Breast Cancer Evaluation
INTRODUCTION ˇ@

Breast cancer incidence

Breast cancer is one of the most important diseases for US women and constitutes one fourth of female cancers, making it the most common cancer in females. Breast cancer develops in as many as 1 in 8 women by the time they are aged 80 years and is 100 times less common in men. Breast cancer accounts for approximately 15% of female cancer deaths. Approximately 182,800 new cases per year occur in the US, causing 40,800 deaths per year. Breast cancer is the leading cause of death in women aged 44-50 years. The 5-year survival rate is 60% overall but is greater than 80% for early disease.

Approach to evaluation

As with all clinical conditions, approach breast cancer evaluation in the systematic way learned at the start of clinical training, namely with an ordered inquiry beginning with symptoms and general clinical history, followed by clinical examination and finally investigation, which can include imaging and ultimately biopsy. This approach naturally lends itself to a gradually increasing degree of invasiveness, so that when a diagnosis is obtained, the process can be stopped with the minimum amount of invasion and, consequently, minimum discomfort to the patient. As the more invasive investigations tend also to be the most expensive, this approach usually is the most economical.

Evaluation goals

The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the most appropriate surgery. Therefore, the ultimate goal is to achieve the most appropriate degree of breast conservation while minimizing the need for reoperation.

Triple assessment

In breast cancer, the general approach to evaluation has become formalized as triple assessment, involving clinical examination, imaging (usually mammography and/or ultrasound), and needle biopsy, but always perform this as part of a more general assessment beginning with clinical history.

CLINICAL ASSESSMENT ˇ@

Clinical History
Many early breast carcinomas may be asymptomatic, particularly if they presented through a breast-screening program. If the patient has not noticed a lump, then symptoms raising suspicion may include the following:

Pain or discomfort is not usually a symptom of breast cancer. The clinician should be alert to symptoms of metastatic spread, such as the following:

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The clinical evaluation should include an assessment of specific risk factors for breast cancer as follows:

Age

Genetics

Other pathology

Risk is increased by previous breast cancer, ovarian cancer, endometrial cancer, ductal carcinoma in situ, lobular carcinoma in situ, hyperplasia (unless mild), complex fibroadenoma, radial scar, papillomatosis, sclerosing adenosis, and microglandular adenosis. Risk is decreased by cervical cancer.

Years menstruating

Factors increasing the number of menstrual cycles increase the risk, probably due to increased endogenous estrogen exposure. Such factors include the following:

Obesity

Increased risk probably is due to adipose conversion of androgens to estrogens.

Socioeconomic class

Incidence is increased in individuals in a higher socioeconomic class

Exogenous factors

Risk is increased by the following:

Other dietary, cultural, and/or geographic influences include the following:

Clinical Examination

Outline the following features in nonmedical terms when instructing a patient in self-examination of the breasts. Explaining to the patient that the axillary tail must be included in the examination is important. Many patients are too anxious to examine their own breasts or find it too difficult, possibly because of generalized nodularity. In this situation, stressing the need of the patient simply to alert a clinician to any change in the breasts, particularly if the change persists through a complete menstrual cycle, often is easier. Findings that raise suspicion include the following:

The nature of palpable lumps is often difficult to determine clinically, but features that raise suspicion include the following:

To detect subtle changes in breast contour and skin tethering, examination must include an assessment of the breasts with the patient upright with arms raised. Assess fixation to muscle by moving the lump in the line of the pectoral muscle fibers with the patient bracing her arms against her hips. A complete examination includes assessment of the axillae and supraclavicular fossae and examination of the chest, sites of skeletal pain, and the abdomen as well as a neurologic examination.

BREAST CANCER IMAGING ˇ@

After clinical assessment, the second part of triple assessment involves imaging. Many modalities of imaging can be applied, and the selection is based on age, sensitivity, specificity, local availability, and cost. It often is appropriate to perform more than one imaging modality to further improve diagnostic accuracy and to clarify indeterminate findings. The different modalities are compared in Table 1.

Table 1. Accuracy of Breast Imaging Modalities

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Modality Sensitivity Specificity Positive Predictive Value Indications
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Mammography 63-95%
(>95% palpable,
50% impalpable,
83-92% in women older than 50)		 14-90%
(90% palpable)		 10-50%
(94% palpable)		 Initial investigation for symptomatic breast in women older than 35 years and for screening. Investigation of choice for microcalcification.
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Ultrasound 68-97% (palpable) 74-94% (palpable) 92% (palpable) Initial investigation for palpable lesions in women younger than 35 years.
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MRI 86-100% 21-97%
(<40% primary cancer)		 52% Scarred breast, implants, multifocal lesions, borderline lesions for breast conservation
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Scintigraphy 76-95% (palpable)
52-91% (impalpable)		 62-94%
(94% impalpable) 		70-83%
(83% palpable,
79% impalpable)		 Lesions greater than 1cm, axilla assessment; may predict drug resistance
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Positron emission tomography (PET) 96%
(90% axillary metastases)		 100%
ˇ@		 Axilla assessment, scarred breast, multifocal lesions
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Mammography

Two-view mammography (ie, craniocaudal and oblique) is the imaging method of choice for breast screening. In the US, annual screening mammography is recommended with clinical examination from the age of 40 years.

