Densty with Age distribution

“BREAST CANCER DETECTION USING SONOGRAPHY IN WOMEN WITH MAMMOGRAPHICALLY DENSE BREAST”

Dissertation submitted to

THE TAMIL NADU DR.M.G.R.MEDICAL UNIVERISTY CHENNAI

In Partial Fulfillment of the Regulations For the Award of the degree M.D. DEGREE EXAMNATION BRANCH VIII RADIODIAGNOSIS MADRAS MEDICAL COLLEGE

&

RAJIV GANDHI GOVERNMENT GENERAL HOSPITAL, CHENNAI -600 003.

THE TAMIL NADU DR.M.G.R.MEDICAL UNIVERISTY CHENNAI -600 003. TAMIL NADU

APRIL-2017

BONAFIDE CERTIFICATE

Certified that this dissertation is the bonafide work of DR.GOMATHI.G on “BREAST CANCER DETECTION USING SONOGRAPHY IN WOMEN WITH MAMMOGRAPHICALLY DENSE BREAST” during her MD(RADIODIAGNOSIS) in Barnard Institute of Radiology in the academic year of 2014-2017 at the Madras Medical College and Rajiv Gandhi Government General Hospital,Chennai-600003.

PROF.DR.K. MALATHY, MDRD, Ph.D PROF.DR.R.RAVI MD.,DMRD

Guide Professor &Head of Department

Professor Barnard Institute of Radiology

Barnard Institute of Radiology Rajiv Gandhi Govt. General Hospital, Rajiv Gandhi Govt. General Hospital Madras Medical College, Madras Medical College Chennai-600 003.

Chennai-600 003

PROF.DR.N.KAILASANATHAN MD.,DMRD PROF.DR.MK.MURALIDHARAN MS, Mch

Director, Dean

Barnard Institute of Radiology Madras medical college &

Madras Medical College & Rajiv Gandhi Government Rajiv Gandhi Government General Hospital, General Hospital,

Chennai – 600 003. Chennai – 600 003.

DECLARATION

I, certainly declare that this dissertation titled “BREAST CANCER

DETECTION USING SONOGRAPHY IN WOMEN WITH

MAMMOGRAPHICALLY DENSE BREAST” represent a genuine work of mine.

The contribution of any supervisors to the research are consistant with normal supervisory practice, and are acknowledged.

I, also affirm that this bonafide work or part of this work was not submitted by me or any others for any award, degree or diploma to any other university board, neither in India or abroad. This is submitted to The Tamil Nadu Dr.MGR Medical University, Chennai in partial fulfilment of the rules and regulation for the award of Master of Radiodiagnosis Branch VIII.

Date : 26.09.2016

Place: Chennai DR.GOMATHI .G

ACKNOWLEDGEMENT

I would like to express my deep sense of gratitude to Prof.MK.Muralidharan MS,Mch(Neurosurgery),Dean, Madras Medical College &

Rajiv Gandhi Government General Hospital Chennai, for giving me permission to conduct the study in this institution.

With extreme gratefulness, I express my indebtedness to Prof.Dr.N.Kailasanathan,MD.,DMRD, Director, Barnard Institute of radiology, MMC & RGGGH, for allowing me to undertake this study on “BREAST CANCER

DETECTION USING SONOGRAPHY IN WOMEN WITH

MAMMOGRAPHICALLY DENSE BREAST”

I was able to carry out my study to my fullest satisfaction, thanks to guidance, encouragement, motivation and constant supervision extended to me, by my beloved Head of the Department Prof.Dr.R.Ravi,MD.,DMRD Hence my profuse thanks are due for him.

I would like to express my deep gratitude and respect to my guide Prof.Dr.K.Malathy,MD Ph.D whose advice and insight was invaluable to me. This work would not have been possible without his guidance, support and encouragement.

My sincere thanks to Prof.Dr.S.Kalpana,MD.,DNB for her practical comments and guidance especially at the inception of the study and I also wish to thank Prof.Dr.S.Babu Peter,MD.,DNB for her valuable support through out the study.

I am also extremely indepted to Prof.Dr.D.Ramesh MD for his valuable suggestions, personal attention, constructive cricticism during my study.

I am bound by ties of gratitude to my respected Associate Professors, Dr.Manimekala MD.,DNB and Dr.KasiVisalakshi,MD and Assistant professors Dr.K.Geetha MD, Dr.J.Chezhian MD, Dr.Mohideen Ashraf MD , Dr.G.Geetha MD , Dr.S.Iyengaran MD, Dr.Saranya DMRD and Dr.Balan DMRD in general, for placing and guiding me on the right track from the very beginning of my career in Radiodiagnosis till this day.

I am fortunate to have my postgraduate colleagues Dr.Amarnath, Dr.Bharathipriya and Dr.Satheesh for their valuable suggestions, relentless help for shouldering my responsibilities. Simply words cannot express its depth for their unseen contributions. My lovable thanks to my family for their moral support.

I would be failing in my duty if I don’t place on record my sincere thanks to those patients who inspite of their sufferings extended their fullest co- operation.

DR.GOMATHI .G

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INDEX

SL.NO CONTENTS PAGE

1 INTRODUCTION 1

2 AIM OF THE STUDY 2

3 ANATOMY OF BREAST 2

4 APPROACH TO BREAST LUMP 5

5 CLASSIFICATION OF BREAST LESIONS 26

6 BREAST CARCINOMA 29

7 BREAST CARCINOMA SCREENING 39

8 DENSE BREAST AND CARCINOMA 42

10 REVIEWED ARTICLE 43

11 MATERIALS AND METHODS 45

12 REPRESENTATIVE CASES 49

13 STATISTICAL ANALYSIS 59

14 RESULTS &DISCUSSION 75

15 CONCLUSION 81

16 BIBLOGRAPHY 82

17 CONSENT FORMS 90

18 PROFORMA 93

19 ABBREVIATIONS 96

20

ANNXETURE

1. ETHICAL COMMITTEE CERTIFICATE 2. PLAGIARISM CERTIFICATE

3. PLAGIARISM DIGITAL RECEIPT 4. MASTER CHART

1

INTRODUCTION

Breast cancer is common in women and a second leading cause of cancer mortality in women world wide¹. Incidence of Breast carcinoma most common in an urban Indian women and second common² in rural women.

Breast carcinoma develops from cells in the lining of ducts and lobules.

Arising from ducts is the ductal carcinoma and that from the lobules is the lobular carcinoma. Most of the cases presented in the late stage with decreased survival time due to lack of awareness, social stigma and lack of screening and paucity of diagnostic aid and illiteracy .

Early detection of breast cancer improve the survival rate, quality of life and reduce the morbidity. Triple assessment is the most useful technique for approach to patient with breast complaint like lump, pain and nipple discharge.

2 AIM AND OBJECTIVES OF THE STUDY

To determine the incremental breast cancer detection rate using sonomammogram of women with mammographic dense breasts.

ANATOMY OF BREAST

The breast is a modified sweat gland that is composed of 15 to 20 lobes.

