A. Symptoms and Signs
The presenting complaint in about 70% of patients with breast cancer is a lump (usually painless) in the breast. About 90% of breast masses are discovered by the patient herself. Less frequent symptoms are breast pain; nipple discharge; erosion, retraction, enlargement, or itching of the nipple; and redness, generalized hardness, enlargement, or shrinking of the breast. Rarely, an axillary mass or swelling of the arm may be the first symptom. Back or bone pain, jaundice, or weight loss may be the result of systemic metastases, but these symptoms are rarely seen on initial presentation.

The relative frequency of carcinoma in various anatomic sites in the breast is shown in

Figure 17-1.

Inspection of the breast is the first step in physical examination and should be carried out with the patient sitting, arms at her sides and then overhead. Abnormal variations in breast size and contour, minimal nipple retraction, and slight edema, redness, or retraction of the skin can be identified. Asymmetry of the breasts and retraction or dimpling of the skin can often be accentuated by having the patient raise her arms overhead or press her hands on her hips to contract the pectoralis muscles. Axillary and supraclavicular areas should be thoroughly palpated for enlarged nodes with the patient sitting (Figure 17-2). Palpation of the breast for masses or other changes should be performed with the patient both seated and supine with the arm abducted (

Figure 17-3). Palpation with a rotary motion of the examiner’s fingers as well as a horizontal stripping motion has been recommended.

Breast cancer usually consists of a nontender, firm or hard mass with poorly delineated margins (caused by local infiltration). Slight skin or nipple retraction is an important sign. Minimal asymmetry of the breast may be noted. Very small (1-2 mm) erosions of the nipple epithelium may be the only manifestation of Paget’s carcinoma. Watery, serous, or bloody discharge from the nipple is an occasional early sign but is more often associated with benign disease.

A lesion smaller than 1 cm in diameter may be difficult or impossible for the examiner to feel and yet may be discovered by the patient. She should always be asked to demonstrate the location of the mass; if the physician fails to confirm the patient’s suspicions, the examination should be repeated in 2-3 months, preferably 1-2 weeks after the onset of menses. During the premenstrual phase of the cycle, increased innocuous nodularity may suggest neoplasm or may obscure an underlying lesion. If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her period. Ultrasound is often valuable and mammography essential when an area is felt by the patient to be abnormal but the physician feels no mass.

Metastases tend to involve regional lymph nodes, which may be palpable. One or two movable, nontender, not particularly firm axillary lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 1 cm are typical of metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). Microscopic metastases are present in about 30% of patients with clinically negative nodes. On the other hand, if the examiner thinks that the axillary nodes are involved, that impression will be borne out by histologic section in about 85% of cases. The incidence of positive axillary nodes increases with the size of the primary tumor. Noninvasive cancers do not metastasize.

In most cases no nodes are palpable in the supraclavicular fossa. Firm or hard nodes of any size in this location or just beneath the clavicle are suggestive of metastatic cancer and should be biopsied. Ipsilateral supraclavicular or infraclavicular nodes containing cancer indicate that the tumor is in an advanced stage (stage III or IV). Edema of the ipsilateral arm, commonly caused by metastatic infiltration of regional lymphatics, is also a sign of advanced cancer.

B. Laboratory Findings
A consistently elevated sedimentation rate may be the result of disseminated cancer. Liver or bone metastases may be associated with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional important finding in advanced cancer of the breast. Carcinoembryonic antigen (CEA) and CA 15-3 or CA 27-29 may be used as markers for recurrent breast cancer but are not helpful in diagnosing early lesions. Many scientists are further investigating breast cancer biomarkers through proteomics and hormone assays. These studies are ongoing and may prove to be helpful in early detection or evaluation of prognosis.

C. Imaging for Metastases
Chest x-ray may show pulmonary metastases. Computed tomographic (CT) scanning of the liver and brain is of value only when metastases are suspected in these areas. Bone scans utilizing 99mTc-labeled phosphates or phosphonates are more sensitive than skeletal x-rays in detecting metastatic breast cancer. Bone scanning has not proved to be of clinical value as a routine preoperative test in the absence of symptoms, physical findings, or abnormal alkaline phosphatase or calcium levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. PET may prove to be an effective single scan for bone and soft tissue or visceral metastases in patients with symptoms or signs of metastatic disease.

