The role of imaging in breast diagnosis including screening and excision of impalpable lesions

A. Robin M. Wilson and R. Douglas Macmillan

Introduction

Breast cancer is a major health problem. Worldwide it has an increasing incidence, with over 1 million newly diagnosed cases each year, and is the commonest cancer to affect women and the commonest cause of cancer death in women. Breast cancer mortality in the UK is among the highest in the world, with approximately 28 deaths per 100 000 women per annum. This equates to around 48 000 new breast cancers diagnosed and 11 500 deaths attributable to breast cancer each year. Approximately 1 in 9 women in the UK will develop breast cancer at some time during their life.¹

Strategies for diagnosing and managing breast cancer are based on our current understanding of breast disease epidemiology. Around 5% of breast cancer is hereditary, mainly associated with the BRCA1 and BRCA2 gene defects. This type of breast cancer tends to occur in younger women. The remaining 95% of breast cancer is sporadic and its incidence increases with age. Breast cancer is rare under the age of 35 years and over 80% of breast cancer occurs in women over the age of 50. The main causes of sporadic breast cancer are believed to be environmental factors. Recognised risk factors include early menarche, late menopause, nulliparity, and long-term use of the contraceptive pill and hormone replacement therapy (HRT).

As there is a poor understanding of the causes of breast cancer, primary prevention is currently not a realistic or achievable option. It is known that earlier diagnosis of breast cancer is more likely to result in a favourable outcome. Tumour size at diagnosis, grade and lymph node stage are the best predictors of outcome. Regardless of tumour type or grade, the smaller a breast cancer is at the time of diagnosis, the more likely it is that it has not spread beyond the breast. As a result the current strategy for reducing breast cancer mortality is to seek diagnosis as early as possible.

Early detection and improvements in treatment have led to a 30% reduction in breast cancer mortality in the UK in all age groups over the past 30 years.²

Early diagnosis is achieved by encouraging women to present as soon as possible to breast clinics when they develop breast symptoms and through regular breast cancer screening. Breast imaging is fundamental to both.

Imaging in symptomatic breast practice

Based on mortality statistics from the 1980s and 1990s, although the UK did not have the highest incidence of breast cancer it did have the highest death rate.

Recognising that breast cancer diagnosis and treatment required significant improvement, in 1995 the UK Department of Health published guidelines for improving outcomes in breast cancer. These guidelines were updated in 2002 and 2010 by the National Institute for Clinical Excellence (NICE).³ The guidelines emphasise the following three key issues in breast cancer care:

• accurate and timely diagnosis;

• appropriate treatment decided by accurate staging of disease;

• appropriate follow-up of patients undergoing treatment.

Imaging is required at all three stages of this process, and mammography and ultrasound have a pivotal role to play. About 60% of breast cancer is diagnosed in symptomatic breast referral clinics. These clinics follow protocols that define the triple test, the combination of clinical assessment, imaging (mammography and ultrasound) and core biopsy or needle cytology, as the required standard.⁴ ‘One-stop’ clinics are recommended at which all the necessary tests required to make a diagnosis, including needle biopsy, are performed at one clinic visit. In order to achieve the earliest possible diagnosis of symptomatic breast cancer, women are encouraged through a variety of health promotion methods to present to these clinics as soon as they develop any change in their breasts. The clinical and imaging assessments in these clinics should be performed by appropriately trained and experienced staff. All such staff do not need to be doctors but they need to be able to give an independent opinion and be trained to an appropriate level.

Breast imaging techniques

Mammography

X-ray mammography has been the basis of breast imaging for more than 30 years. The sensitivity of mammography for breast cancer is age dependent. The denser the breast, the less effective this method is for detecting early signs of breast cancer. Breast density tends to be higher in younger women and increased density obscures early signs of breast cancer. The sensitivity of mammography for breast cancer in women over 60 years of age approaches 95%, while mammography can be expected to detect less than 50% of breast cancers in women under 40 years of age.⁵