Each lobe consists of parenchymal elements, lobar duct, smaller branch ducts, lobules , supporting stromal tissues, compact interlobular stromal fibrous tissue, loose periductal and intralobular stromal fibrous tissue and fat.

Fig 1.Anatomy of breast.

3

Fig.2. Anatomy of ducts and lobules.

The functional unit of the breast is the terminal ductolobular unit (TDLU), which consists of a lobule and its extralobular terminal duct. Each lobule consists of the intralobular segment of the terminal duct, ductules, and loose intralobular stromal fibrous tissue. TDLUs are important because they are the site of origin of most breast pathology and of aberrations of normal development and involution (ANDIs).

Fig 3.Lobular anatomy

4 Layers of breast

• Skin

• Subcutaneous fat

• Cooper‘s Ligaments

• Breast parenchyma

• Retromammary fat

• Pectoralis muscle

• Ribs

• Pleura

• Nipple

Lymphatic drainage of breast Lymph from the breast drains into

o Internal mammary and retromammary lymph nodes.

o Axillary nodes

o Supraclavicular ,cephalic and intercostal nodes.

5 Sonographic level of lymph nodes.

• Level 1-Inferolateral to pectoralis minor

• Level 2-Posterior to pectoralis minor

• Level 3- Supero medial to pectoralis minor .

APPROACH TO BREAST LUMP

Majority of breast lump are benign. The main aim of evaluating patients with breast mass is to rule out carcinoma and to detect early. All palpable lesion are imaged before biopsy.

TRIPLE ASSESSMENT IN WORK UP OF BREAST DISEASE

• Clinical assessment

• Imaging

• Biopsy

6

IMAGING MODALITIES OF BREAST LESIONS 1. Sonomammogram

2. X-ray Mammography 3. MRI mammogram

SONOMAMMOGRAM OF BREAST

Ultrasound is the one of the prime ,easily available imaging modality in screening and diagnosis of breast lesion .

Sonomammgraphic appearance of breast³

• The normal structures of the breast appear as spectrum of echogenicities, from midlevel gray to intensely hyperechoic.

• Normal structures that appear hyper echoic are compact interlobular stromal fibrous tissue, anterior and posterior mammary fasciae, Cooper‘s ligaments, and skin. Duct walls also appear hyper echoic.

7

• Midlevel echogenic (isoechoic) structures include fat, epithelial tissues in ducts and lobules, and loose intra lobular and periductal stromal fibrous tissue.

Sonographic Zones of breast³

• Premammary zone

• Mammary-The mammary zone is covered by thick, tough fascia. It is delineated from the subcutaneous fat anteriorly by the premammary or anterior mammary fascia and posteriorly from the retromammary fat by the posterior or retromammary fascia. The anterior mammary fascia is continuous with Cooper‘s ligaments.

• Retromammaryzone.

Implication :

Mammary zone is more prone for malignancy.

8

Fig 4.Sonographic anatomy of breast

Idendification of location

Fig.5. Model for location idendification First ring – Encompassing area just outside the nipple Zone 1 Second ring – most of the breast surface Zone 2

9 Third ring – Periphery of breast Zone 3

Advantages

o No radiation ,without any patient‘s discomfort o Cost effective

o Differentiates solid lesion from cystic lesion

o Higher sensitivity⁴ than mammography in detecting lesion in women with dense breast.

Elastography

Newer ultrasound technique⁵ ,based on tissue stiffness and hardness . Two types of Elastography

1. Strain elastography 2. Shear wave elastography

Stiffness measured by kPa(qualitative elasticity) and size ratio relative to the grey scale imaging. Benign lesions are softer and malignant lesion were stiffer and harder.

This technique is to improve the specificity of breast USG in differentiating the benign from malignant mass .

10

Fig : 6. Ill defined hypoechoic mass with irregular margin in the left breast.

Fig: 7. Shear wave elastography shows zone of stiffness is larger ,irregular and heterogeneously stiff with elasticity value of 108-180 kPa, suggestive of

malignancy⁵.HPE was confirmed as invasive ductal carcinoma.

11

Characteristics of benign lesion in Sonomammogram

 Benign lesions are appear as well defined ,smooth margin and transverse diameter is greater than the anteroposterior diameter.

 Well compressibile lesions.

 regular outline

 It can be round, oval or ellipsoid in shape.

 The lesion have thin ―pseudocapsule‖

 Uniform internal echoes

 No destruction of planes

Characteristics of Malignant lesion in Sonomammogram A. mass lesion

 Malignant lesions are spiculated, predominantly hypoechoic soft tissue mass lesion with posterior acoustic shadowing and non compressible.

 The lesions are taller- than- wider that is anteroposterior dimension greater than craniocaudal/transverse dimension.

 Angular margin - contour of junction between hypo- or isoechoic solid nodule and surrounding tissue at acute /obtuse/90â° angles and microlobulation.

 Central part of solid lesion very hypoechoic with respect to fat

 Punctate echogenic calcifications within hypoechoic mass .

12

 Radial extension/branch pattern –multiple projection from a nodule which extends radially within or around a duct towards the nipple.

 Adjacent satellite nodules.

B. Ductal dilatation with mass within the duct and calcification.

C. Suspicious intramammary and axillary lymphnode.

X-ray Mammography

X-ray Mammography is the gold standard modality of imaging for breast cancer both for screening and diagnosis. X ray Mammogram is not generally used for less than 35 years ,because of focal ionizing radiation.

X ray Mammography is the gold standard imaging modality for screening and diagnosis of breast cancer with advances in treatment. Early detection has resulted in reduced breast cancer mortality. Dense breast tissue is the most inherent limitation of xray mammography in the diagnosis of breast cancer. As a result of which some cancers are missed, requiring ultrasound ,to complete the breast imaging assessment.

Xray Mammogram used to characterize and determine the extent of mass to evaluate the breast for occult lesion .Sensitivity of mammogram is 90% and specificity is only 88%. False negative rate is 8-10%⁸(Ines buccimazza et al). so negative mammogram needs further investigation if lump is detected clinically.

13 Technique⁶

In Xray mammogram low energy radiation and short exposure time technique used for high spatial resolution to identify the microcalcification.

Molydbdenum target is used because it produce the low energy spectrum with 17.5 and 19.6 keV⁵. Increasing the quality of X ray tubes must have an extremely small focal spot and short exposure time to reduce the movement unsharpness.

Compression provides improved image quality that helps to detect small lesions and microcalcification and also improve the spatial resolution and contrast resolution and reduces the radiation dose.

Automatic Exposure Control

Automatic exposure control (AEC)⁶ system employs phototimers to measure the X-ray intensity and quality. Usually they are kept closer to the image receptor ,to minimize the object to image distance, and improving spatial resolution.

Two types of AEC

1.Ionising chamber type 2.solid state diode type.

14

Each type will have single or multiple detectors along the chest wall –nipple axis .The detectors are filtered differentially to assess the beam quality. It will also assess the level of compression and type target /filter combination that is used.

