Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and is second only to lung cancer as a cause of cancer deaths (1). In the year 2014, approximately 2,36,968 women and 2,141 men in the United States were diagnosed with breast cancer, and the reported deaths from the cancer was 41,211 in women and 465 in men(2) .
In India, the overall incidence of breast cancer is reportedly less in comparison with the United States as given by the statistics in the year 2012, in which around 2,32,000 breast cancer cases were reported in the US, whereas only 1,45,000 new cases were diagnosed in India (3). This apparent statistical disparity, may be attributed to the higher Indian population and the inherent bias against referral and treatment of breast cancer prevalent among the elderly in India, rather than a true reflection.
The incidence of breast cancer is seen to increase with advancement in age, ranging from 1.5 cases per 100,000 in women in the age group of 20-24 years to a peak of 421.3 cases per 100,000 in the age group of 75-79 years. About 95% of newly diagnosed breast cancers occur in women aged 40 years or older and the median age of women at the time of diagnosis is around 61 years.(4),(5). However, approximately 7% of women are diagnosed with breast cancer prior to the age of 40 years (6) and this proportion is seen to be increasing in the recent years. Breast cancers in young females tend to be diagnosed only in the later stages and are noted to be more aggressive with higher mortality rates and higher risk of metastatic recurrence. The reason hypothesized for this aggressive behaviour of breast cancers arising in the younger population is that these cancers may be more enriched with aggressive pathological subtypes of breast cancer (7),(8).
The 5 and 10 year relative survival rates for female breast cancer are 89% and 83% respectively. The early diagnosis of breast cancer increases the survival rates, as more than half (61%) of cases which were diagnosed at a localized stage, had a 5-year relative survival of 99%. Widespread use of screening mammography for early detection of the disease and targeted therapy in management of breast cancers have led to the increase in the survival rates of breast cancers.(9).
RISK FACTORS FOR BREAST CANCER.
Several factors are associated with the development of breast cancer and in the majority of cases, it is not possible to delineate the specific cause. The risk factors of breast cancer can be broadly classified into modifiable and non- modifiable risk factors.
Non modifiable risk factors:
1. Gender:
Female gender is the single most important risk factor associated with the development of breast cancer. Less than 1% of all breast cancer are detected in males , although the incidence of breast cancer among males are increasing in the recent years.(10).
2. Age:
The incidence of breast cancer increases proportionately with advancement in age with the median age at diagnosis being 61years. However, in the recent years, more invasive breast cancers are being diagnosed in the younger age, which include a higher proportion of triple negative and HER-2 over-expressing tumours that are associated with a poor prognosis.(12)(13),(14).
3. Race and ethnicity: Breast cancer are observed to be more common in Caucasian women than in black or Asian women.
4. Family History and Genetic susceptibility.
Genetic predisposition is noted in approximately 20% of breast cancer patients with a positive family history of breast cancer. The risk for breast cancer is 1.5-3 times higher if there is first degree relative who developed the disease before the age of 50, and the younger the relative, the greater the risk. (15). BRCA1 and BRCA2 genes, which are located on the long arms of chromosomes 17 and 13 respectively, account for a major proportion of familial breast cancers. Those with abnormal BRCA1 or BRCA2 gene tend to develop breast cancer at a younger age, with more chances of bilateral disease. Inherited mutations in p53 and PTEN genes are also associated with familial cancer syndromes like Li-Fraumeni and Cowden's respectively, that include a high risk of breast cancer. (16).
5. Reproductive / hormonal factors:
A prolonged reproductive period contribute to the risk of developing carcinoma breast, as in the case of early menarche and delayed menopause, due to prolonged exposure to endogenous oestrogen levels.(16). The risk of breast cancer also increases if a woman is nulliparous or if her first live birth is at or after the age of 30 years.(17). Administration of exogenous estrogen, as in hormone replacement therapy (HRT), increases the risk of developing breast cancer with a relative risk of 1.35 after 5 or more years of use.(18).
6. Prior history of neoplastic disease or hyperplasia in the breast:
Individuals with prior history of invasive carcinoma, carcinoma in situ, or atypical hyperplasia in the breast have a significantly increased risk for the future development of invasive breast carcinoma. The average annual incidence of second cancers in patients with primary breast cancer is 0.7%-0.8% in contrast to 0.11% in the general population. (19). In comparison to patients without hyperplasia, the relative risk for invasive breast cancer was 1.9 times higher in patients with early hyperplasia, 5.3 times in patients with atypical hyperplasia, and 11times in patients with atypical hyperplasia with a positive family history of breast cancer.(20).