Mammography uses ionising radiation to obtain an image and therefore should only be used where there is likely to be a clinical benefit. Consensus is that the benefits of mammography in women over the age of 40 years are likely to far outweigh any oncogenic effects of repeated exposure. Screening of women over the age of 40 by mammography is accepted practice. However, in symptomatic practice, there is rarely an indication for performing mammography in women under the age of 35 unless there is a strong clinical suspicion of malignancy. In many centres, all women over the age of 35 presenting to breast clinics undergo mammography as a routine. Practice is changing and ultrasound alone is being used increasingly for the assessment of women with focal breast symptoms in women under 40 years of age and even in some women aged 40–50. Mammography is routine in all women in the screening age group attending symptomatic clinics who have not had a screening mammogram in the past year.

Most mammography in the UK is now carried out using digital image acquisition.6–9 There are major benefits from acquiring mammograms in direct digital format.⁹ Compared with conventional film/screen mammography, the benefits of full-field digital mammography include better imaging of the dense breast, the application of computer-aided detection and a number of logistical advantages providing potential for more efficient mammography services.¹⁰^,¹¹ The much wider dynamic range of digital mammography means that visualisation of the entire breast density range on a single image is easily achievable. In the clinical setting, comparative studies have shown that digital mammography performs in general as well as film/screen mammography but is better in younger women and in women with dense breasts.⁶^,⁷

Mammography is the basis of stereotactic breast biopsy, which can be carried out using a dedicated prone biopsy table or by using an add-on device to a conventional upright mammography unit. Stereotaxis is used to biopsy impalpable lesions that are not clearly visible on ultrasound (e.g. microcalcifications).

Ultrasound

High-frequency (≥10 MHz) ultrasound is a very effective diagnostic tool for the investigation of focal breast symptoms.¹² Ultrasound does not involve ionising radiation and is a very safe imaging technique. It has a high sensitivity for breast pathology and also a very high negative predictive value.¹³

High-resolution ultrasound easily distinguishes between most solid and cystic lesions and can differentiate benign from malignant lesions with a high degree of accuracy. However, in most circumstances, solid lesions seen on ultrasound require needle sampling for accurate diagnosis.

Ultrasound is the technique of choice for the further investigation of focal symptomatic breast problems at all ages. Under 40 years of age, when the risk of breast cancer is very low, it is usually the only imaging technique required. Over 40, when the risk of breast cancer begins to increase, it is often used in conjunction with mammography. Ultrasound is less sensitive than mammography for the early signs of breast cancer and is therefore not used for population screening. However, ultrasound does increase the detection of small breast cancers in women who have a dense background pattern on mammography.⁵ In the screening setting there is clear evidence that the addition of ultrasound improves small cancer detection rates, particularly in women with dense breasts, but there is currently insufficient evidence of any mortality benefit and insufficient resources to allow for routine ultrasound screening of women with dense breasts on mammography. Adding ultrasound to mammography or magnetic resonance imaging (MRI) screening does increase cancer detection but also significantly increases the false-positive rate. Ultrasound is the technique of first choice for biopsy of both palpable and impalpable breast lesions visible on scanning.

Ultrasound is now used routinely to assess the axilla in women with breast cancer in most units. Axillary nodes that show abnormal morphology can be sampled accurately by fine-needle aspiration (FNA) or needle core biopsy.¹⁶^,¹⁷ Discussion of the role of axillary ultrasound and FNA and core biopsy can be found in Chapter 7.

Up to 50% of patients with axillary metastatic disease can be diagnosed by ultrasound combined with FNA or core biopsy, which may avoid the need for sentinel node biopsy in some women with pathologically proven nodal involvement.¹⁴^,¹⁵

Doppler ultrasound adds little to breast diagnosis and is not widely used. Three-dimensional ultrasound of the breast is said to increase the accuracy of biopsy and the detection of multifocal disease but is not widely available. Elastography is a new application of ultrasound technology that allows the accurate assessment of the stiffness of breast tissue. It is being evaluated at present and may prove to be a useful tool in excluding significant abnormalities, for instance in assessment of asymptomatic abnormalities detected by ultrasound screening.