D. Diagnostic Tests

1. Biopsy - The diagnosis of breast cancer depends ultimately upon examination of tissue or cells removed by biopsy. Treatment should never be undertaken without an unequivocal histologic or cytologic diagnosis of cancer. The safest course is biopsy examination of all suspicious masses found on physical examination and of suspicious lesions demonstrated by mammography. About 60% of lesions clinically thought to be cancer prove on biopsy to be benign, and about 30% of lesions believed to be benign are found to be malignant. These findings demonstrate the fallibility of clinical judgment and the necessity for biopsy. A breast mass should not be followed without histologic diagnosis, except perhaps in the premenopausal woman with a nonsuspicious mass presumed to be a fibrocystic condition. A lesion such as this could be observed through one or two menstrual cycles. However, if the mass does not completely resolve during this time, it must be biopsied.

Figures 17-4 and

17-5 present algorithms for management of breast masses in premenopausal and postmenopausal patients.

The simplest method is needle biopsy, either by aspiration of tumor cells (fine-needle aspiration cytology) or by obtaining a small core of tissue with a hollow needle.

Fine-needle aspiration cytology is a useful technique whereby cells are aspirated with a small needle and examined by the pathologist. This technique can be performed easily with no morbidity and is much less expensive than excisional or open biopsy. The main disadvantages are that it requires a pathologist skilled in the cytologic diagnosis of breast cancer and that it is subject to sampling problems, particularly because deep lesions may be missed. Furthermore, noninvasive cancers usually cannot be distinguished from invasive cancers. The incidence of false-positive diagnoses is extremely low, perhaps 1-2%. The false-negative rate is as high as 10%. Most experienced clinicians would not leave a suspicious dominant mass in the breast even when fine-needle aspiration cytology is negative unless the clinical diagnosis, breast imaging studies, and cytologic studies were all in agreement.

Large-needle (core needle) biopsy removes a core of tissue with a large cutting needle. Hand-held biopsy devices make large-core needle biopsy of a palpable mass easy and cost-effective in the office with local anesthesia. As in the case of any needle biopsy, the main problem is sampling error due to improper positioning of the needle, giving rise to a false-negative test result.

Open biopsy under local anesthesia as a separate procedure prior to deciding upon definitive treatment is the most reliable means of diagnosis. Needle biopsy or aspiration, when positive, offers a more rapid approach with less expense and morbidity, but when nondiagnostic it must be followed by open biopsy. Open biopsy consists of either an incisional biopsy or an excisional biopsy. An incisional biopsy is one in which an incision is made and a portion of the breast abnormality is removed for histologic evaluation. An excisional biopsy is also done through an incision in the skin, but with the intent to remove the entire abnormality, not simply a sample. Incisional biopsies are rarely performed now.

Additional evaluation for metastatic disease and therapeutic options can be discussed with the patient after the histologic or cytologic diagnosis of cancer has been established. This approach has the advantage of avoiding unnecessary procedures, since cancer is found in the minority of patients biopsied for a breast lump. In situ cancers are not easily diagnosed cytologically and usually require excisional biopsy.

As an alternative in highly suspicious circumstances, the patient may be admitted to the hospital, where the diagnosis is made on frozen section of tissue obtained by open biopsy under general anesthesia. If the frozen section is positive, the surgeon can proceed immediately with operation. This one-step method is rarely used today except when a cytologic study has suggested cancer but is not diagnostic and there is a high clinical suspicion of malignancy.

In general, the two-step approach - outpatient biopsy followed by definitive operation at a later date - is preferred in the diagnosis and treatment of breast cancer, because patients can be given time to adjust to the diagnosis of cancer, can consider alternative forms of therapy, and can seek a second opinion if they wish. There is no adverse effect from the short (1-2 weeks) delay of the two-step procedure, and this is the current recommendation of the NCI.

