In patients with BTD the prevalence of BC is significantly higher than the expected, showing the usefulness of screening for breast malignancy of patients with BTD.

An association between thyroid autoimmunity and breast cancer (BC) has been consistently reported, but the cause of this association is still unknown. The role of lymphocytic infiltration (LI) in breast tumorigenesis is controversial and several data suggest that in BC an increase of lymphoid cell infiltrates or a dysfunctional local immune response may be detected very early during tumor development. Chronic autoimmune thyroiditis is characterized by different degrees of LI in thyroid gland and BC cells share some antigenic properties similar to those detected in thyroid tissue, such as sodium iodide symporter (NIS) and peroxidase activity. The aim of this study was to evaluate the frequency and amount of LI in malignant and in normal peritumoral breast tissues, as expression of autoimmune morphological changes, in a group of BC patients with thyroid autoimmunity. We suppose that an increased LI in breast tissues of this group of patients may help explain the association between BC and thyroid autoimmunity. The study group included 26 BC patients with thyroperoxidase antibodies positivity (TPOAb+), 14 of them (53.8%) with Hashimoto's thyroiditis (HT), and 30 BC patients with no evidence of thyroid autoimmune disorders. Malignant and surrounding normal breast tissues were assessed for LI. The amount of LI was scored as very scanty or scanty (LI S) and moderate or marked (LI M), independently by two expert pathologists. LI S was detected in 19/26 (73.1%) BC tissues from patients with TPOAb positivity and LI M in 7 (26.9%). All BC patients with HT had LI S. LI S was detected in 25/30 (83%) and LI M in 5/30 (17%) of BC tissue from patients with no thyroid autoimmunity. The difference in the amount of LI of BC tissues in patient with or without autoimmune thyroid disorders was not significant. The LI was generally absent or very scanty in remote breast tissue in all cases. In conclusion, in breast malignancies the presence of humoral and/or clinical evidence of thyroid autoimmunity is not associated to autoimmune morphological changes of cancer and peritumoral normal tissue. The LI does not seem to have any role in tumorigenesis in patients with BC and thyroid autoimmunity.

IGF-II mRNA expression per se is not an independent predictive factor in breast cancer but may be a marker of poor prognosis when associated with other prognostic factors such as Ki-67 index and p53 expression.

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