Magnetic resonance mammography (MRM)

MRM is now widely available. In order to image the breast the patient is scanned prone and injection of intravenous contrast is required. MRM is the most sensitive technique for detection of breast cancer, approaching 100% for invasive cancer and up to 92% for ductal carcinoma in situ (DCIS), but it has a high false-positive rate.¹⁸^,¹⁹^,²⁰ Rapid acquisition of images facilitates assessment of signal enhancement curves that can be helpful in distinguishing benign from malignant disease. Significant overlap in the enhancement patterns is seen, so needle sampling of the lesions detected is often required. Magnetic resonance-guided breast biopsy is available in a few centres but most breast lesions seen on MRM that are larger than 5 mm can be seen on ultrasound if they are clinically significant.

MRM is the best method for screening younger women (under 40 years) at increased risk of breast cancer but, because of cost, it is unlikely to be used for general population screening.21–24

MRM is the best technique for imaging women with breast implants. It is also of benefit in identifying recurrent disease where conventional imaging and biopsy have failed to exclude recurrence. Provided it is carried out more than 18 months after surgery, MRI will accurately distinguish between scarring and tumour recurrence. MRI is recommended to detect multifocality prior to conservation surgery for women with lobular cancers and those with occult cancer on mammography or with a significant discrepancy of size on conventional imaging. However, it should not be used routinely and a randomised trial (COMICE) showed no benefit in reducing re-excision rates but did increase significantly the mastectomy rates for those who had MRI. Breast MRI is of value in assessing response of large or locally advanced breast cancers to neoadjuvant chemotherapy. MRI of the axilla can demonstrate axillary metastatic disease but its sensitivity is not sufficient to replace surgical staging of the axilla. For advanced breast cancer, MRI is the technique of choice for assessing spinal metastatic disease.

Computed tomography

Computed tomography (CT) has no current proven role in primary imaging of the breast. but dedicated low-dose breast CT is being introduced; its clinical efficacy has yet to be determined. CT is used to diagnose and stage systemic spread of breast cancer and to assess response of metastatic disease to treatment, particularly lung, pleural and liver metastases. Some patients with breast cancer do have their cancers diagnosed incidentally during a routine CT scan.

Isotope imaging

Breast scintigraphy is not widely used because of its lack of sensitivity compared with other techniques. It is used in a few centres to stage the breast prior to surgery and to assess response to treatment. Scintigraphy is widely used to diagnose and assess the presence of skeletal metastatic disease. It is now often combined with a low-resolution non-contrast CT scan.

Positron emission scintigraphy, particularly when combined with CT, is a technology that may have a role in future in staging breast cancer and monitoring response to treatment. It is widely used in the USA but elsewhere, at present, it continues to be regarded as a research tool and its specific uses and indications in assessing breast disease are still being defined.

Breast cancer screening

Aim

The aim of breast screening is to reduce mortality through early detection. Randomised controlled trials and case–control studies carried out between the 1960s and 1980s have demonstrated that population screening by mammography can be expected to reduce overall breast cancer mortality by around 25% and by 35–40% in those who participate.

The validity of these trials was questioned in 2000–2002 but subsequent reviews by the Swedish combined trials group and a World Health Organisation International Agency for Research on Cancer committee of experts have reaffirmed the mortality benefit of mammographic screening and determined that criticisms of the mammographic screening trials were unjustified.25–30

The mortality benefit of screening is greatest in women aged 55–70 years.²⁷^,²⁸ The mortality benefit of screening women aged between 40 and 55 is approximately 20%. Screening women under the age of 40 has not been shown to provide any mortality benefit.²⁷^,²⁸

Population screening

Breast screening has been introduced in many countries over the past 25 years. In most countries, screening is recommended in all women aged 40 and over but in countries that provide population-based screening, women of 50 and over are specifically targeted. Breast cancer screening was introduced in the UK in 1987 and provides screening by invitation, free at the point of delivery, to all women between the ages of 50 and 70.¹ Women over 70 can attend but are not invited. Over 70% of the invited population need to attend for a significant overall mortality benefit to be achieved. Women under the age of 50 are not offered screening in the UK unless they are at increased risk. A randomised trial of extending the screening invitation to the age range 47–73 years was started in 2010. The results of this trial will not be available until after 2020. From 2010 screening with annual MRI in addition to mammography has been offered to women at very high risk of breast cancer, including BRCA1 and BRCA2 gene carrriers.

