FINAL MASTER S THESIS

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FINAL MASTER´S THESIS

Angela Fernandez Gomis

Faculty of Medicine. Nuclear Medicine Department.

Metabolic activity of normal breast tissue detected by PET/CT according to female’s age and hormonal status.

Supervisor: Ilona Kulakiene MD

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2. TABLE OF CONTENTS

5. Ethics Committee Clearance. 6

6. Abbreviations list. 7

7. Terms. 8

8. Introduction. 9

9. Aim and objectives of the thesis. 10

10. Literature review. 11

11. Research methodology and methods. 14 12. Results and their discussion. 15

13. Conclusions. 20

14. Practical recommendations. 21

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3. SUMMARY

Angela Fernandez Gomis

Metabolic activity of normal breast tissue detected by PET/CT according to female´s age and hormonal status

The aim of the research is to evaluate metabolic activity of breast tissue and detect its

relationship with female´s age and hormonal status. Three main objectives were raised in this research: to calculate metabolic activity of breast tissue on PET/CT scan, to compare metabolic activity of breast tissue with female age and to compare metabolic activity of breast tissue with hormonal status.

For this study, information of 60 women´s PET/CT scans were collected using medical records from Nuclear Medicine Department during a period of time between November 2015 and October 2016. All the patients were divided into two groups: 30 pre-menopausal women and another 30, hormonal active women.

During the study the possible effect of weight, diabetes mellitus and other diseases (Ca mammae, lung disease, lymphoma and others) on the composition of the breast and alterations on the metabolic activity of it were also checked.

For each woman a SUVmax and SUVav value of the uptake on PET/CT scan were measured. In the hormonal active group (30 women) a SUVmax mean of 1.2416 and a SUVav mean of 0.725 were obtained. On the other hand, in the postmenopausal group (30 women) a mean SUVmax of 0.8749 and a SUVav mean of 0.50166 were much lower.

The results obtained during the study show an important decrease in the metabolic activity of postmenopausal group in comparison with the hormonal active group.

It can be concluded that age is not related to the metabolic activity of the breast tissue. But this study showed that there is a strong difference of the metabolic activity of woman´s breast in hormonal active women compared to postmenopausal women. Also there is a significant evidence of the

influence of regularity of menstrual cycles of the women during the hormonal active period on the metabolic activity of breast tissue. On the other hand, obese women have lower metabolic activity of the breast tissue comparing to normal weight patients not dependant on hormonal status.

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SUMMARY IN LITHUANIAN

Angela Fernandez Gomis

Normalaus krūties audinio metabolinio aktyvumo priklausomybė nuo moters amžiaus ir hormonalinės būklės nustatyto PET/KT metodu

Tyrimo tikslas buvo įvertinti krūties audinio metabolinį aktyvumą ir įvertinti jo priklausomybę nuo moters amžiaus ir hormonalinės būklės. Šiam tikslui pasiekti iškelti trys uždaviniai: apskaičiuoti krūties audinio metabolinį aktyvumą PET/KT metodu, palyginti skirtingo amžiaus moterų krūties audinio metabolinį aktyvumą, bei palyginti skirtingos hormoninės būklės moterų krūties audinio metabolinį aktyvumą.

Šio tyrimo metu peržiūrėti 60 moterų medicininiai dokumentai Branduolinės medicinos skyriuje ir jų PET/KT tyrimai atlikti 2015 m. lapkričio - 2016 m, spalio mėnesiais. Visos pacientės buvo suskirstytos į dvi grupes po 30 pacienčių kiekvienoje: hormonaliai aktyvių ir esančių

menopauzėje.

Buvo įvertintas ir galimas viršsvorio, cukrinio diabeto ir kitų susirgimų (krūties, plaučių, limfomos ir kt.) poveikis krūties audinio metaboliniam aktyvumui.

Tyrimo metu kiekvienai iš tirtų moterų buvo išmatuota SUVmax ir SUVav vertė PET/KT vaizduose. Hormonaliai aktyvių moterų grupėje (30 moterų) SUVmax vidurkis buvo 1.2416, o SUVav vidurkis 0,725. Tuo tarpu menopauzėje esančių moterų grupėje (30 moterų) SUVmax vidurkis 0.8749 ir SUVav vidurkis 0.50166 buvo mažesni.