In general, thick and dense breast is best imaged with Rh/Rh combination , whereas thin breast imaged with Mo/Mo combination. It must be accurate and reproducible with lesser radiation dose. It should have the optical density within 0.1OD, with varying voltage (23-32)and thickness of breast(2-8 cm).

Digital mammogram

In this technique images are enhanced and transmitted electronically and the ability to alter the contrast and brightness gives identification of lesion. But overall detection rate similar to that of conventional mammogram. Digital mammography directly connected with PACS, leading to further increased efficiencies associated with storage and display.

Advantages

a. Better image quality b. Fewer artifacts c. Fewer patient recall d. Telemammography

15 Computer -aided Detection

It is the software system used to assist the film reader by placing prompts over areas of concern .it is highly sensitive for detecting carcinoma on screening mammogram. It correctly pick up the lesion and microcalcifications.

Digital Breast Tomosynthesis

Routine mammography produce the 2D view, some lesion are missed due to overlapping the normal glandular tissue. It is emerging digital mammographic technique where thin slice were taken and reconstruction can be made.

Standard views :

Medio lateral oblique Cranio caudal

Supplementary views : Lateral

Extended cranio caudal Magnified

16 Localised compressed

Cleopatra view-to visualize axillary nodes X ray mammogram interpretation

x-ray mammographic images shows spectrum of densities varying from fat density ,intermediate ,mixed to higher density.

Types of density in Xray Mammogram Low density

• Fatty tissue

High density

• Calcification

• Silicone

• Foreign bodies

Intermediate density

• Fibroglandular tissue

• Ductal tissue

• Blood vessels

• LN

17

• Contour of breast, skin and subcutaneous fat should be examined. then symmetry of both breast and cooper‘s ligament examined.

• Mass lesions appeared as heterogenous density

• Architectural distortions

• Microcalcifications

• Retromammary and axillary lymphnode.

X-ray Mammographic calcifications Benign calcifications

• Calcification in the skin

• Vessel wall calcification

• Coarse popcorn

• Round or rim

• Dystrophic

• Cord like calcification

18 Malignant calcifications

• Microcalcification.

• Coarse heterogeneous

• Fine pleomorphic

• Fine linear or linear branching calcification

Fig.8. Le Gal classification of calcification

19 Features of Benign lesion in x-ray mammogram

• Well circumscribed lesion with regular margin with partial peripheral halo.

• Oval or rounded massoik

• Coarse calcification

• Thin peripheral halo

Features of Malignant lesion in x –ray mammogram

• Focal asymmetrical density with sudden appearance of heterodensity with spiculated soft tissue mass

• Architectural distortion

• Clustered microcalcification -defined as microcalcification of various size and shape measuring about 0.1 to 1 mm in diameter and more than 10 in number per cubic centrimeter.

• Multiple satelite nodule.

20

Fig.9.Normal craniocaudal view showed skin ,subcutaneous fat ,copper’s ligament and glandular body.

Fig.10. Normal MLO view shows glandular tissue ,fibroussepta and retromammary region.

21 Classification of Breast density (modified wolfe’s)

a. Breast is almost entirely fat (<25% glandular) b. Scattered fibroglandular densities (25-50%) c. Heterogeneously dense breast tissue (51-75%) d. Extremely dense (> 75% glandular)

Fig.11; Type A density fatty breast

22

Fig.12;Type B density Fibroglandular tissues 25-50%

Fig.13.Type C density Fibroglandular tissues >50%

23

Fig.14 Type D density Extremely dense

Limitation of XrayMammography

• Increased breast density

• Painful breast condition

• Diagnosis of lobular carcinoma

• Postoperative breast

• Patient with BRCA and other gene mutation

24 BIRADS categories ⁷

0- incomplete assessment,needs additional evaluation;

1- Negative 2- Benign finding 3-Probably benign;

4- Suspicious abnormality 5- Malignant highly suspicious;

6-Biopsy proven malignancy

The expected risks of malignancy BIRADS 1 and 2-0%;

BIRADS 3- 2% or less;

BIRADS 4

4a- >2% - <10%

4b- >10% - <50%

4c- >50% - <95%

BIRADS 5 - 95% or greater.

25 MRI

Indications

 Detects small lesions, ―unseen‖ by mammogram.

 Suitable for dense breasts

 Enhanced evaluation of augmented breast

 To differentiate post op scarring from local recurrence

 To asses indeterminate mass by x-ray / USG

 For accurate staging of breast cancer in dense breast , multifocal/multicentric tumour, chest wall involvement

 Evaluation of implant integrity

 Detect carcinoma in augmented breast

 Asses response to neoadjuvant chemotherapy

Advatantage

• Avoid radiation exposure.

• More accurte than both mammogram and USG in detecting the lesions.

26 Disadvantage

• Expensive

• Not readily available

• Does not detect microcalcification

• Less sensitive in detecting noninvasive carcinoma.

CLASSIFICATION OF BREAST LESION

Benign Malignant

 Fibroadenoma

 Fibrocystic diease

 Fat necrosis

 Intraductal papilloma

 Breast abscess

 Atypical ductal hyperplasia

 Preinvasive insitu carcinoma

 Ductal invasive carcinoma

 Lobular invasive carcinoma

 Inflammatory breast carcinoma

27 Benign breast lesions

Fibroadenoma

Fibroadenoma is the most common breast lesion in the younger age group and most of the patient are asymptomatic and lesions are detected incidently.

On xray mammogram it appear well defined oval or round radio opacity and coarse calcification in long standing cases. On sonomammogram the lesion appear as solid hypoechoic mass oval or round lobulated and width is greater than height.

Fig.15.Xray-Mammogram and USG images showing well defined benign lesion – fibroadenoma.

Cyst

Usually bilateral and symmetrical peak incidence between 40-50 years. On xray mammogram , well defined round, oval mass with characteristic halo seen. but not able

28

to differentiate solid from cystic mass. On USG it appear as well defined anechoic lesion with no internal echoes with posterior acoustic enhancement.

Fig.16. Xray-mammogram showed well defined rounded mass with peripheral halo ,Sonogram showed cystic lesion with posterior acoustic enhancement.

Papilloma

Patient presented with nipple discharge ,benign lesion arising from duct. on xray rmammogram well defined mass commonly in the retroareolar region. on sonogram there is oval mass seen with in the dilated duct. intraductal papilloma having increased risk of malignancy.

29

Fig.17.Intraductal papilloma.

Lipoma

On mammo-Well defined radiolucent lesion On ultrasound –well defined hyperechoic lesion .

BREAST CARCINOMA

Breast carcinoma arising from epithelial cells of terminal duct unit.the malignant cells seen with in the basement membrane is called as insitu lesions ,malignant cells invade outside the basement membrane is called as infiltrative carcinomas.

30 EPIDEMIOLOGY

Breast cancer is commonest cancer in women world wide. According to ICMR-PBCR data breast carcinoma is commonest in urban women of Delhi,Mumbai, Ahmedabad and second most common in rural women after cervical carcinoma.

Fig.18. Incidence of breast cancer ⁸

There is rising incidence of breast cancer in india due to increase of incidence among the younger age group and late presentation due to lack of awareness and screening .