7. Radiation Exposure:
Therapeutic radiation exposure is now an important cause of radiation-induced carcinogenesis. Multiple fluoroscopies and also radiation to the chest area, as in the treatment of Hodgkin’s lymphoma, significantly increased the risk for breast cancer, especially in the age group less than 30 years.(21),(22).
Modifiable risk factors:
Approximately 21% of all breast cancer deaths worldwide are attributed to modifiable risk factors like alcohol use, overweight and obesity, and physical inactivity. This proportion is observed to be higher in high-income countries (27%), with major contributions from overweight and obesity. In the low- and middle-income countries, the proportion of breast cancers attributable to these risk factors was 18%, and out of these, physical inactivity contributed a major risk of 10%.(23).
These differences in breast cancer incidences between the developed and the developing countries can partly be explained by dietary effects combined with delayed first childbirth, lower parity, and shorter breastfeeding.(24). The rising trend to adopt western life-style in the low and middle-income countries is an important determinant in the increase of breast cancer incidence in these countries.
BREAST ANATOMY
The breast is a modified sweat gland enveloped within a fibrous fascia. It is composed of three major structures – skin, subcutaneous fat and breast tissue which includes the breast parenchyma and the stroma.
The parenchyma comprises of glandular tissue and ducts which are surrounded by fat and supported by Cooper’s ligaments. Cooper’s ligaments arise from stromal tissue and attach to the prepectoral fascia and dermis of skin to support and suspend the breast tissue (Fig.1.1).
Fig. 1.1. Normal anatomy of Breast.
The breast parenchyma is further divided into 15 -20 lobes or segments that converge at the nipple in a radial arrangement. The ducts from the lobes converge into 6 to 10 major collecting ducts which open at the nipple. Beneath the nipple openings, the lactiferous sinuses are seen as a slight dilation of the ampullary portion of the major ducts.
The lobes are made up of 20 to 40 lobules. Each lobule also consists of branching ducts that divide into subsegmental structures and finally terminate in the terminal duct lobular unit.(25).
The terminal duct lobular unit (TDLU).
The terminal ductal lobular units (TDLU) are the functional units of the breast. The TDLU consists of the extralobular terminal ducts and intralobular terminal ducts. The intralobular terminal ducts form the central portion of the lobule and have multiple outpouchings called acini or ductules (Fig.1.2). These ductules differentiate into the secretory units for breast milk production during lactation. Majority of the benign and malignant pathology arises in this duct and lobular network and specifically, most breast cancers are thought to originate in the terminal ductal lobular unit.(26),(27).
Fig. 1.2: The terminal duct lobular unit (TDLU).
ETIOPATHOGENESIS OF BREAST CANCER.
The current understanding of etiopathogenesis breast cancer is that invasive cancers arise through a series of molecular alterations that take place at the cellular level and subsequently results in uncontrolled cell growth. (28).
Breast cancers can be divided into two major groups – carcinomas and sarcomas.
Carcinomas comprise of the majority (approximately 99%) of all breast cancers and include cancers that arise from the epithelial component of the breast, i.e. the cells that line the lobules and the terminal ducts.
Sarcomas on the other hand, are rare cancers (less than 1% of primary breast cancers) that arise from the stromal (connective tissue) components of the breast. These stromal component cells include myofibroblasts, endothelial cells lining the blood vessels, and cancers arising from these supportive cells (eg: Phyllodes tumours and angiosarcomas).
Carcinomas are further histologically classified into many different subtypes.
The first major division is into in situ and invasive carcinoma.
In situ carcinoma or "pre-invasive" carcinoma is the very early stage of breast cancer, in which the malignant cells are confined to the epithelial lining of the breast and has not yet invaded the breast tissue. These types of breast cancers have significant potential to become invasive cancer.
Invasive cancer is the type of cancer in which the malignant cells have infiltrated outside the breast lobules and ducts and into the breast connective tissue. Invasive carcinomas have the potential to metastasize to other sites of the body.
Breast cancers are further classified into ductal carcinomas and lobular carcinomas. Approximately 80% of breast carcinomas are invasive ductal carcinomas and 10-15 % are invasive lobular carcinomas. Invasive ductal carcinomas and invasive lobular carcinomas exhibit distinct pathologic features. Invasive lobular carcinomas present as cells arranged individually, in a single file or in sheets, and have different molecular and genetic alterations that distinguish them from the ductal carcinomas. The rest of invasive carcinomas comprises of other special types of breast cancer that have characteristic pathologic features. These special types comprises of colloid (mucinous), medullary, micropapillary, papillary, and tubular types of breast cancers.
