Yun-Chao Zhang,Ling-Li Li,Lei Qin,Bo-Qun Song,Na Lu,Ying Zhang,Huang-Hui Xie,Yao Tang,Shi-Yu Wang,Yu-Tong Zhang

1Department of Oncology,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China.2Graduate school of Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China.

Abstract Background:Single or multiple thyroid nodules and uterine fibroids are the most common benign gynecologic disease.An increasing number of breast cancer are accompanied with thyroid nodules or uterine fibroids or both of them.However,the incidence of thyroid nodules or uterine fibroids in patients with different subtypes of breast cancer is unclear.Objective:To study the incidence of thyroid nodules or uterine fibroids in patients with different subtypes of breast cancer.Methods:A retrospective cohort study conducted in the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine(China)that included 1,322 female cancer survivors who went to our hospital from January 2014 to November 2019.In this study,we evaluated the frequency of thyroid nodules and uterine fibroids in breast cancer survivors in comparison with other cancer survivors.Besides,we compare the frequency of thyroid nodules and uterine fibroids among different luminal breast cancer.Results:In this study,there were 245 breast cancer survivors,including 58 cases with thyroid nodule,52 cases with uterine fibroids,17 cases with both,152 cases with none.And 1,077 other cancer survivors were collected,including 142 cases with thyroid nodule,172 cases with uterine fibroids,25 cases with both,788 cases with none.According to statistical analysis,the incidence of thyroid nodule and uterine fibroids in breast cancer patients is significantly higher than that in non-breast cancer patients(P＜0.01 and P＜0.05).Between the molecular classification of breast cancer,among 245 BC patients,58 were combined with thyroid nodule,including 57 cases of luminal-A type BC and 22 cases of combined thyroid nodule;101 cases of luminal-B type BC and 20 cases of combined thyroid nodule;50 cases of HER2-positive over expression type BC and 13 cases of combined thyroid nodule;37 cases of TNBC and 3 cases of combined thyroid nodule,Patients with luminal-A BC have a higher incidence of thyroid nodules compared to other types of BC.Among 245 BC patients,there were 52 cases with uterine fibroids,including 57 cases of luminal-A type BC,5 cases with uterine fibroids;101 cases of luminal-B type BC,32 cases with uterine fibroids;50 cases of HER2-positive over expression type BC,11 cases with uterine fibroids;37 cases of TNBC,4 cases with uterine fibroids.Luminal-B breast cancer is more likely to suffer from uterine fibroids than other types of breast cancer.In addition,breast cancer patients with both thyroid nodules and uterine fibroids had significantly higher luminal-B than other subtypes.Conclusions:This study demonstrates that breast cancer women have a significantly greater incidence rate of thyroid nodules and uterine fibroids,and is higher at Luminal A or Luminal B.We consider these findings may contribute to the identification of liver channel of foot jueyin following underlying this disease association.

Keywords:breast cancer;thyroid nodules;uterine fibroids;the meridian of Foot Jueyin

Background

Breast cancer is the most common cancer among global human and ranks as the second leading cause of cancer death among women.It is is the first common cancer in the world by far[1].Breast cancer accompanies thyroid nodules with a high frequency,and the incidence of thyroid cancer is a known risk factor for breast cancer[2].The association of thyroid cancer and breast cancer was first reported by Chalstrey and Benjamin in 1996 after observing that 8 of 92 thyroid cancer patients were subsequently diagnosed with breast cancer[3].

Thyroid nodules are very common and can be found in 67% of the general population.About 5%of thyroid nodules are malignant lesion.Ultrasonography of the thyroid is more sensitive than palpation and detects thyroid nodules in 19 to 67%of the population among persons without suspected thyroid disease[4].The prevalence of thyroid nodules seems to increase with age in women(from 20%to 46%)[5].The prevalence of thyroid nodules has increased significantly in China in recent years.