Gauti tyrimo rezultatai rodo ženklų krūtų audinio metabolinio aktyvumo sumažėjimą po menopauzės lyginant su hormonaliai aktyvių moterų.

Taigi, šis tyrimas parodė, kad yra akivaizdi krūties audinio metabolinio aktyvumo

priklausomybė nuo moters hormonalinės būklės. Taip pat nustatyta, kad krūties audinio metabolinis aktyvumas didesni, jei menstruacinis ciklas nereguliarus, tuo tarpu nutukusių moterų krūtų audinio metabolinis aktyvumas mažesnis lyginant su normalaus svorio moterimis.

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4. CONFLICT OF INTEREST

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6. ABBREVIATIONS LIST

Positron emission tomography/ computed tomography (PET/CT) Standardized uptake value (SUV)

Region of interest (ROI)

Maximum standardized uptake value (SUVmax) Average standardized uptake value (SUVav) 18Fluoro-2-deoxyglucose (18F-FDG)

Body mass index (BMI) Deep vein thrombosis (DVT)

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7. TERMS

Standardized uptake value (SUV) is a ratio between image-derived radioactivity

concentration and the whole concentration on patient´s body of the radioactive material. This ratio is calculated following this formula:

𝑆𝑈𝑉 = 𝑟 (𝛼´/𝑤)

Where r is the radioactivity activity concentration by PET scanner [kBq/ml] within a region of interest (ROI), 𝛂´ is the corrected amount of injected radiolabelled FDG (kBq) and w is the patient´s weight (gr.).

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8. INTRODUCTION

Breast tissue is the lactation source responsible for milk production. It is composed of glandular and fatty tissue; the glandular tissue contains glands that produce the milk and a collection of ducts that drain the milk to the nipple and the fatty tissue is located interspersed over the glandular tissue [1].

During woman´s life breast undergoes several changes till complete development is achieved. Complete maturation occurs only after first pregnancy (full-term pregnancy). After complete maturation, during pregnancy period on which several hormones are involved and after the

pregnancy especially during lactation, the effect of hormones becomes increased more significant. When menopause period starts parenchyma starts a regression loosing estrogen and progesterone causing the loss of stroma and lymphatics [2]; glandular tissue that corresponds to the

hormonal/metabolic active part of the breast is changed by fatty tissue.

Nowadays, breast cancer is the leading cause of cancer among women followed by lung cancer but become a lesser death cause due to the combination of screening with self-palpation and strict mammography studies together with the treatment that is combined with imaging techniques that evaluate the progression of the disease and the response to the treatment [3] [4]. One of the techniques that are commonly used in the progression, metastasis and control of treatment effect is the new combination of positron emission tomography and computed tomography (PET/CT) scan that allows a combination of physiology with the PET scan and an exact anatomy location of those physiologic results with the CT.

PET/CT scan is based on the intravenous administration of a radioactive material 18F-FDG (2-fluoro-2-desoxi-D-glucose) which is trapped in the tumor cells that have higher metabolic activity and better affinity to glucose in comparison to healthy cells. The increase of glucose metabolism is seen as increased uptake of 18F-FDG in the place where the tumor is located in comparison with the healthy tissue/organ [5].

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9. AIM AND OBJECTIVES OF THE THESIS

Aim:

To evaluate metabolic activity of breast tissue and detect relationship with female´s age and hormonal status.

Objective:

1. To calculate metabolic activity of breast tissue on PET/CT scan. 2. To compare metabolic activity of breast tissue with female´s age. 3. To compare metabolic activity of breast tissue with hormonal status.

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10. LITERATURE REVIEW

Anatomic, histologically and hormonal changes during women´s life

The breast is located over the pectoral major muscle under the skin; horizontally from the sternum and a middle axillary line; vertically from the 2nd clavicle till the 6-7th clavicle. It is formed from the ectoderm. At the 4-6week the breast tissue is located along the path from axillae to inguinal region being located on the upper mid part of the chest as two breast buds on the 9th week when epithelium and mesenchyme differentiate.

Anatomically is composed of 15-20 lobes which drain into small lobules that contain several numbers of alveoli where milk is produced. All the structure is arranged on circular way around the center that is the nipple. The functional unit of the breast is the terminal duct and the lobule.