31

According to globocan project year 2012 ,144937 new cases of breast carcinoma were detected , of which 70218 deaths were reported and approximately every 2 women of the newly diagnosed ,one dies.

In India there is unprecedented rise in number of cases. Breast carcinoma could not be prevented but definitely can be detected early and treated. Only way to reduce the mortality is early detection of breast carcinoma.

Outcome of breast cancer depends on the carcinoma type, extent of the disease and age of the patient . The 5 year Survival rates of breast carcinoma in the developed countries is about 80-90%⁹ in England and Unites states . In India it roughly not more than 60%⁹ because of lack of awareness and screening.

RISK FACTORS

• Increasing age

• Female sex

• First degree relative with breast cancer

32

• Factors affecting unopposed estrogen load a. Early menarche

b. Late menopause c. Nulliparity

• Genetic mutation

• BRCA1/BRCA2

• Li-Fraumeni syndrome

• Dense breast

PATHOPHYSIOLOGY

Breast carcinoma occurs because of interaction between an environmental factors and genetic factors. Normally cell cycle was going on continuously with regeneration and cell apoptosis, that is programmed cell death due to normal ageing process.

Normally cells are undergoes programmed cell death when they are no longer needed. Some cell signal pathways control the programmed cell death to avoid unnecessary cell death and protect the cell.

33

Fig.19.Pathophysiology of breast carcinoma

One of the protective pathway is P13K/AKT and second one is RAS /MEK/ERK pathway .Mutation of protective pathway gene produces uncontrolled cell proliferation and lack of programmed cell death.then abnormal cell proliferate continuously .

Normally PTEN protein turns off the P13K/AKT pathway when the cells are ready for apoptosis.if the PTEN gene mutated this cell signal pathway is stuck in the ON position and no apoptotic cell death occurred.it leads to abnormal proliferation of cancer cells.

34

Abnormal growth factors signaling in the interaction between stromal cells and epithelial cells can stimulate malignant cell growth.

Genetic factors BRCA1,BRCA2 &P⁵³gene mutation have life time risk of breast cancer ,it had familial tendency to develop the cancer ,that is called hereditary Breast –ovarian cancer syndrome. Inherited mutation in BRCA 1& BRCA 2 gene can interfere with repair of DNA cross links and DNA double strand breaks.

Levin et al said breast carcinoma may not be inevitable in all carriers of BRCA1 & BRCA 2 genes.

GATA-3 directly controls the expression of estrogen receptor and other gene associated with epithelial differentiation .Loss of GATA-3 leads to loss of differentiation and poor prognosis due to cell invasion and metastasis.

CLASSIFICATION OF BREAST CARCINOMA 1. Carcinoma in situ

2. Infiltrative carcinoma

Two types of invasive carcinoma⁵

 Invasive carcinoma of special type

 No special type.

35 Histological type

• Ductal carcinoma in situ

• Lobular carcinoma in situ

• Invasive ductal carcinoma

• Invasive lobular carcinoma

• Medullary carcinoma

• Tubular carcinoma

• Papillary carcinoma

Imaging feature of Malignant lesion X-RAY MAMMOGRAM

Ductal carcinoma insitu appear as microcalcification and same invasive carcinoma appeared as,focal asymmetrical density with sudden appearance of heterodensity with spiculated soft tissue mass and architectural distortion and also multiple satellite nodules.

Clustered microcalcification defined as microcalcification of various size and shape measuring about 0.1 to 1 mm in diameter and more than 10 in number per cubic centrimeter.

Axillary lymphadenopathy with loss of fatty hilum seen.

36 SONOMAMMOGRAM

Ill defined hypoechoic mass ,irreguilar margin, lesion taller than wider noncompressible and showing posteroir acoustic shadowing and axillary lymphadenopathy.

FIG .20 Xray mammogram showing spiculated mass lesion and USG showing illdefined hypoechoic mass lesion with irregular margin .feature of breast carcinoma.

37 MRI

Dynamic contrast-enhanced MRI is becoming increasingly important, largely because of its high sensitivity for detecting insitu breast cancer and early detection. This technique plays a major role in detecting the multifocality of breast carcinoma.

Newer imaging techniques, such as diffusion-weighted imaging (DWI) and spectroscopy, are being used and improve the specificity of breast MRI.

Fig. 21. MRI showed well defined hperintense lesion with spiculated margin in the left breast. Time intensity curve showed the enhancement curve -rapid uptake of

contrast agent followed by a washout phase.

38 HISTOPATHOLOGICAL EXAMINTION

Needle biopsy provides accurate information on the nature of malignant disease, such as histological type and grade, and allows assessment of tumor biology, cell markers and genetics.

The methods available for breast tissue diagnosis are:

• Fine-needle aspiration for cytology (FNAC)

• Needle core biopsy for histology & J wire biopsy.

• Vacuum-assisted biopsy (VAB)

• Open surgical biopsy.

Treatment of breast carcinoma Based on 1.type of breast cancer 2.stage of carcinomaa

3.whether the lesion sensitive to hormones

4.whether the lesion overexpress the HER2/neu protein

• Surgery

• Radiotheraphy

• Chemotheraphy

• Hormone theraphy.

39

Most of the patient received combination theraphy. All patient should be followed up with mammogram and ultrasound and also metastatic work up.

Breast carcinoma screening

Most of breast carcinoma patient presented with locally advanced disease which leads to increasing mortality and low survival rate.

According to International agency for research on cancer approximately 250,000new cases in 2015, about 30,000 women die from breast cancer.

Only way to reduce the burden of diease is early detection through screening(alka agrawal et al).A normal individual means who does not have any symptom and sign.If the patient presented with lump by the time diease was already stage 2.The increasing the of size of lesion, high risk to spread anywhere and skin infiltration.

Main aim of screening to detect the lesion before it felt, that is stage1 , that patient had long survival and low morbitity.

Following factors makes screening extremely important in india.

a. Age shift more young women are affected b. Increasing number of cases

c. Late presentation d. Lack of awareness

e. Aggressive cancers in young population.

40 ACS recommendation

 Women with average risk should be screened with regular mammography starting at the age of 45 years.(storng recommendation).

 Women with age 45 to 54 should screened annually.

 Women 55 or older should transition to beninal screening or have the opportunity to continue screening annually.

 Women should have opportunity to begin annual screening between the age of 40 and 44 years and continue as long as overall health is good.

Screening modality

• Clinical breast examination

• Screening x ray mammography

• Sonomammogram

• MRI

41

Fig.22.Schematic representation of screening protocol

42

Dense breast and Breast carcinoma

Breast density is increasingly important predictor of risk of breast carcinoma. Breast density depends on the amount of fat or the glandular component present in the breast. Denser the breast more the glandular and fibrous tissue than fat.

In younger females the breast is more glandular which decreases as age goes on when it is replaced by fat.

Women with dense breast are four to six times⁶ more likely to develop breast carcinoma.