Despite its use as the tool of choice for breast screening, mammography has significant limitations when used in isolation.

Although in general a highly sensitive investigation, sensitivity is much reduced in the younger or more dense breast; therefore, mammography is considered inappropriate in patients younger than 35 years. However, many centers now are using mammography in patients aged 30 years and older who are in high-risk groups. Evaluation of breast tissue is not possible when obscured by implants or in the presence of heavy scarring from previous surgery.

The positive predictive value of mammography can be as low as 10%, demonstrating the need for other imaging modalities, such as ultrasound, to distinguish solid from cystic radiodensities.

However, mammography remains the investigation of choice for detecting and classifying microcalcification, as follows:

Mammography is also efficient in detecting larger patterns of calcification, such as the outlining of calcified arterioles or the coarse patchy calcification in long-standing fibroadenomata.

Other features that raise suspicion on mammography include the following:

Indeterminate radiodensities can be assessed further mammographically by the following:

Ultrasound

Mammographic features often require further ultrasound evaluation, for example to distinguish between solid and cystic lesions or to determine accurately the size of a spiculated lesion. Ultrasound therefore is an indispensable adjunct to mammography and is one of the most useful investigations of a palpable breast lump.

Ultrasound is becoming ever more sophisticated. Higher resolutions are being achieved, and the introduction of Doppler enables definition of characteristic blood flow patterns. This can aid the separation of benign and malignant lesions and distinguish lymph node metastases from normal or reactive lymph nodes. Tridimensional images also may be useful in the future.

Ultrasonic features of malignancy include the following:

Features of benign lesions include the following:

MRI

MRI is a particularly useful modality for detailing architectural abnormalities in the breast and can detect lesions as small as 2-3 mm. In cancers, it is useful in defining the precise size of the tumor and in detecting multifocal disease. This is particularly helpful when deciding whether borderline cases are appropriate for breast-conserving surgery.

MRI allows for the construction of tridimensional images, and its versatility is enhanced by the use of different sequences, including high resolution, rapid imaging, fat suppression, subtraction, and dynamic.

Dynamic imaging is the most specific sequence and can distinguish between benign and malignant lesions, which is particularly useful in the scarred breast when looking for tumor recurrence. Dynamic imaging relies upon the shape of the time-signal curves using gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement; malignancies typically show rapid, strong enhancement because of high vascularity.

Scintimammography

Scintimammography, while less sensitive than MRI for lesions smaller than 1 cm, is more specific for palpable lesions and is useful for detecting axillary involvement.

The label typically used is 99mTc-Sestamibi, a compound that concentrates in mitochondria. The efflux of this label is related to expression of the multidrug resistance protein. Therefore, the size of the signal distinguishes the high metabolic rate of a malignant tumour and may predict resistance to chemotherapy.

Single photon emission computed tomography (SPECT) promises to advance scintimammography in the same way that CT scans have advanced plain radiographs.

Positron emission tomography

PET is the most sensitive and specific of all the imaging modalities in breast disease, but it is also one of the most expensive and least widely available. Using a wide range of labeled metabolites (eg, fluorinated glucose [18FDG]), changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status can be detected. At present, its main use may be for detection of recurrences in the scarred breast, but it also is useful in multifocal disease and in detecting axillary involvement.

BIOPSY ˇ@

Pathologic diagnosis of a breast lesion can be achieved using a number of biopsy techniques. With a larger biopsy sample, greater accuracy and amount of information is obtained, but this is at the expense of increased invasiveness. Ideally, needle biopsies should be performed after imaging to prevent distortions of imaging because of hematoma. Table 2 compares the accuracy of needle biopsy techniques.

Table 2. Accuracy of needle biopsy techniques

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Needle type Sensitivity Specificity
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Fine needle aspiration 52-95% 95-100%
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Tru-Cut 68-84% 100%
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Biopty cut 18G 93-96% 100%
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Biopty cut 14G 88-98% 100%
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Mammotome
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Fine needle aspiration

The least invasive method of biopsy is fine needle aspiration (FNA). The technique of FNA is determined largely by individual preference, which may, in part, reflect hand size and strength. A 21-gauge (green) needle is used most commonly, although a 23-gauge (blue) needle can yield as much information in some people’s hands, with less discomfort and bruising. Some clinicians opt for a hand-held 10-mL syringe, while others prefer a 20-mL syringe used with a syringe holder. Syringe holders allow a vacuum to be maintained easily but can make control of the needle tip less precise.