On the sight of histology the breast is divided into glandular and fatty tissue. The glandular tissue is composed of the epithelial cells and the stroma; the fatty tissue is located between the breast lobules.

Thelarche (development of mature breast) begins at puberty and continues till the completion by age 20. Few years after menarche (first menstrual period) the terminal duct lobular units form but is not till the first full-term pregnancy when the breast develops entirely; if the pregnancy doesn’t occur, may never differentiate completely.

Structural changes during development, pregnancy and after with the lactation are mediated by several hormones that have a great influence on the breast composition [16]. The main hormones that interact on those processes are estrogen, progesterone, placental hormone, prolactin, glucocorticoids and oxytocin [6].

During the women´s menstrual cycle there are regular fluctuations that produce an increment of cellular proliferation during the second part of the menstrual cycle that corresponds to the follicular phase, leading to an increment of glandular volume and water content.

When the woman enters into the menopause period (around 52 years of age) or even before on the climacteric period regression of parenchyma of the breast increase and there is a loss of

endogenous estrogen and progesterone that produce the apoptosis of the glandular epithelium and loss of lymphatics and stroma; all of this is replaced by fat [7].

Menopause is the cessation of the ovarian function leading to a decrease of estrogen and progesterone having a strong influence in the composition of breast and its function mainly by the exposure of exogenous estrogen that was proved that has a strong influence on the breast composition [8].

Women breast undergoes a rapid development during all life, mainly at puberty, getting its complete maturation after the full first pregnancy and is followed by a slow regression of glandular and structural differentiation along the last period of life that is accelerated during menopause [2]. Increasing age the density of the parenchyma decreases what results into a decrease of metabolic activity of the breast.

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How is women´s life divided?

Women´s life is divided into infancy, puberty (adolescence), sexual maturation (reproductive age), climacteric period, and post-climacteric (elderly) years. In each period woman undergoes

important changes: at first woman starts the development of anatomic parts that give them their female characteristics [9].

After development of primary and secondary sexual characteristics woman enters into the reproductive age from adolescence till premenopausal period in which the sexual maturation is completed [10]. Key point during this period is menstruation, during this part of life woman is hormonal active what expose them to different disorders related to hormones misbalances, diseases-related and important changes in main sexual organs as breast, uterus and ovaries mainly. The main disadvantage at this period is the increased risk of endometriosis, ovarian and uterine cancer. During menstrual cycle the main hormones FSH/LH/estradiol/progesterone are changing their levels

characteristically producing modifications of endometrial lining and blood levels of such hormones having consequences in the mood, physical status, alterations with sleep and sometimes pain- related. Few disorders are contraceptive use-related being the most dangerous the deep vein thrombosis (DVT) and the most common the benign fibroadenoma of the breast [11].

The next period is the climacteric period; corresponds to the end of reproductive age and the beginning of the menopause (5 years before and after menopause). This part of woman´s life is characteristic for abnormal sweating, vertigo, mood changes, sleeping disturbances, hot flushes and even urinary incontinence and migraine; those alterations are caused due to de decreased estrogen secretion what induces vasomotor symptoms. Due to the deficiency of estrogen is also possible the appearance of osteoporosis (resorption of bone is increased), increased of cholesterol and

atherosclerosis [12].

The last period, the post-climacteric/elderly period, is the almost no function of ovaries which increases the risk of malignant neoplasm and is characteristic by depression, increase of comorbidities and atrophy of sexual organs as well as breast tissue and glands [13].

What is PET/CT scan and which are their principles?

Nowadays, the most common cancer among women is the breast cancer followed by lung cancer [3] [4]. Recently due to the earlier diagnosis, screening and combination therapies breast cancer has less mortality [14]. Combination of PET/CT scan is one of the main techniques for the control of the progression including metastatic manifestations and in the response to the treatment more than for diagnosis of primary tumor [15] [16].

Breast cancer is a progressive disease that easily disseminated if is not treated or not diagnosed on time [17]. Small tumors are common in early stages of the disease with greater prognosis and better treatment response [18]. Main principles for screening are self-palpation to check any presence of lumps or other abnormalities and mammography that is established as a routine screening in women between 50/74 years of age; if abnormal findings are detected during the screening women should undergo biopsy under ultrasound or MRI guidance to check histology to define presence or absence of malignancy.