Xray Mammogram is prime modatilty of imaging of breast carcinoma in which lesion are appeared as radiodensity. In case of dense breast ,dense tissues will obscure the underlying lesion from view and very difficult to find the small lesions, even large lesion also. Normally post menopausal women have fatty breast inspite of that higher the breast density increase the risk of specific type of breast cancer with relatively poor prognosis.

43

REVIEWED ARTICLE

Jimmey okello et al studied out of 148 women with mammograghically dense breast 22/148(15% )were malignant lesion .mammography detected 16/22(73%)cases and missed 6/22(27%) cases. The six missed cases were correctly detected by ultrasound.Breast ultrasound scan as a supplementary imaging tool detected 27%more malignant mass lesion.

Oxford university studies showed dense area on mammogram makes cancer detection more difficult and also serve as a marker of hormonal status of the patient.

Norman F boyd et.al women with density in 75% or more had an increased risk of breast carcinoma whether detected by screening or with in 12 months after negative screening.

One of the previous study showed risk of breast cancer was higher for women with higher breast density. Women with 50% or higher density on mammogram where three times more likely to be diagnosed with breast cancer over 15 years period than with less than 10%breast density and also stronger for more aggressive lesion.

44

Mc Cormack and doss antos silva conducted a systemic meta analysis of association between patient of mammographic density and risk of breast cancer.

Extensive mammographic density was associated with increased risk of breast cancer.

Ursin et al found that ductal carcinoma insitu occurred in the region of breast that were mammographically dense.

Canadian national breast screening study showed that compared with mammographic density women with greater than 75% mammographic density had increased risk of insitu breast cancer and atypical hyperplasia.

Isabelle leconte et al; Sensitivities of mammography and subsequent sonography for the detection of nonpalpable breast cancers were 69% and 88% in grades 1–4, 80% and 88% in grades 1 and 2, and 56% and 88% in grades 3 and 4 breasts, respectively. The relative risk for detecting nonpalpable breast cancers using sonography was statistically significantly greater than that for detecting nonpalpable breast cancers using mammography in grades 1–4 (relative risk, 1.29; p = 0.024) and in grades 3 and 4 (relative risk, 1.57; p = 0.013) but not in grades 1 and 2(relative risk, 1.1; p = 0.445) breasts. Sonography is a useful adjunct after mammography for the detection of nonpalpable breast cancer, particularly in the dense breast.

45 MATERIALS AND METHODS

STUDY AREA : Barnard Institute of Radiology, Madras Medical College, Chennai.

STUDY PERIOD : 6 months SAMPLE SIZE : 75 patients

STUDY DESIGN : Prospective observational INCLUSION CRITERIA

 Women of age 35-65 years having Grade3&4 dense breast

 Family history of breast carcinoma with high risk women

EXCLUSION CRITERIA

 Age <30 years

 Pregnancy and lactating women,

 Previous breast disease

 Hormonal replacement theraphy

 Tender breast

 Grade1&2 dense breast

46 MODE OF INVESTIGATION :

Studies were performed with Allergens x-ray mammography, MAM-VENUS model and SIEMENS USG machine and biopsy taken by USG guidance.

,

Fig.23.1.Xray Mammogram machine

47

Fig.23.2 Xray mammogram equipment STUDY PROCEDURE & DATA COLLECTION

Women who were referred for diagnosis in symptomatic breast and for screening in asymptomatic high risk patients. Those with mammographically dense breasts were included for this study , after obtaining an informed written consent to participate in the study.

Patient‘s data were collected such as Age, gender, menopausal status, indication for mammography, then xray mammogram was done ,mass lesion visibility

48

on xray mammogram, Sonographic BI-RADS descriptors, then BI-RADS final assessment categorization as well as histological diagnosis was done.

Standard mammographic views (Mediolateral oblique and Cranio caudal views) were performed. The mammographic breast density was categorized ,final mammographic diagnosis was documented, then whole breast ultrasound was performed on all the study participants. Both breasts were systematically scanned with overlapping scans in a radial and anti radial pattern from the nipple to the periphery.

The retro areolar region including both axilla were scanned separately with angled probe views to ensure the complete coverage of all breast tissue. ultrasound guided biopsy of the detected breast lesions was done.

An informed consent for biopsy was obtained after thorough explanation of the procedure to the study patients. Under local anaesthesia and aseptic precaution ultrasound guided core needle biopsy of solid breast masses and FNAC of cystic lesion were performed. Sample was put in a biopsy bottle containing formalin and taken for histopathological analysis.

Data of participants together with mammogram , ultrasound findings and histopathological report were collected and statistically analyzed and show the relationship between findings and how is ultrasound is useful in mammographically dense breast which is independent risk factor for breast cancers.

49 REPRESENTATIVE IMAGES

CASE-1

50 years old patient presented with lump in the left breast

Fig.24.1 .Mammogram CC view showed type D density both breast. Well defined radio opacity with spiculated margin noted areolar region in the left breast.

Fig24.2. USG showed well defined hypoechoic mass lesion with speculated margin &

lobulated appearance noted . HPE came as invasive ductal carcinoma. In this case inspite of the dense breast lesion is identified.

50 CASE 2

45 year old female asymptomatic came for screening.

Fig.24.3 CC view showed extremely dense breast.

Fig.24.4. well defined hypoechoic lesion noted in the right breast HPE came as intraductal carcinoma. That lesion not seen in the mammogram.

51 CASE-3

40 Year old patient presented with lump in the right breast.

Fig.24.5.Type C density noted in the right breast.

Fig.24.6 USG showed welldefined smooth margin hypoechoic lesion in right breast HPE came as fibroadenoma.

52 CASE- 4

38 year old patient presented with pain in the right breast 0n &off.

Fig.24.7. Dense breast.

Fig.24.8. USG- ill defined hypoechoic lesion noted in the right breast.

HPE was chronic inflammation.

53 CASE 5

48 year old patient presented with lump in the left breast

Fig.24.9.Type C density noted.multiple well defined radioopacity noted in the left breast.

Fig.24.10. USG multiple well defined benign looking hypoechoic lesion. Case of HPE proven fibroadenoma.

54 CASE 6

Fig .24.11. Type D density with well defined radio opacity in the left breast.

Fig.24.12.well defined hypoechoic lesion with posterior acoustic shadowing noted left breast. HPE proven as ductal invasive carcinoma.

55 CASE-7

48 year old female presented with pain in the both breast.

Fig.24.13 extremely dense breast

Fig.24.14. ill defined hypoechoic lesion noted in the left breast. HPE came as ductal carcinoma.This lesion not detected by mammogram.

56 CASE- 8

38 year old presented with pain in the both breast.

Fig.24.15.Type D density noted in the both breast.

Fig.24.16.USG shows multiple dilated ducts and cysts noted in the both breast.

A case of fibrocystic disease.

57 CASE- 9

45 year old patient presented with mass in the right breast

Fig.24.17 Type D density with asymmetrical density noted in the right breast

Fig.24.18.well defined hypoechoic lesion noted in the right breast.

HPE proven as fibroadenoma.