The Cancer Genome Atlas Network (TCGA) states that there are 4 major pathological subtypes of breast cancer, based on the presence or absence of molecular markers like estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). These are classified as:
• Luminal A.
• Luminal B.
• HER2-positive.
• Triple negative (Basal-like).
• Luminal A.
This is the most common subtype, comprising of approximately 75% of all breast cancers. These cancers express the estrogen receptor (ER+) and/or the progesterone receptor (PR+) but not HER2 (HER2-). Breast cancers belonging to this subtype tend to be slow growing, have lower histological grade and are less aggressive than the other subtypes. Luminal A tumours are seen in the older age group and have the most favourable prognosis, since the expression of hormone receptors makes these cancer subtype eligible for hormonal therapy.(29).
• Luminal B.
Similar to luminal A breast cancers, luminal B subtypes are ER+ and/or PR+ and are further defined by being positive for Ki67 (indicator of a large proportion of actively dividing cells) or HER2. Around 10% of breast cancers are ER+ and/or PR+ and HER2+ and belong to this subtype. Luminal B breast cancers tend to be of a higher grade and are more aggressive than luminal A breast cancers.(30).
• HER2-positive.
This subtype of breast cancer is less common and contribute to approximately 4% of breast cancers. The breast cancers produce excess HER2 with no expression of the estrogen and progesterone hormone receptors. They tend to grow faster and spread more aggressively than the above mentioned subtypes of breast cancers due to higher histological grade. Younger age group (<40 years) are at a higher risk for this subtype when compared to Luminal A subtype. It is also associated with poorer short-term prognosis compared to ER+ breast cancers. (29). However, with the recent widespread use of targeted therapies for HER2+ cancers in the recent years, the survival rates of these cancer subtypes have increased.
• Triple negative (Basal- like).
About 12% of breast cancers belong to this subtype. These subtypes doesnot express the hormone receptors or HER2 receptors and are nearly two times more common in black women than white women. They are also more common in premenopausal women (less than 40 years) and those with a BRCA1 gene mutation. Triple negative breast cancers have the worst short-term prognosis than other breast cancer types because they tend to be of higher histological grade, highly aggressive and have no current targeted therapy. (29),(31).
IMAGING MODALITIES FOR DETECTION OF BREAST CANCER.
The field of breast imaging has transitioned through a wide variety of technological advances, starting from the early days of direct-exposure film mammography to screen-film mammography to the current era of full-field digital mammography and digital breast tomosynthesis. Ultrasonography and magnetic resonance imaging of breast serves complementary to mammography, for the diagnostic workup and screening for breast cancer in high-risk subgroups of women. In addition, interventional procedures like percutaneous biopsy to obtain tissue diagnosis and localization procedures like stereotactic wire localization has emerged to guide in surgical excision of non palpable breast lesions.
1. Mammography.
Mammography, which utilizes low energy x- rays (approximately 30 kVp) for the detection of abnormal densities in breast tissue, is the primary screening modality for breast cancer. Early detection of breast cancer increases the probability of cure and mammography has been shown to reduce breast cancer mortality rate by 25%-30% in population-based screening programmes.(32). Although mammography is the gold standard in the screening for breast cancer, the sensitivity is highly variable, ranging from 98% in women with fatty breast parenchyma, to 36% in women with dense breast.(33).
The two basic types of mammographic examination are screening mammography and diagnostic mammography.
Screening mammography refers to the examination of an asymptomatic woman to detect clinically occult breast cancer.(34). This type of examination includes the two standard views of the breast- the mediolateral oblique (MLO) and the craniocaudal (CC)view.
Diagnostic mammography is performed when there is clinical suspicion of breast cancer like a palpable breast lump or an abnormal screening mammogram. This examination may require additional views of the breast, such as spot compression and magnification views, and sometimes correlative ultrasonography.(35).
According to ACR BI-RADS Atlas (fifth edition), the parameters taken into consideration in the analysis of a mammographic image include:(36).
1. Breast composition
A- Entirely fatty
B- Scattered areas of fibroglandular density.
C- Heterogeneously dense breast, which may obscure small masses.
D- Extremely dense breast, which lowers sensitivity.
2. Mass
Table. 1.1
Shape • Oval (including lobular margins)
• Round.
• Irregular.
Margin • Circumscribed-well defined margin.
• Obscured- margin hidden by superimposed fibroglandular tissue.
• Microlobulated- small undulating margins.
• Indistinct- ill- defined margin.
• Spiculated- radiating lines from a mass.
Density • Fat.
• Low.
• Equal.
• High.
3. Calcifications
A) Morphology
Table 1.2
Suspicious • Amorphous- small and/or hazy in appearance with no particular shape.
