Breast cancer is a very common cancer among women world-wide.

Women have an average lifetime risk of 1 in 8 of being diagnosed with breast cancer, making it the most common non-skin cancer in women in the Western world. While the incidence has increased, the overall breast cancer death rate has shown a steady decrease since the early 1990s, (1) most likely as a result of improved detection techniques, increased sensitivity of investigations, and better treatment protocols. In developing countries such as South Africa, statistics are less reliable, but breast cancer remains a major health problem, affecting women of all population groups and of all ages, and causing significant morbidity and mortality.

Invasive ductal carcinoma is the most common histological type, accounting for 70 - 80% of cases, while invasive lobular carcinoma is the second most common, accounting for 5 - 10% of cases. Less common epithelial cancers include tubular, medullary, mucinous and papillary carcinomas. Phylloides tumour, angiosarcoma and lymphoma are non-epithelial cancers that occur infrequently.

The suspicion of breast cancer is raised either during investigation of a complaint, routine examination, or screening mammography.

The diagnosis of breast cancer is based on the triple assessment (2) and comprises:

* physical examination

* imaging--mammography and/or ultrasonography

* biopsy--fine-needle aspiration biopsy (FNAB) and/or core-needle biopsy.

The three modalities are complementary, enabling the diagnosis of most cases of breast cancer.

Physical examination (2-5)

Breast cancer may present as a lump or increased tissue thickening in the breast, with skin or nipple changes, nipple discharge or may be incidentally discovered by radiological imaging.

The examination of the breast should proceed with the patient in the upright sitting position with inspection for obvious masses, asymmetry, skin or nipple retraction and skin changes. Raising the arms above the head or tensing the pectoralis muscles may accentuate asymmetry or skin dimpling. Then, with the patient supine, and the hands placed above the head, the breasts should be gently palpated against the chest wall, feeling for any masses or thickening. Next, the axillae are palpated for any nodal involvement while supporting the patient's arm. Lastly, the supraclavicular areas are palpated for the presence of lymph nodes.

A non-tender breast lump is the most common finding in women with breast cancer. The stronger the risk factors for developing breast cancer (Table I), the more likely it is that a lump is cancerous. It is important to remember that most breast cancers occur in women without any overt risk factors at all.

Differential diagnosis of a breast lump

Common causes of benign breast lumps are fibroadenomas, cysts and fat necrosis (Table II). The differential diagnosis is strongly influenced by the patient's age (Fig. 1). Breast lumps should be characterised according to their size, consistency and location. Carcinomas are typically firm and less well circumscribed, and their movement produces a drag of the adjacent tissue. Cysts and fibroadenomas are typically firm, but well-circumscribed and mobile.

Some carcinomas may not necessarily present with a well-defined discrete lump on examination, but rather an area of focal breast thickening, with or without overlying skin dimpling. In the majority of cases, these clinical findings reflect fibrocystic changes, but it is important to consider that some carcinomas, particularly lobular in type, may present with similar subtle clinical findings. An area of focal breast thickening should be evaluated thoroughly with breast imaging and directed needle biopsy.

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Oedema of the skin produces a clinical sign known as peau d'orange (skin of the orange) and, when associated with breast cancer, is a sign of locally advanced disease. When combined with erythema, warmth and tenderness, these signs are the hallmark of inflammatory carcinoma, and may be mistaken for mastitis or breast abscess.

Nipple discharge is common and rarely associated with an underlying breast cancer. Common causes include physiological discharge, intraductal papilloma, duct ectasia and periductal mastitis. A spontaneous unilateral non-milky discharge from a single duct orifice is significant and warrants further investigation, although in the absence of a palpable mass or suspicious mammogram, this symptom is usually not associated with cancer. This clinical scenario is best investigated with a microdochectomy (excision of breast duct).

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An eczematous nipple reaction is highly suggestive of Paget's disease. Histologically, this condition is produced by intraductal carcinoma occurring in the large lactiferous sinuses just under the nipple. Carcinoma cells invade into the epidermal layer of skin of the nipple, and may then spread radially onto the areola. By contrast, benign skin conditions such as eczema usually originate on the areola. Paget's disease may or may not be associated with an underlying mass. A punch biopsy of the affected skin is diagnostic.

Breast imaging (7)

Mammography

Mammography is the traditional first-line radiological test for breast cancer, and can be used for diagnostic and screening purposes. Standard mammography comprises a craniocaudal and oblique view of each breast, but this can be augmented with a coned compression (paddle) view and magnification of a suspicious lesion. The classic appearance of invasive ductal carcinoma is a hyperdense, spiculate mass, although architectural distortion, asymmetry, stellate lesions and calcification may also indicate carcinoma (Fig. 2a). The development of digital mammography has further increased the quality of this technique, particularly in patients with dense breast parenchyma. It is important to remember that mammography has a false negative rate of approximately 15%. A normal mammogram, therefore, does not exclude breast cancer, and clinical signs should not be ignored.