Disinfect the skin with an alcohol wipe and pass the needle through the lesion a number of times while maintaining suction and steadying the breast tissue with the other hand. With all needle biopsies of the breast, appreciating the risk of causing a pneumothorax is important; wherever possible, angle the needle tangentially to the chest wall. Continue sampling until aspirate is observed at the bottom of the plastic portion of the needle.

Transfer the aspirate to the slides. Spreading of the aspirate must be thin enough to visualize individual cells. The slides may be air dried or fixed according to local preference of the laboratory. Cytospin preparations of the aspirate may allow a greater number of slides to be made.

Wide bore needle biopsy

Core biopsy uses a Tru-Cut needle, ideally 14-gauge. Because of the fibrous nature of much breast tissue, adequate samples can be obtained best using a spring-loaded firing device, such as the Biopty-Cut system. The procedure is often less painful than FNA despite the wider bore needle.

Inject local anesthetic beneath the skin. The cores from a few passes of the needle are fixed immediately in formalin. If the lesion contains calcification on the mammogram findings, the cores are x-rayed to confirm presence of calcification and, therefore, are representative. The risk of bruising is higher than with FNA, and typically a pressure dressing is applied for at least 24 hours.

Often, the samples are large enough to give detailed histologic assessment, including type and grade of tumor and hormone receptor status, but sampling error may occur if the cores are not representative of the entire lesion.

Some centers now provide even wider bore core biopsies, up to 11-gauge, using the Mammotome vacuum system. This apparatus is relatively expensive but may point to new methods of therapeutic excision biopsy without resorting to open surgery.

Excision biopsy

The ultimate diagnostic biopsy is open excision biopsy of a lesion, normally performed under general anesthetic. Open excision biopsy should be reserved for lesions for which some doubt remains regarding diagnosis after less invasive assessment or for benign lesions that the patient wants removed. A wide clearance of the lesion usually is not the goal in diagnostic biopsies, thus avoiding unnecessary distortion of the breast. Ongoing audit is essential to help reduce an excessive benign-to-malignant biopsy ratio.

EVALUATION OF SCREEN-DETECTED LESIONS ˇ@

Criteria for screening

In women older than 40 years, breast screening in the US occurs annually by clinical examination and 2-view mammography (ie, oblique and craniocaudal). In patients aged 20-39 years, clinical examination is advised every 3 years, supplemented by breast self-examination every month.

Recall

Any abnormalities detected through screening are observed by recall of the patient to assessment clinics, where further imaging may be undertaken. This is usually in the form of ultrasonography or further mammographic views, such as lateral, magnified, or compression views, or alterations in exposure.

Biopsy

Because most of the lesions detected by screening are early impalpable abnormalities, subsequent needle biopsy must be image-guided. Ultrasound-guided biopsy is the most straightforward approach, but lesions better seen on mammography, particularly microcalcifications, require stereotactic localization. More modern stereotactic imagers allow the use of core biopsy or the Mammotome. These larger samples then may be x-rayed to ensure that they contain representative microcalcification.

Ultimately, open biopsy, which may be aided by skin marking by the ultrasonographer or by ultrasound-guided or stereotactic wire localization, may be necessary. If the procedure is diagnostic rather than therapeutic, a maximum biopsy size of 20 g is desired to reduce unnecessary cosmetic distortion. To avoid too many unnecessary biopsies, a breast unit’s benign biopsy rate should not greatly exceed the malignant rate.

STAGING ˇ@

Before deciding on definitive treatment for a newly diagnosed breast cancer, staging the disease is necessary, since staging may affect the choice of first-line treatment. Lymph node involvement makes a full axillary clearance more appropriate, whereas distant spread of disease may indicate primary chemotherapy.

The most common method of denoting the stage of the disease is the TNM (tumor, node, metastases) system, shown in Table 3.

Table 3. TNM Classification of Breast cancer

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TX Not assessable

T0 No primary tumor

Tis Carcinoma in situ

T1a 0.5 cm

T1b >0.5-1 cm

T1c >1-2 cm

T2 >2-5 cm

T3 >5 cm

T4a Involvement of chest wall

T4b Involvement of skin

T4c T4a and T4b

T4d Inflammatory cancer		 NX Not assessable

N0 No regional lymph node metastases

N1 Palpable ipsilateral axillary lymph nodes

N2 Fixed ipsilateral axillary lymph nodes

N3 Ipsilateral internal mammary nodes

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MX Not assessable

M0 No evidence of metastasis

M1 Distant metastasis including

ipsilateral supraclavicular nodes
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Evaluation of the Axilla

Clinical

Clinical evaluation of the axilla for lymph node metastases is not a particularly sensitive method, although some use it for selecting patients for preoperative staging investigations.

