BREAST CANCER

BREAST CANCER

Jemal A., et al. CA Cancer J Clin 2008; 58:71-96Breast cancer is the most common cancer and the second leading cause of cancer-related death for women in USATen Leading Cancer Types for the Estimated New Cancer Cases and Deaths, by Sex, United States, 2008. *Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates are rounded to the nearest 10.Breast cancer is the most common cancer and the leading cause of cancer-related death for women around the world. Although breast cancer is more frequently diagnosed in affluent countries, the death rate associated with breast cancer is higher in economically disadvantaged countries. The reasons for this disparity are complex but are likely due to both earlier detection programs and improvements in treatments in developed countries. Accurate statistics regarding incidence and mortality rates for breast cancer are not available in many developing regions of the world.

Overview of breast health care guidelines for countries with limited resources. Breast J. 2003 May-Jun;9 Suppl 2:S42-50. Global Summit Consensus Conference on International Breast Health Care: guidelines for countries with limited resources.Breast J. 2003 May-Jun;9 Suppl 2:S40-41. Early detection of breast cancer in countries with limited resources. Breast J. 2003 May-Jun;9 Suppl 2:S51-59.

Five Year Relative Survival Rates for Breast Cancer: 1973 - 2005

Cancer survivors increased from 3 M to 9 M in the same periodCA, Jan 1973 and Jan 2005Functional Anatomy

The breast looks like a thickened circular disk of tissue. The mature female breast extends from the level of the second or third rib to the inframammary fold at the sixth or seventh rib. It extends transversely from the lateral border of the sternum to the anterior axillary line. Fibrous bands of connective tissue travel through the breast (suspensory ligaments of Cooper), insert perpendicularly into the dermis, and provide structural support. The deep or posterior surface of the breast rests on the fascia of the pectoralis major, serratus anterior, and external oblique abdominal muscles, and the upper extent of the rectus sheath. The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants. The breast has a protuberant conical form. The base of the cone is roughly circular, measuring 10 to 12 cm in diameter. Considerable variations in the size, contour, and density of the breast are evident between individuals. The nulliparous breast has a hemispheric configuration with distinct flattening above the nipple. With the hormonal stimulation that accompanies pregnancy and lactation, the breast becomes larger and increases in volume and density, while with senescence, it assumes a flattened, flaccid, and more pendulous configuration with decreased volume.

The breast is composed of 15 to 20 lobes (Fig. 16-3), which are each composed of several lobules. Drained by ducts that lead to the nipple. Breast alveoli are grape-like clusters which produce milk. Blood Supply (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries(3,4,5); (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery

The breast receives its principal blood supply from (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries; and (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery (Fig. 16-6). The second, third, and fourth anterior intercostal perforators and branches of the internal mammary artery arborize in the breast as the medial mammary arteries. The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and minor, and subscapularis muscles. It also gives rise to lateral mammary branches. The veins of the breast and chest wall follow the course of the arteries with venous drainage being toward the axilla. The three principal groups of veins are (1) perforating branches of the internal thoracic vein; (2) perforating branches of the posterior intercostal veins; and (3) tributaries of the axillary vein. The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lymph vessels generally parallel the course of blood vessels.Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the intercostal spaces between slips of the serratus anterior muscle. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm.The lymphatic drainage of the breast

75%20-25%Apical groupThe boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. Several routes of lymphatic drainage of breast.

The 6 axillary lymph node groups recognized by surgeons (Figs. 16-7 and 16-8) are (1) the axillary vein group (lateral) that consists of 4 to 6 lymph nodes, which lie medial or posterior to the vein and receive most of the lymph drainage from the upper extremity; (2) the external mammary group (anterior or pectoral group) that consists of 5 or 6 lymph nodes, which lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels and receive most of the lymph drainage from the lateral aspect of the breast; (3) the scapular group (posterior or subscapular) that consists of 5 to 7 lymph nodes, which lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels and receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder; (4) the central group that consists of 3 or 4 sets of lymph nodes, which are embedded in the fat of the axilla lying immediately posterior to the pectoralis minor muscle and receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes and directly from the breast; (5) the subclavicular group (apical) that consists of 6 to 12 sets of lymph nodes, which lie posterior and superior to the upper border of the pectoralis minor muscle and receive lymph drainage from all of the other groups of axillary lymph nodes; and (6) the interpectoral group (Rotter's) that consists of 1 to 4 lymph nodes, which are interposed between the pectoralis major and pectoralis minor muscles and receive lymph drainage directly from the breast. The lymph fluid that passes through the interpectoral group of lymph nodes passes directly into the central and subclavicular groups.The lymph node groups