58 CASE -10

40 year old patient presented with lump in the right breast.

Fig.24.19 Type C density with well defined radio opacity noted in the right breast and multiple discrete macrocalcification seen.

Fig.24.20.Well defined hypoechoic lesion seen in the right breast HPE -Fibroadenoma

59

STATISTICAL ANALYSIS

Tab.1.Frequency of patient attending for Breast imaging

Frequency Percent

FOLLOW UP SCREENING 1 1.3

LUMP 13 17.3

NIPPLE DISCHARGE 3 4.0

PAIN 24 32.0

SCREENING 34 45.3

TOTAL 75 100.0

60

Fig.25. Bar chart of patient attended for breast imaging.

Out of 75 patient of this study 35 were came screening ,remaining 40 were presented with symptoms.out of which pain is the most common presenting symptom.

Tab.2 X ray Mammographic breast Density frequency in the study population Density distribution

Frequency Percent

TYPE-C 49 65.3

TYPE -D 26 34.7

Total 75 100.0

.

1

13 3

24

34

0 5 10 15 20 25 30 35 40

FOLLOW UP SCREENING LUMP NIPPLE DISCHARGE PAIN SCREENING

Screening /Symptoms

61

Fig 26. Diagrammatic representation of density frequency

Out of 75 study patients 49 patients had type C density and 26 patients had type D density.

Tab.3.Frequency and characterization of the lesiondetected by sonomammogram.

Frequency Percent

BENIGN 40 53.3

INCONCLUSIVE 1 1.3

MALIGNANT 13 17.3

Nil 21 28.0

Total 75 100.0

TYPE C 65%

TYPE D 35%

Density

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Fig.27.Frequency distribution of lesion detected by sonomammogram .

Diagnostic performance of sono and xray mammogram in detecting breast carcinoma in dense breast

Tab.4 Diagnostic performance of sonomammo in detecting breastcarcinoma

Frequency Percent

TRUE + ve 13 24.5

- ve 40 75.5

Total 53 100.0

63

Tab.5 Diagnostic performance of Xray mammo in detecting breast carcinoma

Frequency Percent

TRUE + ve 10 18.9

- ve 43 81.1

Total 53 100.0

Tab.6.BOTH

Frequency Percent

TRUE + ve 13 24.5

- ve 40 75.5

Total 53 100.0

64

SONO XRAYMAMMO

+ ve 24.5 18.9

- ve 75.5 81.1

Tab.7 Comparison of diagnostic performance of sono and xray mammogram in detecting breast carcinoma

Fig.28. Bar chart representation of diagnostic performance of sono and xray Mammogram in detecting breast carcinoma.

24.5

75.5

18.9

81.1

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0

+ ve - ve

SONO vs XRAYMAMMO

USG MAMMO

65

66

Fig.29. Density with age distribution in the study population.

Tab.8.Age wise distribution of Breast density

62.2% 68.4%

37.8% 31.6%

0%

20%

40%

60%

80%

100%

< 45 yrs >= 45 yrs

Densty with Age distribution

TYPE C TYPE D

67

Tab.9.Frequency of breast lesion HPE correlation

HPE

1 MALIGNANT 13

2 FIBROADENOMA 23

3

FIBROCYSTIC

DIEASE 16

4

CHRONIC

INFLAMMATION 1

5 INCONCLUSIVE 1

TOTAL 54

Fig.30.Distribution of breast lesion with HPE correlation

0 5 10 15 20 25

1 2 3 4 5 6

68

Tab.10. Sensitivity of xray mammogram in detecting the breast carcinoma in dense breast

Sensitivity 76.9230769

Specificity 100

PPV 100

NPV 93.0232558

69 .

Sensitivity 100 Specificity 100

PPV 100

NPV 100

Tab.11 Sensitivity of sonomammogram in detecting the breast carcinoma in dense breast

NPV 93.0232558

70 ROC Curve for SONOMAMMOGRAM

Case Processing Summary

sonogram Valid N (listwise)

Positive^a 13

Negative 40

Smaller value of the test result variable(s) indicate stronger evidence for a positive actual state

Area under curve =1.00 which is significant at p =.0005 and 95% confident interval 1.000 to 1.000

71

72 ROC Curve for Xray Mammogram Case Processing summary

XRAY MAMMO Valid N (listwise)

Positive^a 10

Negative 43

Smaller values of the test result variable(s) indicate stronger evidence for a positive actual state.

Area Under the Curve

Area under curve =.965 which is significant at p=.0005 and confident interval 0.91 to 1.000.

73 Test Result Variable(s): BOTH

74

Tab.12.Consolidated table of statistical variables for xray mammogram and sonomammogram.

Sensitivity Specificity NPV PPV AUC

P-

VALUE

LL UL

SONOMAMMO 100 100 100 100 1 0.0005 1 1

XRAYMAMMO 76.9 100 93 100 0.96 0.0005 0.918 1

75 RESULTS

In this study both symptomatic patients and asymptomatic patient who came for screening were included.75 patients of type C and type D density were included for this study and all patients underwent bilateral breast ultrasound was done.

Totally 54 lesion were detected, then ultrasound guided biopsy were done for the 54 patients. The histopathological reports were collected and correlated with sono and xray mammogram reports.

Table.1& Figure.24 showed the frequency of patients attending for breast imaging in both symptomatic as well as asymptomatic patients. Out of 75 patients 40 (55%) were presented with symptoms like pain in the breast ,lump and nipple discharge.35 patients (45%) were asymptomatic came for screening .Most common presenting complaints were pain and next common complaint is lump in the breast.

Table 2& Figure 25 explained prevalence of type of density in the study population.65%of the patient had type C dense breast and remaining 35% had type D.

Type C is high prevalence in the study population.

Table 3&Figure 26 showed frequency and characterization of benign and malignant lesions. Benign lesions are round ,oval in shape ,parallel orientation and well defined margin.

Malignant feature of the lesion are irregular in shape nonparallel orientation.

According to this features benign and malignant lesion were detected. Out of 75

76

dense breast patient 54 lesion were detected. For which biopsy was done. Ultrasound differentiate the 40 benign and 13 malignant lesion, one case was inconclusive and 21 patients had no detectable lesion.

All the 54 lesion were underwent biopsy and reports are analysed.Out of 54 cases 13 cases were malignant,23 were fibroadenoma,16 were fibrocystic disease and 1 case came as chronic inflammation and one is came as inconclusive .that patient was under followup.

Diagnostic ability of Sonomammogram and Xray mammogram in detecting breast carcinoma in dense breast.

In this study showed out of 75 dense breast 13 cases had carcinoma that was 17.3%(13/75) which were confirmed by HPE .Out of 13 cases, xray mammography detected 10 cases ,but sonogram detected all the 13 cases.

Jimmy okello et al study showed out of 22 cases of breast carcinoma in dense breast( 148 case) mammogragram detected 73% of cases.remaining missed lesion 27% were detected by ultrasound.

77

In this study out of 13 cases of carcinoma in 75 dense breast, xray mammogram detected 10 cases that is 76.9% and remaining 3 cases(23.1%) were missed which is detected by ultrasound. These results were similar to the previous study.