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The addition of CT scan to the basic PET scan allows better understanding of the results of PET scan because it is easier to differentiate between pathologic or not pathologic uptake, to define the exact location of the lesion (accurate anatomic information) as well as the reduction of false positive and negative results. It combines anatomic and physiologic aspects of both techniques [19] [20].

The test is based on the administration of intravenous 18F-FDG (2-fluoro-2-desoxi-D-glucose) 60 minutes before the beginning of the imaging technique; both PET and CT scan are performed at the same time and the patient cannot move to ensure a valuable result. Malignant cancer cells

characteristically have a better affinity to the glucose that’s why after few steps of the metabolism of the injected modified glucose (this glucose has small amount of radioactive component) it becomes trapped producing higher uptake and giving out a characteristic image if is compared with the normal tissue image on PET/CT scan [5].

The uptake of the FDG from the tumor cells is studied with the SUV (standardized uptake value) that is a value based on the degree of uptake on a given volume. From this value we obtained SUVmax (maximum uptake value obtained) and the SUVav (average uptake value) on the breast tissue.

There is strong evidence that the implantation of CT together with PET scan is one of the best options for the study of the breast tissue mainly for metastatic affection of other tissue secondary from breast tissue. This addition ensure an important advance because it reinforce the physiological point of view of the PET which shows the changes in metabolic activity of breast tissue with age adding CT scan complete and confirm those findings with the exact anatomic imaging findings and allows to be sure if those are pathologic or not [19] [20].

It is known that with the increasing age the breast tissue that mainly is composed of glandular tissue is replaced by fatty tissue leading to decrease of metabolic and non-hormonal active tissue in the breast; all those conditions mark an important decrease of F-FDG uptake and both SUVmax and SUVav [10] [21].

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11. RESEARCH METHODOLOGY AND METHODS

Medical records of women who already underwent a PET/CT scan at the Nuclear Medicine department of HLUHS in the period of time from November 2015 to October 2016 were reviewed. From all those cases checked we selected 60 women following the next criteria: PET/CT scan should be done from entire body, diagnosis and information of woman including hormonal status, date of last menstrual period, regularity, presence of any surgery of gynaecological origin (hysterectomy,

mastectomy, uterine ablation…), glycaemia levels together with data from presence or not of diabetes treatment with insulin or oral pills, age, weight and height.

According their hormonal status women were divided into two groups, one group of 30 hormonal active women (median age, 36.3; age range, 23-54) and another group of 30

post-menopausal women (median age, 63.3; age range, 36-83). Study was based on changes of breast tissue metabolic activity (different uptake) on PET/CT scan in women of different age and hormonal status.

Patients underwent PET/CT scan due to different indications, lymphomas (n=24) from which 11 cases correspond to the post-menopausal group and 13 cases to the hormonal active group. Lung pathology was present in 14 cases out of 60 and the majority was in the post-menopausal group. Only 5 women out of 60 had breast cancer. The rest of women underwent PET/CT scan due to other types of tumours.

After selection of all patients, the PET/CT scans were reviewed. On the scan a ROI of fixed volume was drawn on both breasts in an area surrounding the nipple in every patient. A maximum and average SUV value of the ROIs were obtained. Those values obtained for each group were compared to evaluate the difference between hormonal active and postmenopausal group.

The hormonal status (menstrual period, lactation, use of hormonal therapy), glucose levels, height and weight were included to the information of each woman. The research was based on the comparison of those values obtained from the PET/CT scan (SUVmax, SUVav) together with the information of women. Body mass index (BMI) of each woman was obtained from the height and weight and compared with the breast metabolic activity to check the possibility of an interaction between woman´s BMI and breast metabolism.

Statistical analytic analysis was performed and SUVmax and SUVav were used to compare metabolic activity between hormonal active women against postmenopausal women. Comparison between both variables was performed using null hypothesis (H0): there is no difference on the metabolic activity of breast tissue between hormonal active women and postmenopausal women; and alternative hypothesis (H1): There is difference.

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12. RESULTS AND THEIR DISCUSSION

Table 1. Clinical and pathological characteristics of the patients.

Figure 1. SUVmax and SUVav of hormonal and postmenopausal women.