1. level I LN(14-19). located lateral to or below the lower border of the pectoralis minor muscle: the axillary vein4-6): external mammary5-6), scapular groups 5-72. Level II LN (5-8): located superficial or deep to the pectoralis minor muscle the central(3-4), interpectoral groups (Rotters(1-4) 3. Level III LN : located medial to or above the upper border of the pectoralis minor muscle: the subclavicular group6-12)

the lymph node groups are assigned levels according to their relationship to the pectoralis minor muscle. Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which consist of the subclavicular group. Risk factors - unchangeable1. Being a woman2. Age3. Genetic factors - mutations in BRCA1 or BRCA2; 50-60% of women inheriting a BRCA1 mutation from either parent will have breast cancer by age 704. Family history of breast cancer (not related to BRCA mutations)5. Personal history of hyperplastic breast diseaseRisk factors - unchangeable6. Personal history of breast cancer7. Race: incidence is higher in Caucasian compared with African-American, Hispanic or Asian women.8. Radiation treatment: chest irradiation as a child/young woman can significantly increase risk of developing breast cancer. 9. Dense breast tissue.10. Menstrual history: early menarche (50yr) has some association with increased risk. Also nulliparous, or first childbirth at >30 yrs. Risk factors associated with lifestyle1. Oral contraceptives - remains controversialHormone replacement therapy - >5 years of therapy with combined estrogen and progesterone may increase risk Not breast feeding4. Obesity, lack of physical activity5. Alcohol - 2-5 drinks/day can increase risk x 1.5 over non-drinkers.Factors with uncertain, controversial or unproven effects on risk of developing breast cancerHigh fat diet Induced abortionsBreast implantsEnvironmental chemical exposure (e.g. pesticides)Tobacco smokeNight shift workHuman mammary tumor virus ?

Hereditary Breast CancerHereditary breast-ovarian cancer (HBOC) syndromeMutation in BRCA1, BRCA2 genes

Ataxia telangiectasia (A-T) : Mutation in ATM gene

Li-Fraumeni syndrome: Mutation in p53 gene (? CHEK2 gene).

Cowden syndrome: Mutation in PTEN gene

Peutz-Jeghers syndrome: Mutation in STK11 gene

The tumor suppressor genes BRCA1 and BRCA2 are involved in familial breast-ovarian cancer. It is estimated that about 80% of hereditary breast cancer is caused by mutations in BRCA1 or BRCA2.Women who inherit a BRCA mutation have a 50% to 85% chance of breast cancer developing in their lifetime. Men with BRCA1 and BRCA2 mutations may be at increased risk of breast and prostate cancers. Both women and men with BRCA2 mutations may be at increased risk of breast cancer or other types of cancer. Approximately one in 50 women with Ashkenazi Jewish heritage carry a mutation in BRCA1 or BRCA2 genes that raises their lifetime risk of breast cancer to between 50% and 85%.

Ataxia telangiectasia is caused by mutations on chromosome 11 of the ATM gene. An ataxia-telangiectasia mutation raises a womans breast cancer risk.

Li-Fraumeni syndrome is rare and accounts for less than 1% of all breast cancers. People with Li-Fraumeni syndrome have up to a 90% lifetime risk of cancer. The p53 tumor suppressor gene is associated with the syndrome. The CHEK2 gene may also be responsible for features of Li-Fraumeni syndrome in some families, and mutations in this gene may raise the risk of breast cancer two to five times in women and increase the risk by as much as 10 times in men.

Cowden syndrome confers a 25% to 50% lifetime risk of breast cancer and a 65% lifetime risk of benign breast changes. The tumor suppressor gene PTEN is associated with the syndrome.