2. Ultrasonography - Ultrasonography is performed primarily to differentiate cystic from solid lesions. Though not diagnostic, ultrasound may reveal features highly suggestive of malignancy such as irregular margins on a new solid mass. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and feels like a cyst, an 18-gauge needle can be used to aspirate the fluid and make the diagnosis of cyst. If a cyst is aspirated and the fluid is nonbloody, it does not have to be examined cytologically. If the mass does not recur, no further diagnostic test is necessary. Nonpalpable mammographic densities that appear benign should be investigated with ultrasound to determine whether the lesion is cystic or solid. These may even be needle biopsied with ultrasound guidance.

3. Mammography - When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the lesion should be biopsied by a computerized stereotactic guided core needle technique. These units have been added to mammographic suites to localize abnormalities and perform needle biopsy without surgery. Under mammographic guidance, a biopsy needle can be inserted into the lesion by the mammographer, and a core of tissue for histologic examination or cells for cytology can then be examined. Vacuum assistance increases the amount of tissue obtained and improves diagnosis.

Mammographic localization biopsy is performed by obtaining a mammogram in two perpendicular views and placing a needle or hook-wire near the abnormality so that the surgeon can use the metal needle or wire as a guide during operation to locate the lesion. After mammography confirms the position of the needle in relation to the lesion, an incision is made and the subcutaneous tissue is dissected until the needle is identified. Using the films as a guide, the abnormality can then be localized and excised. It often happens that the abnormality cannot even be palpated through the incision - this is the case with microcalcifications - and thus it is essential to obtain a mammogram of the specimen to document that the lesion was excised. At that time, a second marker needle can further localize the lesion for the pathologist. Stereotactic core needle biopsies have proved equivalent to mammographic localization biopsies. Core biopsy is preferable to mammographic localization for accessible lesions.

4. Other Imaging Modalities - Other modalities of breast imaging have been investigated. Automated breast ultrasonography is useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography. Ductography may be useful to define the site of a lesion causing a bloody discharge, but since biopsy is always indicated, ductography may be omitted and the blood-filled nipple system excised. Ductosopy has shown some promise in identifying intraductal lesions, especially in the case of pathologic nipple discharge, but the utility of this procedure is still being studied. MRI is highly sensitive but not specific and should not be used for screening, but it may be of value in highly selective cases. It is useful, for example, in differentiating scar from recurrence postlumpectomy and may be valuable to screen high-risk women (eg, women with BRCA mutations) and to examine for multicentricity when there is a known primary cancer or to examine the contralateral breast in women with cancer. PET scanning does not appear useful in evaluating the breast but may prove to be of value in examining regional lymphatics.

5. Cytology - Cytologic examination of nipple discharge or cyst fluid may be helpful on rare occasions. As a rule, mammography (or ductography) and breast biopsy are required when nipple discharge or cyst fluid is bloody or cytologically questionable. Ductal lavage, a technique that washes individual duct systems with saline and loosens epithelial cells for cytologic evaluation, is being evaluated as a risk assessment tool but appears to be of little value.

_{Baker JA et al: Breast US: assessment of technical quality and image interpretation. Radiology 2002;223:229. Pubmed: 11930071}

Dooley WC: Routine operative breast endoscopy for bloody nipple discharge. Ann Surg Oncol 2002;9:920. Pubmed: 12417516

Hollingsworth AB: Perspectives on preoperative staging with breast MRI. J Am Coll Surg 2004;199:173. Pubmed: 15217651

Lenahan C et al: The role of tumor markers in breast cancer management. Curr Surg 2004;61:532. Pubmed: 15590016

Ljung BM et al: Cytology of ductal lavage fluid of the breast. Diagn Cytopathol 2004;30:143. Pubmed: 14986293

van der Hoeven JJ et al: Determinants of diagnostic performance of [F-18] fluorodeoxyglucose positron emission tomography for axillary staging in breast cancer. Ann Surg 2002;236:619.