Ductal carcinoma in situ (DCIS) is diagnosed on mammography and by core biopsy, and consists of malignant cells contained within the basement membrane of the breast ducts. It is usually asymptomatic and not clinically palpable, being detected on mammography as multiple pleomorphic microcalcifications arranged in clusters or linear formations.

Less commonly, it presents as a mass, nipple discharge or Paget's disease of the breast. Approximately 30-50% of patients with DCIS will develop invasive ductal carcinoma over a 10-year period. In contrast, lobular carcinoma in situ arises from the terminal duct lobules and is considered a marker of increased risk of breast cancer rather than a precursor of cancer.

A suspicious lesion detected by mammogram should be referred to a specialist centre, regardless of whether it is palpable or not.

Ultrasound

Ultrasound has a sensitivity of about 75% for the diagnosis of breast cancer. It is seldom used in isolation, but it is useful in assessing a breast mass where mammography is nonspecific, particularly in young women with dense breasts. Benign lumps appear as iso- or hypoechoic, well-circumscribed masses, and lack hypoechoic shadows. Malignant tumours appear as mixed echogenic, irregular masses, and cast hypoechoic shadows (Fig. 2b).

Magnetic resonance imaging

The use of MRI has exponentially increased in the last decade. The best documented role for MRI is as a screening modality in young women carriers of BRCA1 or 2 mutation, and in the evaluation of patients who may have a local recurrence after previous breast-conserving surgery and irradiation.

Tissue diagnosis

Fine-needle aspiration (6)

If a mass is palpable, fine-needle aspiration biopsy (FNAB) should be performed after mammography. In the case of a sonographically detected mass, FNA may be done under ultrasound guidance. It is carried out using a 22 G needle on a 10 ml syringe. Leaving 2 ml of air in the syringe, negative pressure is applied while making multiple passes through the lump (Fig. 3). Thin smears of aspirate are prepared on slides which are either air dried or sprayed with a fixative, depending on the unit protocol.

After specialised staining the slides are examined by a breast cytopathologist. The findings fall into one of five categories: inadequate, benign, atypical, suspicious and malignant. The presence of carcinoma cells on FNAB may not differentiate between in situ and invasive carcinoma and most units do not recommend definitive treatment based on cytological assessment. False-positive diagnoses are rare (<0.5%), but well documented. Benign cells on a breast aspirate tend to show cohesion, and regularity of nuclear detail. Malignant cells are discohesive and depending on the size and arrangement of the cells suggest malignancy of either the ductal or lobular components of the breast epithelium. As can be seen from Fig. 4, the size of the cells of a lobular carcinoma is smaller, and therefore can cause more problems in false-negative diagnosis.

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Core biopsy

Core biopsy establishes a histological diagnosis. Using a cutting needle device (e.g. Trucut), it is carried out immediately after FNAB. A core biopsy can establish cell type, differentiate between in situ and invasive cancer, and will often establish receptor status and tumour grade. Core biopsy is more technically difficult than FNAB but, when positive, establishes an unequivocal diagnosis of carcinoma.

Both needle techniques have a false-negative rate, mostly as a result of technical error or geographic mis-sampling.

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Excision biopsy

In most breast units the diagnosis of carcinoma is made without resorting to excision biopsy. However, approximately 5% of cases of breast cancer are not confidently diagnosed with a triple assessment, and require formal excision (Table III). For small lesions, radiologically guided biopsies may greatly simplify the diagnostic process. Some breast tumours are particularly difficult to characterise with needle biopsy only, particularly low-grade phylloides tumours, and solid-cystic papillary carcinomas in the elderly.

Impalpable breast cancer

With the use of imaging modalities an increasing number of breast cancers are identified before they present with any clinical signs. In this context the diagnosis may be made by using stereotactic (Fig. 5) or US-guided core biopsies, or by guided excision biopsy, either using hookwire or radio-guided tracers (radio-guided occult lesion localisation (ROLL)). The narrow diameter of the biopsies can represent a special challenge to the pathologist as the 'whole' lesion is seldom sampled. Close liaison between radiologist, clinician and pathologist is essential when selecting patients for these procedures.

Staging breast cancer (9)

The tumour, node, metastases (TNM) classification system is used worldwide to stage breast cancer (Tables IV and V). There are two parts to this classification: a clinical staging relating to the clinical assessment of tumour size (T), node status (N) and presence of metastases (M), and a final pathological T and N staging of the resected breast and axillary specimen.