The lifetime risk of breast cancer associated with Peutz-Jeghers syndrome is approximately 50%. Associated with the tumor suppressor gene STK11.

Breast cancer risk assessment tool (BCRAT)BCRAT- based on Gail model, using womans personal medical history (previous breast biopsies, ATH), reproductive history, whether first degree relatives had breast cancer, to estimate risk of invasive breast cancer over specific periods of time (www.cancer.gov/bcrisktool)CARE model gives more accurate estimates of breast cancer risk for African-American women. Gail et al, JNCI 99: 1782-1792, 2007.

Carcinoma In Situ 5457 Cancer cells are in situ or invasive depending on whether or not they invade through the basement membrane. Broder's original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confinement within natural ductal and alveolar boundaries. As areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopy sections to exclude invasion. In 1941, Foote and Stewart published a landmark description of lobular carcinoma in situ (LCIS), which distinguished it from DCIS. In the late 1960s, Gallagher and Martin published their study of whole breast sections and described a stepwise progression from benign breast tissue to in situ cancer, and subsequently to invasive cancer. They coined the term minimal breast cancer (LCIS, DCIS, and invasive cancers smaller than 0.5 cm in size) and stressed the importance of early detection. It is now recognized that each type of minimal breast cancer has a distinct clinical and biologic behavior. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted less than 6% of all breast cancers, and by a ratio of more than 2:1, LCIS was more frequently diagnosed than DCIS. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and by a ratio of more than 2:1, DCIS was more frequently diagnosed than LCIS. Table 16-9 lists the clinical and pathologic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer, whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer. Multicentricity occurs in 60 to 90% of women with LCIS, while the rate of multicentricity for DCIS is 40 to 80%. LCIS occurs bilaterally in 50 to 70% of cases, while DCIS occurs bilaterally in 10 to 20% of cases.Invasive Breast CarcinomaPaget's disease of the nipple

Invasive ductal carcinoma.A. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80%B. Medullary carcinoma 4%C. Mucinous (colloid) carcinoma 2%D. Papillary carcinoma 2%E. Tubular carcinoma (and ICC) 2%

3 Invasive lobular carcinoma 10%

4 Rare cancers (adenoid cystic, squamous cell, apocrine)nvasive breast cancers have been described as lobular or ductal in origin. Early classifications used the term lobular to describe invasive cancers that were associated with lobular carcinoma in situ, while all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by specific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. Eighty percent of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classification for invasive breast cancer:Paget's disease of the nipple was described in 1874. It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle, but may progress to an ulcerated, weeping lesion. Paget's disease is usually associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. Biopsy of the nipple will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget's cells) in the rete pegs of the epithelium. Paget's disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on S-100 antigen immunostaining in melanoma and carcinoembryonic antigen (CEA) immunostaining in Paget's disease. Surgical therapy for Paget's disease may involve lumpectomy, mastectomy, or modified radical mastectomy, depending on the extent of involvement and the presence of invasive cancer.Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in 60% of cases. This cancer usually presents in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologies with variable cellular and nuclear grades (Fig. 16-18).Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent phenotype of BRCA-1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physical examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by (1) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (2) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and (3) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation (Fig. 16-19). Approximately 50% of these cancers are associated with DCIS, which is characteristically present at the periphery of the cancer, and fewer than 10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma.Mucinous carcinoma (colloid carcinoma), another special-type breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the elderly population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consistency to the cancer. Approximately 66% of mucinous carcinomas display hormone receptors. Lymph node metastases occur in 33% of cases and 5- and 10-year survival rates are 73 and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopy sections and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma.Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a disproportionate number of nonwhite women. Typically, papillary carcinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. McDivitt and colleagues noted that it showed a low frequency of axillary lymph node metastases and had 5- and 10-year survival rates similar to those for mucinous and tubular carcinoma.Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammography screening and is usually diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases, which are usually confined to the lowest axillary lymph nodes (level I). However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%.Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 16-20). Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive lobular carcinoma varies from clinically inapparent cancers to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammography features, invasive lobular carcinoma may be difficult to detect.