Imaging

Conventional 2-view mammography does not adequately cover all of the axillary contents, whereas ultrasound and Doppler can be directed to cover all of the axilla. Similarly, MRI, scintimammography, and PET reliably can detect abnormalities in the axilla because of their wider field.

Intraoperative assessment

Intraoperative assessment of axillary samples helps to determine whether to continue on to a full axillary clearance during the same operation. Techniques include the following:

Laboratory evaluation of specimen

As many as 45-48 lymph nodes can be present according to the level of axillary clearance. These are identified and assessed by a number of techniques, as follows:

Serologic tests

Serological tests provide general information on the patient’s overall health in the face of disseminated disease but more specifically can suggest sites of possible metastases or, in the case of tumor markers, can give an indication of the disease load.

Imaging

Imaging is a useful noninvasive form of assessment, with the simplest staging scans plain chest radiograph and liver ultrasonic scan. Often, technical difficulties with the liver scan (eg, due to patient body habitus) necessitate CT scans. With contrast, CT scans can specify lesions with high vascularity. CT scan also is useful for detecting lung and brain metastases and high axillary and intrathoracic lymphadenopathy.

Bone scans, for example using 99mTc-methylene diphosphonate (99mTc-MDP), are sensitive at detecting increased osteoclastic activity, but their specificity relies on the pattern of distribution of the tracer in the body in view of the frequent detection of degenerative disease. Attention must be made to the history of old fractures or arthritis. Ultimately, the whole body scan can be used to direct further, more localized, corroborative imaging such as plain radiographs or CT scan and/or MRI of the spine.

Suggestive characteristics of tracer distribution include single high-signal areas in the spine, asymmetric distribution, and occurrence away from joints and tendon insertions (ie, not arthritis).

Biopsy

Final confirmation of suggested metastases may be needed using biopsy, which may involve cytologic analysis of pleural or ascitic tap fluid or direct image-guided needle biopsy into lymph node, liver, or bone.

Micrometastases in bone marrow aspirates or lymph node biopsies can be determined using immunocytochemistry (cytokeratins CK19 and CAM 5.2), PCR, and RT-PCR.

PROGNOSTIC INDICATORS ˇ@

Criteria for Prognostic Indicators

For a prognostic indicator to be accepted as clinically useful, it ideally must have the following criteria:

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One of the most successful indices of prognosis in breast cancer is the Nottingham Prognostic Index (NPI), which can be used to select patients for adjuvant treatment and which makes use of the following 3 proven prognostic indicators:

NPI = [0.2 X tumor size cm] + tumor grade [1-3] + lymph node stage [1- 3]

Prognostic Indicators

Tumor size

Prognosis deteriorates with increasing tumor size, which is an independent predictor of survival in node-negative patients and correlates with incidence of nodal metastases.

Staging

The status of the axillary lymph nodes is one of the most useful prognostic indicators for breast cancer, with average 10-year survival of 60-70% for node-negative patients, dropping to 20-30% in node-positive patients. Metastatic spread in other parts of the body invariably indicates axillary node positivity.

Histopathology

Other prognostic indicators

FOLLOW UP ˇ@

Need for follow-up care

Whether regular follow-up care affects overall or disease-free survival is debatable, as is whether significantly more recurrences are detected than would be otherwise by the patients themselves or their general practitioners. However, a number of reasons support continuing evaluation of breast cancer patients following their initial treatment plan, as follows:

Frequency of follow-up care

Different centers vary in the precise scheduling of hospital follow-up appointments, but the general trend is to reduce frequency of clinic visits until final discharge to the breast screening service after 10 years if no new disease has occurred. Following is a suggested schedule for the hospital follow-up care of breast cancer patients who have undergone ”curative?resection:

Types of follow-up evaluation

Clinical assessment at each visit is mandatory, paying special attention to symptoms and signs of local or distant recurrence.

Mammography every year for patients who have had breast conservation is standard, although other modalities of imaging may be appropriate, such as MRI in the scarred breast or in patients in whom the primary tumor was not detected on mammography. For postmastectomy patients, twice yearly mammograms of the other breast may be sufficient.

Special investigations may be indicated by new symptoms or signs suggestive of local or distant recurrence, encompassing all imaging, serologic, and biopsy evaluations covered in the previous sections.

BIBLIOGRAPHY ˇ@