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The metastatic screen (M) should include a full blood count, serum urea and electrolytes and calcium, liver function test, chest X-ray, bone scan and liver ultrasound. Investigations such as PET imaging or bone marrow biopsy are not routinely used for staging purposes. The combining of the T, N and M is used for the final determination of the stage of the disease, which has prognostic and therapeutic implications.

Pathological considerations

* Ductal carcinoma--not otherwise specified (NOS)--accounts for 70 - 75% of all malignancies. It shows some similarity to the breast duct, therefore a degree of tubule differentiation is often seen.

* Invasive lobular carcinoma constitutes 10% of all invasive cancers. It grows in a typically 'Indian file' pattern and has a tendency toward multi-focality and bilaterality (Fig. 6).

* Other types of breast cancer include tubular carcinoma, mucinous carcinoma, cribriform carcinoma, medullary-like carcinoma and papillary carcinoma.

* Ductal carcinoma in situ (DCIS) is diagnosed on mammography and core biopsy, and consists of malignant cells contained within the basement membrane of the breast ducts. It is usually asymptomatic and not clinically palpable, being detected on mammography as multiple pleomorphic microcalcifications arranged in clusters or linear formations. Less commonly, it presents as a mass, nipple discharge or Paget's disease of the breast. Approximately 30-50 % of patients with DCIS will develop invasive ductal carcinoma over a 10-year period.

* Lobular carcinoma in situ (LCIS), on the other hand, arises from the terminal duct lobules and is considered a marker of increased risk of breast cancer rather than precursor of cancer.

Prognostic factors

The most important prognostic factor is stage. However, grade, lymphovascular invasion, hormonal and Her2 status also have significance:

* Histological grade (Fig. 7) provides important prognostic and management information. The internationally accepted system is that defined by Elston and Ellis. (1) Assessment is made by evaluating acinar formation, nuclear size/pleomorphism and mitotic activity. Each element evaluated is given a score of 1-3.

* Angiolymphatic invasion is best assessed around the periphery of tumour. It is an independent prognostic factor.

* Hormone receptor (Fig. 8) analyses are made in almost all invasive breast cancers. Oestrogen receptor (ER) is positive in 80% of cancers. Progesterone (PGR) receptors are rarely positive if ER is negative. There is some evidence that ER-positive/PGR-negative tumours behave differently.

* Her2 Neu testing (Fig. 9) is now carried out on all newly diagnosed breast cancers, and approximately 20% are positive. Fluorescence in situ hybridisation (FISH) is used to evaluate Her2 gene copy numbers when immunohistochemistry produces equivocal results (Fig. 10).

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Conclusion

Diagnosing breast cancer is simple and rapid in the majority of cases. It relies on clinical acumen, the liberal use of breast imaging, usually mammography, together with fine-needle cytology and core-needle biopsy. In cases of discordant information arising from the above triple assessment, an excision biopsy is indicated.

In a nutshell

* Invasive duct carcinoma accounts for 70-80% of breast carcinomas.

* Breast lumps should be evaluated using the triple assessment, enabling the diagnosis of breast cancer in the majority of cases.

* The stronger the risk factors for developing breast cancer, the more likely it is that a lump is cancerous.

* The subtle mammographic features of DCIS are important to recognise, as up to half of these lesions will progress to invasive duct carcinoma within 10 years.

* Diagnostic doubt, despite triple assessment, of a lump or mammographic lesion should be referred for excision biopsy.

* Mammography is the first-line radiological investigation for breast cancer, with ultrasound and MRI being used in selected cases.

* There are 2 parts to the TNM classification of breast cancer: clinical staging and a final pathological staging.

References

(1.) Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403-410.

(2.) Gendy R, Rainsbury D. Clinical examination and special investigations of the breast. Surgery 2001; 19: 79.

(3.) Edwards P, Gately C. The breast--benign disorders and mastalgia. Surgery 2001; 19.

(4.) Paget DL, Dupont WD, Rogers LW, et al. Intraductal carcinoma of the breast: follow-up after biopsy only. Cancer 1982; 49(4): 751-758.

(5.) Rosen PP, Kosloff C, Lieberman PH, et al. Lobular carcinoma in situ of the breast. Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 1978: 2(3): 225-251.

(6.) Chianakwalam C, Bates T. Diagnosis and management of a breast lump. Surgery 2001; 19: 75.

(7.) Bartella L, Smith CS, Dershaw DD, Liberman L. Imaging breast cancer. Radiol Clin North Am 2007; 45: 45-67.

(8.) NHSBSP National Quality Assurance Coordinating Group for Radiography. Information and Advice for Health Professionals in Breast Screening. NHSBSP Publication No 53, December 2002 Revision of the American Joint Committee on Cancer Staging System for Breast Cancer. J Clin Oncol 2002; 17: 3628-3636.