• Coarse heterogeneous- irregular, conspicuous calcifications between 0.5 mm and 1 mm.
• Fine pleomorphic- discrete calcifications (<0.5mm) without fine linear and linear branching forms.
• Fine linear or linear branching- Thin, linear irregular calcifications (<0.5mm), with occasionally branching.
Typically benign • Skin calcifications.
• Vascular calcifications.
• Coarse or Popcorn calcification.
• Large rod like.
• Round.
• Rim calcification.
• Milk of calcium.
• Suture.
B) Distribution (Fig. 1.3).
• Diffuse- distributed randomly throughout the breast.
• Regional- occupying a large portion of breast tissue > 2 cm greatest dimension.
• Grouped (previously termed clustered)- few calcifications occupying a small portion of breast tissue. Lower limit is 5 calcifications within 1 cm and upper limit is a larger number of calcifications within 2 cm.
• Linear- arranged in a line – suggests deposits in a duct.
• Segmental-arranged in a triangular pattern, with the apex directed towards the nipple – suggests deposits in a duct or ducts and their branches.
Fig. 1.3:
C) Asymmetries
• Asymmetry- area of fibroglandulair tissue visible on only one mammographic projection, mostly caused by superimposition of normal breast tissue.
• Global asymmetry- asymmetry over at least one quarter of the breast.
• Focal asymmetry- asymmetry visible on two projections.
• Developing asymmetry – interval new, larger and more conspicuous than on a previous examination.
D) Architectural distortion – The term architectural distortion is used, when the normal architecture of the breast is distorted with no definite mass visible. This can include thin straight lines or spiculations radiating from a point, and focal retraction, distortion or straightening at the edges of the parenchyma.
Architectural distortion can also be seen as an associated feature.
E) Associated features.
• Nipple retraction.
• Skin retraction.
• Skin thickening.
• Trabecular thickening.
• Axillary adenopathy.
• Architectural distortion.
• Calcifications.
F) Location of lesion – includes laterality, quadrant and clock face, depth and distance from the nipple.
Final assessment category.
Table 1.3:
Assessment category. Description Management Likelihood of malignancy
Category 0
Incomplete.
Requires additional imaging evaluation Recommend additional imaging and/or comparison with prior examination(s).
N/A
Category 1 Negative. Routine mammography
screening. Essentially 0% likelihood of malignancy
Category 2 Benign. Routine mammography
screening. Essentially 0% likelihood of malignancy
Category 3 Probably Benign. Short-interval (6-month)
follow-up or continued
surveillance mammography. ≥ 0% but ≤ 2% likelihood of malignancy
Category 4
• Category 4A: Low suspicion for malignancy.
• Category 4B: Moderate suspicion for malignancy
• Category 4C: High suspicion for malignancy. Suspicious abnormality. Tissue diagnosis > 2% but < 95% likelihood of malignancy.
> 2% to ≤ 10% likelihood of malignancy
> 10% to ≤ 50% likelihood of
Malignancy
> 50% to < 95% likelihood of
malignancy
Category 5
Highly suggestive of
malignancy. Tissue diagnosis ≥ 95% likelihood of malignancy
Category 6
Known biopsy proven malignancy. Surgical excision when clinically
appropriate N/A
The general morphological features of a mass which are considered suspicious for malignancy include irregular shape and poorly circumscribed / spiculated / microlobulated margins. Calcifications with suspicious morphology are classified as amorphous, coarse heterogeneous, fine pleomorphic, fine linear or fine-linear branching. According to the distribution, grouped (or clustered), linear and segmental microcalcifications are suspicious for malignancy. Associated features like nipple retraction, skin retraction, skin thickening, trabecular thickening and axillary adenopathy if present , increases the likelihood of a malignant lesion.
Approximately 40% of breast cancers present with microcalcifications and frequently serve as the only mammographic feature indicating the presence of a tumour. Almost 90% of ductal carcinoma in situ (DCIS) appear as microcalcifications, 40% of which progress to an invasive breast cancer.(37)
Recently, characteristic mammographic imaging features were found to be associated with the molecular subtypes of breast cancer. Triple- negative tumours were more frequently found to be round, oval, or lobulated (67.7%) with indistinct margins (61.5 %), while HR-positive/HER-2-negative tumours were more frequently irregular (80%), with spiculated margins 68.3% (38). Triple- negative tumours can less commonly presents as focal asymmetry (9%–22%), or as calcifications associated with a mass (15%).(39),(40).
As regarding calcifications, HER2-enriched subtype were associated with pleomorphic microcalcifications (87%) while Luminal A/B subtype often presented with amorphous or coarse heterogeneous calcifications. (41).