Uterine fibroids are the most common benign gynecologic disease.In a recent systematic review,prevalence estimates range from 4.5%to 68.6% at reproductive age.The precise causes remain obscure;researchers have found that the main inducing factor of uterine fibroids is associated with estrogen and estrogen receptors[6].Pathologies of the uterus and breast,including endometrial cancer,uterine fibroids,and breast cancer,are highly associated with estrogen and are considered to be a risk factor.

The coincidence of thyroid nodules and breast cancer remains controversial;most studies have evaluated the association between breast cancer and thyroid disorders.However,the relationship between thyroid nodules,uterine fibroids,and breast cancer is unclear.In this study,we aim to examine the association of thyroid nodules and uterine fibroids with breast cancer compared to a cross-sectional study comprising 1,322 Chinese cancer patients.

Methods

(1)Patients:This cross-sectional study included 1,322 Chinese cancer patients diagnosed according to standard criteria,undergoing their observation at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,China,from January 2014 to November 2019.The study was approved by the Research Ethics Committee of First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,China.Written informed consents were obtained from the patients before participating in this study.(2)The inclusion criteria included:(a)All non-breast cancer and breast cancer patients were female;(b)All the non-breast cancer patients had a clear pathological diagnosis.(c)Breast cancer was diagnosed by pathology with complete molecular typing data,ER,PR and HER2-positive were determined by immunocytochemical method on tissue frozen sections of breast cancer;(d)All women were examined by ultrasound(HDI 3,500,detector C9-5ICT)of the breast and thyroid gland for the detection of thyroid nodules and uterine fibroma.(e)The patient’s age is less than 75 years old;(f)Complete clinical and follow-up data are available.The exclusion criteria included the following:a second primary tumor;Incomplete clinical and follow-up data.(3)Statistical analysis:Chi square test was used for counting data in this study.The pearson product-moment correlation coefficient,with the two-tailed test of significance,was used to assess the correlation studied relationships.Correlations with a critical value ofP＜0.05 were considered significant.All statistics were performed using SPSS for Windows,version 22.

Ethical standards

The experimental approaches used in the present manuscript comply with the current law of China.

Results

Basic information about the patients

Concerning age,BMI,cardiovascular risk factors,marital,menopausal status,smoking habits and drinking habits,no statistically significant difference was detected between women with breast cancer and non-breast cancer,as shown in Table 1.

The incidence of thyroid nodules and fibroid is higher in breast cancer patients than in non-breast cancer patients

In this study,1,077 cases of non-breast cancer patients were collected(all are female),including 142 cases with a thyroid nodule,935 cases without a thyroid nodule,172 cases with uterine fibroids,and 905 cases without uterine fibroids.There were 245 cases of breast cancer,including 58 cases with a thyroid nodule,187 cases without thyroid nodule,52 cases with uterine fibroids and 193 cases without uterine fibroids.According to statistical analysis,the incidence of thyroid nodule and uterine fibroids in breast cancer patients is significantly higher than that in non-breast cancer patients,as shown in Table 2.

Among 245 BC patients,58 were combined with thyroid nodule,including 22 cases of luminal-A type BC and 20 cases of luminal-B type BC and 13 cases of HER2-positive BC and 3 cases of TNBC;52 were combined with uterine fibroids,including 5 cases of luminal-A type BC and 32 cases of luminal-B type BC and 11 cases of HER2-positive BC and 4 cases of triple negative breast cancer(TNBC);152 were combined with thyroid nodule or uterine fibroids,including 32 cases of luminal-A type BC and 63 cases of luminal-B type BC and 27 cases of HER2-positive BC and 30 cases of TNBC;17 were combined with thyroid nodule and uterine fibroids,including 2 cases of luminal-A type BC and 14 cases of luminal-B type BC and 1 cases of HER2-positive BC,as shown in Table 3.

Differences in the incidence of thyroid nodules in breast cancer

Among 245 BC patients,58 were combined with thyroid nodule,including 57 cases of luminal-A type BC and 22 cases of combined thyroid nodule;101 cases of luminal-B type BC and 20 cases of combined thyroid nodule;50 cases of HER2-overexpression BC and 13 cases of combined thyroid nodule;37 cases of TNBC and 3 cases of combined thyroid nodule(Table 4).