For the research two groups consisting of 30 women each were selected according to their hormonal status. In the hormonal active group we count on an average of 36.3 years, 2 cases of Ca mammae, 3 cases of lung pathology, 13 cases of lymphoma and 12 cases of other pathologies. After all the calculations on both breasts of each woman a SUVmax mean of 1.2416 and a SUVav mean of 0.725 were obtained.

Hormonal Active Women Postmenopausal Women

Number of patients 30 30

Age average 36.3y. 63.3y.

Ca mammae 2 3 Lung carcinoma 3 11 Lymphoma 13 11 Others 12 5 SUVmax 1.2416 0.8749 SUVav 0.725 0.5016 0 0,2 0,4 0,6 0,8 1 1,2 1,4 SUVmax SUVav

Hormonal active women Postmenopausal women

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On the other hand, for the postmenopausal group was obtained an average age of 63.3 years, 3 cases of Ca mammae, 11 cases of lung pathology, 11 cases of lymphomas and 5 cases of other

pathologies; in this group we include 3 cases of diabetes mellitus. The calculations of the uptake we obtained a SUVmax mean of 0.8749 and a SUVav mean of 0.5016.

As a result of all calculations and after comparison between both groups a significant decrease of SUVmax and SUVav of the breast tissue of the postmenopausal women was noted in comparison with the hormonal active group. This result is easily explained after all the studies that show an important atrophy of the breast along life and strongly marked with the cessation of the hormones in women´s life that predominates close and during postmenopausal age because normal hormonal breast tissue is replaced by fatty non-functional tissue resulting on a decrease of metabolic activity of breast that is presented as a decrease on the PET/CT scan uptake values [8].

Table 2. BMI values in two patient groups.

Figure 2. Influence of women´s weight on the SUVmax and SUVav.

Hormonal Active Women Postmenopausal Women

Mean BMI 24.6 (normal weight) 29.3 (Overweight)

Underweight (<18.5 BMI) 3 1

Normal weight (18.5-24.9 BMI) 16 6

Overweight (25-29.9 BMI) 5 9 Obesity (≥30 BMI) 4 14 0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 SUVmax premenopause SUVmax Hormonal active

SUVav Premenopause SUVav Hormonal active

Underweight Normal weight Obesity

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Another part of the work consists of analysis of possible BMI influence on SUVmax and SUVav values. In the hormonal active group was present 3 cases of underweight, 16 cases of normal weight, 5 cases overweight and 4 cases of obesity resulting on a BMI mean of 24.6 (normal weight). In the postmenopausal group was 1 case of underweight, 6 cases of normal weight, 9 cases of overweight and 14 cases of obesity resulting on a BMI mean of 29.3 (overweight).

All those calculations show that as much obesity is present less uptake is noted in the breast tissue; this conclusion is based on the manifestation of the values on PET/CT scan that show a decreased SUVmax and SUVav value that is not influenced by the hormonal state of the women; in both groups independently if they are hormonal active or postmenopausal women. In the presence of obesity there is a decrease on SUVmax and SUVav that is explained by a bigger amount of fatty tissue in all the body including the breasts, so there is more fatty tissue in the parenchyma of the breast in young women and even much more fatty tissue replacement in elderly women [4].

Figure 3. Difference of SUVmax and SUVav in postmenopausal women with and without diabetes. 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 SUVmax SUVav Postmenopausal women Postmenopausal women with diabetes

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In our study just 3 cases of women affected with diabetes mellitus (DM) were present - all of them in the postmenopausal group; there was no case of DM in the hormonal active group that’s why the results are not completely valuable because our comparison is based only on 3 cases out of 30 and just from the postmenopausal group.

In this small sample we noted that postmenopausal women with diabetes mellitus have lesser uptake on PET/CT scan obtaining lower SUVmax and SUVav of there breast tissue than those without diabetes mellitus. This result can be real or can be the effect of randomly coincidence.

Figure 4. SUVmax and SUVav of hormonal active women with regular and irregular menses.

In this table appears the comparison between women with regular menses against those who have irregular menstrual cycle and the effect on SUVmax and SUVav. In the study were present 23 women with regular menses versus 7 women with irregular menses out of 30 women in total in the hormonal active group.