Table 8 explained that age wise distribution of breast density.

Table 9& figure 29 explained frequency distribution of breast lesion with HPE . Most common breast lesion were benign lesion .out of 54 cases 13 cases were malignant,23 were fibroadenoma,16 were fibrocystic disease and 1 case came as chronic inflammation.

Table 11 showed sensitivity of xray mammogram in detecting the carcinoma that was 76% but specificity was 100 %,some lesion were missed.

Isabelle leconte et al; Sensitivities of mammography and subsequent sonography for the detection of breast cancers were 69% and 88% in grades 1–4, 80%

and 88% in grades 1 and 2, and 56% and 88% in grades 3 and 4 breasts, respectively.

In this study sensitivity of xray mammogram for detection of breast cancer in grade 3 and grade 4 was 76%,and sensitivity of ultrasound was 100%..In compare with previous study this study showed the higher the sensitivity ,it may be due to small sample size.

78

Mondel son et al.showed mammographic sensitivity of 80% in women with fatty breast that decreased to 30% in women with dense breast.

Sensitivity and specificity of ultrasound in dense breast is 100% for detecting the breast carcinoma and other breast lesions.

The prevalence of breast cancer in dense breast was 13/75(17.3%), xray mammography detected 10/13(76.9%) 3/13(23.1%) case were missed which were detected by sonogram.

79 DISCUSSION

This study was conducted to investigate the incremental breast carcinoma detection rate by using sonogram in xray mammographically dense breast.

Ultrasonography is the supplemental tool in evaluating the dense breast.

The study found that ultrasonogram detected 23% more malignant lesion than xray mammogram in the dense breast.

Patient with xray mammographic dense breast had more of dense fibro glandular tissue which cause obscuration small lesion that was missed to diagnosed.

These findings are important because it might be the early breast cancer lesion and are amenable to curative treatment .In addition USG is more assesible .MRI also another imaging tool for detecting the early cancer in dense breast,but it is not easily available and its high cost.

Total malignant rate of 17% is three fold higher compared to previous study by Paulo et al which showed a prevalence of 4.2% in dense mammogram.

Breast carcinoma age incidence will be changed and seen relatively in younger age group, mainly 30-50 years. Most of the women were symptomatic .

Tumors and fibroglandular tissue have similar density on mammography, difficult to differentiate metabolically active breast tissue from carcinoma . As a result performance of xray mammography in women with the high breast density is poor.

80

The relative available modality ultrasound is the best for evaluating women with dense breast in detecting the breast cancer if other modalities like MRI not readily available.

Limitation of xray mammography increased prevalence in breast carcinoma is 30-50 years who frequently have dense breast so sensitivity is reduced ,next is radiation exposure. Advantage of use of ultrasound is cost effective ,easily available and no limitation by fibroglandular tissue and used for taking biopsy.

According to latest BIRADS atlas it is mandatory that a xray mammographically dense breast needs further additional imaging evaluation in order to make conclusive diagnosis.

81

CONCLUSION

Sonomammogram is the supplemental tool in evaluating the dense breast. The study found that sonogram detected 23% more malignant lesion than xray mammogram in the dense breast. Breast ultrasound resulted in significant incremental breast cancer detection rate among the women with xray mammographically dense breast. Ultrasound should be done in mammographically dense breast.

.

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BIBLOGRAPHY

1. Sandy C. Lee,Payal A jain samir c.jethwa:Radiologist ‗s role in breast cancer staging ;providing key information for clinicians,radiographic vol34, march 2014.

2. Gaurav Agarwal , pooja ramakant :Breast cancer care in india The Scenario and the changes for future 2008 Mar3(1):21-27.

3. A.Thomas Stavrous, The breast ,carol M.Rumock editor.Text book of diagnostic ultrasound 4 th edition. p.773-838. .

4. Ines buccimaza et al: approach to the diagnosis of a breast lump CME vol.29 january 2011.

5. Jonathan J.James,A.Robin M.wilson,Andrew J.Evans ,The breast .Andreas adam editor Grangier &Allison‘s diagnostic radiology,text book of medical imaging 6 th edition.p.1664-1689.

6. K.Thayalan Mammography ,The physics of radiology and imaging 1^st edition.p.226-243.

7. American college of Radiology BI-RADS atlas 5^th edition

8. National cancer registry programme :sourse of official Indian data :consolidated report of the hospital based cancer registries 2007-2011.

9. Overall 5year survival for various cancer in united states :published by Amercian society of clinical oncology 2009.

83

10. Jjudith white :breast density and cancer risk:what is the relationship;oxford journal 15 mar 2000.

11. Kelly KM, Dean J, Comulada WS, Lee SJ: Breast cancer detection usingautomated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol 2010, 20:734–742.

12.Boyd N, Guo H,Martin LJ, Sun L, Stone J, Fishell E, et al: Mammographic density and the risk and detection of breast cancer. N Engl J Med 2007, 356:227–

236.

13.Galukande M, Kiguli-Malwadde E: Rethinking breast cancer screening strategies in resource-limited Settings. Afr Health Sci 2010, 10(1):89–92.

14.Stomper PC, D‘Souza DJ, Di Nitto PA, Arredondo MA: Analysis of parenchymal density on mammograms in 1353 women 25–79 years old.AJR Am J Roentgenol , 167:1261–1265.

15.Kelemen LE, Pankratz VS, Sellers TA: Age-specific trends in mammographic density: the Minnesota breast cancer family study. Am J Epidemiol 2008,167:1027–1036.

16.Hersh MR: Imaging the dense breast. Appl Radiol 2004, 33:22.

17.Buist DSM, Porter PL, Lehman C, Taplin SH, White E: Factors contributing tomammography failure in women aged 40–49 years. J Natl Cancer Inst 2004, 96:1432–1440.

84

18.Bevers TB, Anderson BO, Bonaccio E, Buys S, Daly MB, et al:

NationalComprehensive Cancer Network: Breast cancer screening and diagnosis.J Natl Compr Canc Netw 2009, 7:1060–1096.

19.Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Böhm-Vélez M, Pisano ED, et al: Combined screening with ultrasound andmammography vs mammography alone in women at elevated risk of breast cancer. JAMA 2008, 299:2151–2163.

20.Mandelson MT, Oestreicher N, Porter PL, White D, Finder CA, Taplin SH,et al:

Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 2000, 92:1081–1087.

21. American College of Radiology. BI-RADS: 11. American College of Radiology. BI-RADS: Mammography Atlas. 4th edition.Reston, VA: American College of Radiology; 2003.

22.American College of Radiology BI-RADS: Ultrasound, 1st Ed. In Breast imaging reporting and data system: BI-RADS atlas 4th ed. Reston, VA:American College of Rad; 2003.Zanello PA, Felipe A, Robim C, Mendes T, Oliveira G, et al.

23.Breast ultrasound diagnostic performance and outcomes for mass lesions using Breast Imaging Reporting and Data System category 0 mammogram, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072469/.