According to the molecular classification of breast cancer,the incidence of thyroid nodule was different in four groups(P＜0.05).Further comparison between groups,the incidence of thyroid nodule in luminal-A type BC patients was higher than that in luminal-B type BC patients and TNBC patients(P＜0.05).There was no significant difference between the incidence of thyroid nodule in luminal-A type BC patients and that in HER2-overexpression BC patients(P＞0.05).There was a difference between the incidence of TNBC and HER2-overexpression thyroid nodules(P＜0.05).There was no significant difference between the incidence of thyroid nodule in the other two types BC patients.Analysis showed higher incidence of thyroid nodules in luminal-A BC patients,as shown in Table 5.

Differences in the incidence of uterine fibroids in breast cancer

Among 245 BC patients,there were 52 cases with uterine fibroids,including 57 cases of luminal-A type BC,5 cases with uterine fibroids;101 cases of luminal-B type BC,32 cases with uterine fibroids;50 cases of HER2-overexpression BC,11 cases with uterine fibroids;37 cases of TNBC,4 cases with uterine fibroids,as shown in Table 6.

According to the molecular classification of breast cancer,the four groups were statistically different in the incidence of uterine fibroids(P＜0.01).Further comparison between groups,the incidence of uterine fibroids in patients with luminal-B was higher than that of luminal-A(P＜0.01)and triple negative(P＜0.05),and there was no statistical difference with HER2-overexpression(P＞0.05).There was no significant difference in the incidence of the other three types of uterine fibroids(P＞0.05).Analysis showed a higher incidence of uterine fibroids in BC patients with luminal-B,as shown in Table 7.

Table 1 Demographics of breast cancer and non-breast cancer data

Table 2 Thyroid nodules and uterine fibroids conditions between breast cancer and non-breast cancer

Table 3 Thyroid nodules and uterine fibroids conditions in different luminal breast cancer

Table 4 Distribution of thyroid nodules in breast cancer patients

Table 5 Comparison of the incidence of thyroid nodules in different molecular types of breast cancer

Table 6 Distribution of uterine fibroids in patients with breast cancer

Table 7 Comparison of the incidence of uterine fibroids in different molecular types of breast cancer

Finally,we found that among the 17 breast cancer patients with both thyroid nodules and uterine fibroids,luminal-B(14 cases)was much higher than in patients with other subtypes of breast cancer.

Discussion

Our study found that the incidence of thyroid nodule and uterine fibroids in breast cancer patients is significantly higher than that in non-breast cancer patients,and a higher incidence of thyroid nodules in luminal-A BC patients,and a higher incidence of uterine fibroids in BC patients with luminal-B.In addition,breast cancer patients with both thyroid nodules and uterine fibroids had significantly higher luminal-B than other subtypes.

To our knowledge,an essay has not been published about the association between breast cancer,thyroid nodules,and uterine fibroids.Breast cancer,thyroid nodules,and uterine fibroids are particularly common diseases of women.The association between BC and thyroid disease,or between BC and uterine fibroids has been reported in several epidemiological studies.There has not been a large sample of clinical experimental observation on the three.

Thyroid nodule is a common disease,especially in areas with insufficient iodine supply.A number of cross-sectional studies have shown that the incidence of thyroid nodules in different areas of China is 22.3%–44.02%,and the incidence of thyroid nodules in women is higher than that in men[7–9].The probability of turning into a malignant tumor is 2%–5%.Uterine leiomyoma is a common disease of female reproductive tract,and its incidence is closely related to age.It has been reported that the incidence of uterine leiomyoma increases with the age of menarche[10].Other studies have shown that the risk of uterine leiomyoma in premenopausal women increases with age[11].The risk of uterine leiomyoma was 23% lower after menarche after age of 13 compared with women before age 11[12].