Method and frequency

The optimum screening method is two-view mammography; clinical examination of the breast and breast self-examination have not been shown to contribute to mortality reduction through early detection and so are not recommended.⁹^,³¹^,³²

Women aged 50–70 in the UK are invited for mammography every 3 years. There has been some concern that this screening interval is too long. Mammography can be expected to detect breast cancer approximately 2 years before it becomes clinically apparent. The frequency of mammographic screening is determined by the lead-time of breast cancer. Based on the average growth time of breast cancer in different ages, this means that mammographic screening should ideally be carried out yearly in women aged 40–50, every 2 years in women aged 50–60 and every 3 years thereafter. However, the UK breast screening frequency trial completed in 1995 did not show any predicted benefit for women aged 50–64 screened every year compared with those screened every 3 years.³³ Screening once every 3 years can be expected to detect approximately two-thirds of all breast cancers that will arise during the 3-year screening interval.

One-third of breast cancers present in the interval between screens and are called interval cancers. Half of these present in the third year after screening.

Factors affecting the effectiveness of screening

HRT increases breast density and in a proportion of women this reduces the sensitivity of mammography for breast cancer.⁹^,^32–40 Up to 25% of women taking combined oestrogen/progestogen preparations continuously show increased density on mammography. This effect is significantly less with other HRT preparations. As well as reducing sensitivity HRT also reduces the specificity of mammographic screening. HRT also increases the risk of developing breast cancer.³⁴

Quality assurance

Breast screening programmes should have inbuilt quality assurance; the UK NHS Breast Screening Programme is subject to comprehensive quality assessment and all 100 screening units across the country have to comply with nationally defined standard guidelines. There are national targets for screening set by a central Department of Health Advisory Committee (Table 1.1).

Table 1.1

NHS Breast Screening Programme: screening targets, June 2005

The screening process

Women invited for screening attend either a static or mobile screening unit where two-view mammography is performed. The images are then double read within a few days. The vast majority of women (95%) are informed by letter within 2 weeks of attendance that their mammograms show no evidence of breast cancer. Those women in the appropriate age range will be invited for screening 3 years later. They are advised to contact their general practitioner as soon as possible if they become aware of any change in their breasts in the meantime.

The screening process includes a fully integrated multidisciplinary assessment process for all screen-detected mammographic abnormalities; screening programmes should ideally retain responsibility through to definitive diagnosis. Approximately 5% of women screened are recalled for further assessment of a problem identified at screening. Some women are recalled for further assessment of a clinical sign or symptom identified at the time of screening but the vast majority of women are recalled because of a mammographic abnormality.

The most important cancers detected at screening are high-grade DCIS, as most cases of this type will progress to grade 2 or 3 invasive breast cancer within the following 3 years, and grade 2 and 3 invasive breast cancers under 10 mm in diameter, as at this size these tumours are much less likely to have metastasised.⁴¹^,⁴²

The common types of mammographic abnormality and their positive predictive value for cancer are shown in Table 1.2. Well-defined masses are almost always benign and do not require recall, whereas ill-defined masses and spiculated lesions always require further assessment (Figs 1.1 and 1.2). Clustered microcalcifications account for a high proportion of recalls that result in needle biopsy. More than 20% of screen-detected breast cancer is DCIS, mostly high or intermediate grade, and most of this type of cancer is detected by the presence of clustered microcalcifications (Fig. 1.3). Invasive cancer is usually represented on mammography by either an ill-defined or spiculated mass. It is essential to detect these lesions at small size as they more commonly represent grade 2 or 3 invasive cancer.

Table 1.2

Positive predictive value (PPV) for malignancy of mammographic signs

Sign	PPV (%)
Well-defined mass	<1
Ill-defined mass	35–50
Spiculated mass	50–90
Architectural distortion	20–40
Asymmetric density	<2
Clustered microcalcifications	15