85

24.Hong AS, Rosen EL, Soo M, Jay A, et al: BI-RADS for Sonography: Positive and Negative Predictive Values of Sonographic Features. AJR 2005, 184:1260–

1265.

25.Sseggwanyi J, Galukande M, Fualal J, Jombwe J: Prevalence of HIV/AIDS among Breast Cancer Patients and the associated Clinico-pathological features.

Annals of African Surgery 2011, 8:22-27

26 .Zanello PA, Andre Felipe Cica Robim, Tatiane Mendes Gonçalves Oliveira et al.

27.Breast ultrasound diagnostic performance and outcomes for mass lesions using Breast Imaging Reporting and Data System category 0 mammogram.

28.http://www.ncbi.nlm.nih.gov/pubmed/21552670 Accessed on line June 2014 29.Gakwaya A, Kigula-Mugambe JB, Kavuma A, Luwaga A, Fualal J, Jombwe J,Galukande M, Kanyike D: Cancer of the breast: 5-year survival in a tertiary hospital in Uganda. Br J Cancer 2008, 99:63–67.

30.IAEA;Quality assurance programme for screen film mammography.

Volume 2.Viena; ISSN 2075–3772; 2009.

31.Birdwell, R.L., Ikeda, D.M., O‘Shaughnessy, K.F. and Sickles, E.A. (2001) Mammographic Characteristics of 115 Missed Cancers Later Detected with Screening Mammography and the Potential Utility of Computer-Aided

86 Detection.Radiology,219,192-202.

http://dx.doi.org/10.1148/radiology.219.1.r01ap16192

32.Pinsky, R.W. and Helvie, M.A. (2010) Mammographic Breast Density: Effect on Imaging and Breast Cancer Risk. Journal of the National Comprehensive Cancer Network, 8, 1157-1164.

33. Wirth, W., Nikitenko, D. and Lyon, J. (2005) Segmentation of Breast Region in Mammograms Using a Rule-Based Fuzzy Reasoning Algorithm. ICGST Graphics, Vision and Image Processing Journal, 5, 45-54.

34.Asselin-Labat, M.L., Vaillant, F., Sheridan, J.M., Pal, B., Wu, D., Simpson, E.R., Yasuda, H., Smyth, G.K., Martin,T.J., Lindeman, G.J. and Visvader, J.E.

(2010) Control of Mammary Stem Cell Function by Steroid Hormone Signalling.

Nature, 465, 798-802. http://dx.doi.org/10.1038/nature09027

35.Baker, S., Wall, M. and Bloomfield, A. (2005) Breast Cancer Screening for Women Aged 40-49 Years—What Does the Evidence Mean for New Zealand? The New Zealand Medical Journal, 118, 1-8.

36.Carney, P.A., Miglioretti, D.L., Yankaskas, B.C., Kerlikowske, K., Rosenberg, R., Rutter, C.M., Geller, B.M., Abraham, L.A., Dignan, M., Cutter, G. and Ballard- Barbash, R. (2003) Individual and Combined Effects of Age, Breast Density, and Hormone Replacement Therapy Use on the Accuracy of Screening Mammography.

87

Annals of Intern Medicine, 138, 168-175. http://dx.doi.org/10.7326/0003-4819- 138-3-200302040-00008

37.Dummin, L.J., Cox, M. and Plant, L. (2007) Prediction of Breast Tumor Size by Mammography and Sonography—A Breast Screen Experience. The Breast Journal, 16, 38-46. http://dx.doi.org/10.1016/j.breast.2006.04.003

38.David, N., Jackie, S., Butler, L. and Lewis, R. (2006) Hole‘s Human Anatomy and Physiology. 11th Edition, McGraw Hill Higher Education, 880-881.

39.Liberman, L., Feng, T.L., Dershaw, D.D., Morris, E.A. and Abramson, A.F.

(1998) US-Guided Core Breast Biopsy: Use and Cost-Effectiveness. Radiology, 208, 717-723.

40.Warner, E., Plewes, D.B., Hill, K.A., Causer, P.A., Zubovits, J.T., Jong, R.A., Cutara, M.R., DeBoer, G., Yaffe, M.J, Messner, S.J., Meschino, W.S., Piron, C.A.

and Narod, S.A. (2004) Surveillance of BRCA1 and BRCA2 MutationCarriers with Magnetic Resonance Imaging, Ultrasound, Mammography, and Clinical Breast Examination. Journal of the American Medical Association, 292, 1317-1325.

http://dx.doi.org/10.1001/jama.292.11.1317

41.Dempsey, P.J. (2004) The History of Breast Ultrasound. Journal of Ultrasound in Medicine, 23, 887-894.

88

42.Berg, W.A., Gutierrez, L., NessAiver, M.S., Carter, B., Bhargavan, M., Lewis, R.S. and Ioffe, O.B. (2004) Diagnostic Accuracy of Mammography, Clinical Examination, US, and MR Imaging in Preoperative Assessment of Breast Cancer.

Radiology, 233, 830-849. http://dx.doi.org/10.1148/radiol.2333031484

43. Kopans, D.B. (2008) Basic Physics and Doubts about Relationship between Mammographically Determined Tissue Density and Breast Cancer Risk.

Radiology, 246, 348-353

44.American College of Radiology (2003) Breast Imaging Reporting and Data System (BI-RADS). 4th Edition, American College of Radiology, Reston.

45.Vacek, P.M. and Geller, B.M. (2004) A Prospective Study of Breast Cancer Risk Using Routine MammograBreast Density Measurements. Cancer Epidemiology, Biomarkers Prevention, 13, 715-722.

46.Barlow, W.E., White, E., Ballard-Barbash, R., Vacek, P.M., Titus-Ernstoff, L., Carney, P.A., Tice, J.A., Buist, D.S.M., Geller, B.M., Rosenberg, R., Yankaskas, B.C. and Kerlikowske, K. (2006) Prospective Breast Cancer Risk Prediction Model for Women Undergoing Screening Mammography. Journal of the National Cancer Institute, 98, 1204-1214. http://dx.doi.org/10.1093/jnci/djj331

47.American Cancer Society (2009-2010) Breast Cancer Facts & Figures.

American Cancer Society, Inc., Atlanta

89

48.Pisano, E.D., Hendrick, R.E., Yaffe, M.J., Baum, J.K., Acharyya, S., Cormack, J.B., et al. (2008) Diagnostic Accuracy of Digital Mammography versus Film Mammography: Exploratory Analysis of Selected Population Subgroups in DMIST. Radiology, 246, 376-383. http://dx.doi.org/10.1148/radiol.2461070200 49.Tabar, L., Chen, H.H.T., Yan, M.F.A., Tot, T., Tung, T.H., Chen, L.S., Chiu, Y.H., Duffy, S.W. and Smith, R.A. (2004) Mammographic Tumor Features Can Predict Long-Term Outcomes Reliably in Women with 1-14-mm Invasive Breast Carcinoma. Cancer, 101, 1745-1759. http://dx.doi.org/10.1002/cncr.20582

.