The physiological and pathological changes of the breast are significantly different during pregnancy,lactation,and menopause,which are closely related to the levels of estrogen and progesterone in the body.The breast,thyroid,and uterus are all hormone reactive organs,all of which are regulated by the hypothalamus-pituitarygland axis.The changes of the hypothalamus-pituitary axis can affect multiple glands.Hormones secreted by glands or downstream organs can also act on the pituitary gland or other glands/organs through positive/negative feedback,and eventually lead to glandular co-disease.Although no consensus has been reached on the pathogenesis,more and more studies have shown that breast cancer is closely related to the pathogenesis of thyroid nodules and uterine leiomyomas.

Crowd characteristics

Thyroid nodules mostly occur in women of childbearing age,and the incidence of thyroid nodules in women is significantly higher than that in men,about 4 times higher than that in men[13].Pregnant women have a significantly increased risk of finding thyroid nodules,and nodules are usually characterized by rapid enlargement and easy malignant change,but thyroid nodules usually grow slowly in postmenopausal women,and there is no significant change in nodule volume after follow-up for 5 years[13,14].In women of childbearing age,the risk of uterine leiomyoma increases with age.However,girls who do not enter puberty do not develop uterine fibroids,and postmenopausal women are significantly less likely to develop uterine fibroids.For postmenopausal women,existing uterine fibroids usually shrink in size after menopause,and their related symptoms are alleviated[15].

Mechanism research

Thyroid hormone receptor belongs to the nuclear hormone receptor superfamily.It is distributed in breast,thyroid and other tissues.The expressed gene subtypes are divided into two types:TR-α and TR-β.Their high levels expression can inhibit breast cancer.Growth and vice versa promote the progression of breast cancer[16–18].Some scholars have studied the immunological host chemical expression of estrogen,progesterone receptors,and transmembrane protein HER2 in postoperative thyroid specimens.The results showed that ER and PR were strongly positive(more than 75%of the nucleus),and HER2 was moderately positive.In response,these three biomarkers have a positive predictive effect on the prognosis of early and metastatic breast cancer.At the same time,ER and PR expression also exist in thyroid tumor cells,which indicates that sex hormones may lead to the progression of thyroid tumors[19,20].In addition,the mislocation of sodium-potassium cotransporter may lead to abnormal expression of sodium-potassium cotransporter,leading to impaired iodine uptake,further stimulating the secretion of gonadotropins,leading to a state of high estrogen.This change in endocrine status may increase breast cancer and the risk of thyroid disease.

Modern medical research shows that uterine fibroids are sex hormone-dependent benign tumors.In the case of estrogen and progesterone alone,uterine fibroids and smooth muscle layer cells do not increase.Only when the two cooperate can they proliferate.The expression of ER and PR is the strongest in fibroids,followed by surrounding tissues.The expression of ER is significantly higher in the proliferative phase than in the secretory phase,and there is no difference in PR between the two phases[21,22].Research by Kim et al.showed that the normal endometrium is a mucosa containing a large number of different stromal cells rich in PR.Progesterone antagonizes estrogen-driven endometrial growth.Insufficient progesterone can significantly increase the risk of endometrial cancer.However,In uterine fibroids,progesterone promotes tumor growth by promoting cell proliferation,hypertrophy,and deposition of extracellular matrix.

Clinical research

Shi Yanling investigated the status of thyroid nodules and thyroid function in Chinese women with breast cancer from 2015 to 2017,and evaluated the clinical data of women with breast cancer,benign breast diseases,and normal people,suggesting that thyroid nodules are in newly diagnosed breast cancer patients[2].The incidence of in is much higher than that of normal people and patients with benign breast diseases.The incidence of thyroid nodules in newly diagnosed breast cancer patients,benign breast disease patients,and healthy people were 56.17%,43.64%,and 34.49%,respectively(P＜0.001).It is pointed out that breast diseases,especially breast cancer,may be related to the high incidence of thyroid nodules.A study also pointed out that the incidence of breast cancer in female patients with thyroid disease was significantly higher than that of the general population,and it was more pronounced in younger patients.The study also pointed out that both benign thyroid diseases and malignant thyroid tumors can increase the incidence of breast cancer rate[23].However,a study by wise showed that uterine fibroids have nothing to do with the overall incidence of breast cancer.And the positive correlation between uterine fibroids diagnosed early before age 40 and premenopausal breast cancer needs to be confirmed in future studies[24].