IAN MARR, MB ChB, FCS (SA)

Consultant Surgeon, Groote Schuur Hospital, Cape Town

Ian Marr is a graduate of the University of Cape Town, and a consultant surgeon in the Endocrine and Surgical Oncology Unit and the Breast Clinic at Groote Schuur Hospital. His main areas of interest are breast and laparoscopic surgery.

EUGENIO PANIERI, MB ChB, FCS (SA)

Head, Endocrine and Surgical Oncology Unit and Breast Clinic, Groote Schuur Hospital, Cape Town

Eugenio Panieri is a graduate of the University of Cape Town, and Head of the Endocrine and Surgical Oncology Unit and the Breast Clinic at Groote Schuur Hospital. His main areas of interest are sentinel lymph node biopsy and immediate reconstruction in breast cancer, and the use of minimal access surgery for endocrine conditions.

JUDY WHITTAKER, MB ChB, MMed Path Anat, FIAC

Pathologist in private practice, Cape Town

Judy Whittaker is a graduate of the University of Cape Town, and is a pathologist in private practice in Cape Town. Her main areas of interest are breast and gynaecological histopathology and cytopathology.

Table I. Major risk factors for breast cancer

Increasing age
  Postmenopausal
BRCA gene positive or strong family history
  Multiple 1st- and 2nd-degree relatives with breast and
  ovarian cancer
  1st-degree relative diagnosed with breast cancer before
  50 years
  Male relatives diagnosed with breast cancer
  Jewish ancestry with family history
Previous breast cancer or DCIS or LCIS or atypia
Longstanding exposure to unopposed oestrogens
Chest wall irradiation

Table III. Indications for excision biopsy

Discordant results of needle biopsy or mammography

* Cytology report suspicious or malignant but mammogram and core
  biopsy inconclusive / benign

* Mammogram suspicious / malignant, cytology and core biopsy
  inconclusive / benign
Patient request
Symptomatic discrete mass in patient older than 35 years

Table II. Differential diagnosis of a breast lump

Benign                     Malignant

Fibroadenoma               Non-invasive
Cysts                        Lobular carcinoma in situ (LCIS)
Breast abscess               Ductal carcinoma in situ (DCIS)
Fat necrosis               Invasive epithelial
Papilloma                    Ductal carcinoma
Hamartoma/adenoma            Lobular carcinoma
Other sclerosing lesions     Medullary/mucinous/papillary carcinoma
  Radial scar              Other non-epithelial neoplasms
  Sclerosing adenosis        Phylloides tumour
                             Angiosarcoma
                             Lymphoma
                             Metastasis to the breast

Table III. Indications for excision biopsy

Discordant results of needle biopsy or mammography

* Cytology report suspicious or malignant but mammogram and core biopsy
inconclusive/benign

* Mammogram suspicious/malignant, cytology and core biopsy inconclusive/benign

Patient request

Symptomatic discrete mass in patient older than 35 years

Table IV. TNM staging

TNM clinical classification         TNM pathological classification

T--primary tumour                   Same as clinical stage

Tx   Can't be assessed
T0   No evidence of primary
       tumor in the breast
Tis  Carcinoma in situ
T1   <2 cm
T2   2-5 cm
T3   >5 cm
T4   Any size, with direct
       extension onto skin or
       chest wall, or inflammatory
       carcinoma

N--regional lymph nodes

Nx   Can't be assessed              Can't be assessed
N0   No regional nodes              No regional nodes
N1   Mobile ipsilateral axillary    1-3 axillary nodes, and/or
       nodes                          non-clinically apparent
                                      internal mammary node
                                      involvement
N2   Fixed or matted axillary       4-9 axillary nodes, or
       nodes, or palpable             clinically apparent internal
       internal mammary nodes         mammary node involvement

N3   Palpable infra- or             10 or more axillary nodes, or
       supraclavicular nodes, or      infraclavicular or
       palpable axillary and          supraclavicular node
       internal mammary nodes         involvement, or axillary
                                      and internal mammary node
                                      involvement

M--distant metastases               Same as clinical stage

Mx   Can't be assessed
M0   No distant metastases
M1   Distant metastases
M    Distant metastases

Table V. Staging and clinical outcome

Stage         Tumour (T)   Node (N)   Metastasis (M)

Stage 0       Tis          N0         M0
Stage 1       T1           N0         M0
Stage IIA     T0           N1         M0
              T1           N1         M0
              T2           N0         M0
Stage IIB     T2           N1         M0
              T3           N0         M0
Stage IIIA    T0           N2         M0
              T1           N2         M0
              T2           N2         M0
              T3           N1, N2     M0
Stage IIIB    T4           Any N      M0
              Any T        N3         M0
Stage IV      Any T        Any N      M1

Stage         5-year relative survival rate

0             100%
I             100%
IIA           92%
IIB           81%
IIIA          67%
IIIB          54%
IV            20%