We can conclude that women with irregular menses obtained an important increasing value of SUVmax and SUVav. This result can be explained because with an irregular menstrual cycle women underwent much more hormonal changes and alterations that in a regular menstrual cycle in which every month the women´s body is used to those periodical increase and decrease of hormonal levels on the correct period of time [12] [10]; during an irregular menstrual cycle women can underwent long periods without menstrual cycle or so often cycles what is an alteration of the hormone equilibrium and has its effect on the breast metabolism affecting uptake on PET/CT scan.

0 0,5 1 1,5 2 2,5 3 SUVmax SUVav Regular menses Irregular menses

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13. CONCLUSIONS

It can be concluded that age is not related to the metabolic activity of the breast tissue. But this study showed that there is a strong difference of the metabolic activity of woman´s breast in hormonal active women compared to postmenopausal women. Also there is a significant evidence of the

influence of regularity of menstrual cycles of the women during the hormonal active period on the metabolic activity of breast tissue. On the other hand, obese women have lower metabolic activity of the breast tissue comparing to normal weight patients not dependant on hormonal status.

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14. PRACTICAL RECOMMENDATIONS

Methodology can be improved if a bigger sample of patients and in a longer period of time would be analysed to ensure that the study is not influenced by the causality.

More studies should be done to adequately check the influence of diabetes mellitus and the use of hormonal contraceptives on the metabolic activity of the breast tissue.

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15. LITERATURE LIST

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[2] Bogin, Barry A, Smith, Holly B. Evolution of the human life cycle; 1996. [3] Surveillance, Epidemiology, and End Results (SEER); 2012.

[4] Qi Cao, Hersl J, La H,Smith M,Jenkins J, Goloubeva O, Dilsizian V, Tkaczuk K, Chen W, Jones L. A pilot study of FDG PET/CT detects a link between brown adipose tissue and breast cancer; 2014. [5] Groheux D, Espié M, Giacchetti S, Hindié E. Performance of FDG PET/CT in the Clinical

Management of Breast Cancer; 2012.

[6] Lamar CA, Dorgan JF, Longcope C, Stanczyk FZ, Falk RT, Stephenson HE Jr. Serum sex hormones and breast cancer risk factors in postmenopausal women; 12(4):380-3; 2003.

[7] Mandelson MT, Oestreicher N, Porter PL, et al. Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers. 92:1081–1087; 2000.

[8] McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiology Biomarkers. 15:1159–1169; 2006.

[9] Takeda Y. Understanding the Life Stages of Women to Enhance Your Practice. JMAJ 53(5): 273– 278; 2010.

[10] Mavi A, Tevfik, Cermik F, Urhan M, Puskulcu H, Basu S, Andrew J. Cucchiara,JQ, Alavi A. The Effect of Age, Menopausal State, and Breast Density on 18F-FDG Uptake in Normal Glandular Breast Tissue; 2010.

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[12] Mavi A, Cermik TF, Urhan M, et al. The effects of estrogen, progesterone, and CerbB-2 receptor states on 18F-FDG uptake of primary breast cancer lesions. 48(8):1266–1272; 2007.

[13] Vranjesevic D, Schiepers C, Silverman CD, Quon A, Villalpando J, Dahlbom M, Phelps ME, Czernin J. Relationship Between 18F-FDG Uptake and Breast Density in Women with Normal Breast Tissue; 2003.

[14] Jemal A, Siegel R, Ward E, et al. Cancer statistics. 58:71–96; 2008.

[15] Ulaner GA, Castillo R, Goldman DA, Wills J, Riedl CC, Pinker-Domenig K, Jochelson MS, Gönen M. (18) F-FDG-PET/CT for systemic staging of newly diagnosed triple-negative breast cancer; 2016.

[16] Ueda S, Tsuda H, Asakawa H, et al. Clinical-pathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer. 38(4):250–258; 2008.

[17] Croswell JM, Ransohoff DF, Kramer BS. Principles of Cancer Screening: Lessons from History and Study Design Issues; 2010.

[18] Al Munawara AM . Breast Cancer Screening: Implications and Clinical Perspectives; 2013.

[19] Zytoon AA . Standardized uptake value variations of normal glandular breast tissue at dual time point FDG-PET/CT imaging; 2014.

[20] Lim HS, Yoon W, Woong Chung T, Kim JK, Park JG,Keun Kang H,Seung Bom H, Yoon JH. FDG PET/CT for the Detection and Evaluation of Breast Diseases: Usefulness and Limitations; 2007.