This retrospective study showed that compared with other malignant tumor groups,the rates of breast cancer patients with thyroid nodules and uterine fibroids were 23.67%(58/245)and 21.24%(52/245),respectively,significantly higher than other malignant tumors Group 13.18%(142/1077)and 15.97%(172/1077)(P＜0.05);and this study confirmed that the molecular classification of patients with Luminal A breast cancer,the incidence of thyroid nodules was 38.60%(22/57),which is significantly higher than that of non-Luminal A patients,19.15%(36/188)(P＜0.05);in breast cancer patients whose molecular classification is Luminal B type,the incidence of uterine fibroids is 31.68%(32/101),It was significantly higher than 13.89%(20/144)of patients with Luminal B type.As we all know,Luminal A breast cancer patients are positive for ER and/or PR,negative for HER-2,and ki-67＜14%.Combined with the conclusions of the study,it seems to indicate that ER and/or PR are expressed and the degree of malignancy of breast tumors is low.Patients with thyroid nodules have a higher probability of developing thyroid nodules,and the expression of HER-2 is not closely related to the incidence,which indirectly indicates that the onset of thyroid nodules may also be regulated by ER/PR;Luminal B breast cancer patients.The higher risk of uterine fibroids seems to indicate that the occurrence of uterine fibroids is positively correlated with theexpression of ER,PR,and HER-2,and the higher the degree of malignancy,the stronger the clinical susceptibility of tumor patients.

We consider these findings may contribute to the identification of liver channel of foot jueyin following underlying this disease association.From the anatomical position,thyroid is located on both sides of thyroid cartilage and trachea ring in front of neck,breast is located in front of chest.According to the circulation of the Liver Meridians of Foot-Jueyin,thyroid and breast are located on it.The lesions of Jueyin meridian can affect thyroid and breast.Refer to the classic works of traditional Chinese medicineLingshu meridian(Warring states,Huang Di):The Liver Meridian of Foot-Jueyin originates from the clustered hair on the back of the big toe.It travels along the dorsum of the foot to 1 cun in front of malleolus,ascending along the medial aspect of tibia and going back of the Spleen Meridian of Foot-Taiyin 8 cun above the medial malleolus.It passes through the medial of knee and goes along the medial of thigh into the pubic hair,surrounding the genital area and reaching the abdomen.It runs alongside the stomach and enters the liver,its pertaining organ,and connects with the gall bladder.Then it traverses the diaphragm and distributes in the chest and hypochondrium.After that it goes along the back of the throat,up into the nasopharynx,connecting the eyes and going from the forehead.At the end,it links with the Governor Meridian at the top of the head.All of the above results indicate that breast cancer and thyroid nodules,uterine fibroids are probably related to each other,but it still need further investigation.According to the circulation of the Foot Jueyin liver meridian,small bupleurum decoction can soothe liver and relieve depression,adjust qi to treat breast cancer,thyroid nodules,uterine fibroids.We had achieved satisfactory effect.

In conclusion,the present findings call attention to the usefulness of screening for thyroid nodules and uterine fibroids in Chinese breast cancer patients.Further studies are needed with a large case-study to estimate the real impact of this disease association and its clinic significant factors.

Limition

The sample size of breast cancer patients is small and the relationship between the grade of thyroid nodules and the degree of uterine fibroid size and the type of breast cancer needs to be explored.

Conclusion

This study demonstrates that breast cancer women have a significantly greater risk of thyroid nodules and uterine fibroids,which is higher at Luminal A or Luminal B.We consider these findings may contribute to the identification of liver channel of foot jueyin following underlying this disease association.