Invasive ductal carcinomaInfiltrating lobular carcinoma

Blood vessel invasion

Diagnosing breast cancer 20Triple assessmentClinicalImagingPathologyAgeExaminationUltrasoundMammographyMRIFine needle aspiration cytologyCore-cut biopsyClinical PresentationNew lumps or a thickening in the breast or under the armNipple tenderness, discharge, or physical changesSkin irritation or changes (puckers, dimples, scaliness, or new creases)Most women with early stage breast cancer have no symptoms. Pain in the breast is not usually a symptom.Symptoms that may indicate breast cancerLumps in the breast: single, hard and painless, irregular in shape

Lumps in the armpit

Breast pain: seldom (most the menstrual cycle, cyclic mastalgia)

Bleeding or discharge from the nipple (5%)

Involution or inversion of the nipple

Swelling of the arm (lymphedema)

Dimpling, ulceration of skin

Changes in size or shape of the breast

Symptoms of secondary tumors

A breast lump is most often the clinical problem that causes women to seek treatment and remain the most common presentation of breast carcinoma. 65% of breast cancer cases.

Other less frequent presenting signs and symptoms of breast cancer include (1) breast enlargement or asymmetry; (2) nipple changes, retraction, or discharge; (3) ulceration or erythema of the skin of the breast; (4) an axillary mass; and (5) musculoskeletal discomfort.

However, some of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease.Lump62,63 The surgeon inspects the woman's breast with her arms by her side (Fig. 16-21A), with her arms straight up in the air (Fig. 16-21B), and with her hands on her hips (with and without pectoral muscle contraction). Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d'orange), nipple or skin retraction, and erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Dimpling: skin retraction, tumors deep within the substance of the breast that involves the Coopers ligaments) Peau dorange: edema of the breast. Usually obstruction of the dermal lymphatics with tumor, extensive axillary LN involvement related met tumor, primary disease of the axillary nodes, axillary dissection. (also after irradiation of the breast).

Changes in the skin of the breast (DPUSE)Ulceration: in advanced case, the tumor may involve the skin, leading to it. Satellite change: tumor cells enter the lymphatic vessels and form masses around the primary site.

Erythemainflammatory breast cancer, usually involves the entire breast and is distinguished from the inflammation due to infection by the absence of breast tenderness and fever.

Nipple retractiontumor involves the tissue beneath the nipple. Bleeding: Eczematous change: Paget'sChanges in the character of the skin.

The nipple change

Lymph nodes

Breast self-examinationEncourage Adverse effect: a lifetime of uncertainty and anxiety for the patient (of proven harm!)Controversy

MammographyAnnual screening mammography beginning at age 40 years is recommended in the United StatesMammography is shown to reduce mortality from breast cancer by as much as 44%American Cancer Society (ACS) 1997 Aged > 40 Annual mammogramIn the United States, annual screening mammography beginning at age 40 years is recommended by the American Cancer Society, the American College of Surgeons, the National Cancer Institute, and the American College of Radiology because randomized trials have shown a 44% reduction in mortality. Additionally, screening mammography can detect clinically occult cancer in the form of suspicious microcalcification, a mass, or architectural distortion. Disease can thus be detected before the tumor becomes palpable to the patient or the health care providers and diagnosed at an earlier stage. Interpretation of screening mammograms requires radiologists with training and expertise in this area.

Screening mammography includes a two-view mammogram (taking two x-rays of the breast). It is important to note that current mammography techniques use low doses of radiation and the odds of inducing breast cancer because of radiation from mammography are extremely remote (more than 3,333,332 to 1).

Kopans DB. An overview of the breast screening controversy. J Natl Cancer Inst Monogr. 1997;22:1-3.Kerlikowske K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr. 1997;22:79-86.Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003;361:1405-4510.

Screening Mammography (cont.)

Invasive cancer (4 mm)Malignant microcalcificationsScreening mammography detected a four-millimeter, nonpalpable invasive ductal carcinoma, identified by the white arrow on the left (it is enlarged with a coned view in the small box). On the screening mammogram on the right, obviously malignant calcifications can be seen.Ultrasonography Ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities.Breast cysts are well circumscribed, with smooth margins and an echo-free centerBenign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior marginsBreast cancer characteristically has irregular wallsSecond only to mammography in frequency of use for breast imaging, ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. On ultrasound examination, breast cysts are well circumscribed, with smooth margins and an echo-free center (Fig. 16-25). Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior margins. Breast cancer characteristically has irregular walls (Fig. 16-26), but may have smooth margins with acoustic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization of breast lesions. It is highly reproducible and has a high patient acceptance rate, but does not reliably detect lesions that are 1 cm or less in diameter.

MRIHigh sensitivity (94 100%)Low specificity (37 97%)Better screening tool than mammography in high-risk populationsExpensive, invasive and more time consumingIn the process of evaluating MRI as a means of characterizing mammography abnormalities, additional breast lesions have been detected. However, in the circumstance of both a negative mammogram and a negative physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in using MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women with a strong family history of breast cancer or who carry known genetic mutations require screening at an early age, but mammography evaluation is limited because of the increased breast density in younger women. In the second case, a study of MRI of the contralateral breast in women with a known breast cancer showed a contralateral breast cancer in 5.7% of these women. Breast Biopsy 1. Fine-needle aspiration (FNA) biopsy Sensitivity: 6598% Specificity: 34100% False-positive Rate: 0.17%2. Core-needle biopsy Automated biopsy gun (14-guage, 5 core samples for mass and 5-10 for microcalcification) Directional vacuum-assisted biopsy (Mammotome, EnCore) Stereotactic Core Biopsy Nonpalpable Lesion Sensitivity: 92100% Nonpalpable Lesion Imaging-guide Needle Localization

3. Incisional or Excisional Biopsy

Biomarkers and Circulatory tumor cells Carcinoembryonic antigen (CEA): positive rate 20%-70%.

The MUC -1 gene product (CA15-3: positive 33-60%; CA27.29).(Ch 1q21-24).

The HER-2/neuextrocellular domain (Ch 17q11-12). 20-30% overexpression.

New serum tumor markers (uPAurokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1).

Circulatory tumor cells (CTC), 5 or more CTC cells in the blood of patients with MBC. Comparative frequency of fibrocystic changes, fibroadenomas, and carcinomas by age groups

StagingTNMHistologic type (DCIS. LDIS, IBC)Hormone receptors (ER,PR)Oncogenes (Her-2)Staging procedures

TNM stagingTNM 'Staging' takes into account the size of the tumour (T); whether the lymph nodes (N) are affected and; whether the tumor has matastasized (M) anywhere else.

The TNM system for staging is a frequently used staging system used all over the world.

More likely to use this staging system because it describes stage more accurately than others.

Treat breast cancer according to the staging and grade.

TNM 'Staging' takes into account the size of the tumour, whether the lymph glands (lymph nodes) are affected and whether the tumour has spread anywhere else. The tests and scans you have when diagnosing your cancergive some information about the stage. The stage is important because it helps your breast cancer specialist to decide on the best treatment for you. Doctors also treat breast cancer according to its grade.

A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has modified the TNM system for breast cancer

The T0 and Tis StageTx: primary tumor cannot be assessedT0 No evidence of primary tumorTis: Carcinoma in situ Tis (DCIS), Ductal carcinoma in situ Tis (LCIS), lobular carcinoma in situ Tis (Pagets), pagets disease of the nipple with no tumor.

Modified from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed. New York: Springer, 2002, pp 227228. Primary tumor (T) Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3); if other measurements, such as mammographic or pathologic measurements, are used, the subsets of T1 can be used. Tumors should be measured to the nearest 0.1-cm increment Paget's disease associated with a tumor is classified according to the size of the tumor) T1 StageT1mic: 0.1- 0.5 cmT1b: >0.5- 1.0 cmT1c: >1.0- 2.0 cm

T1mic:microinvasion 0.1 cm or less in great dimension.T1a:the tumor is more than 0.1 cm but not more than 0.5 cm across.T1b:the tumor is more than 0.5 cm but not more than 1.0 cm.T1c:the tumor is more than 1.0 cm but not more than 2.0 cm.

T2 StageT2: > 2.0 - 5.0

T2:the tumor is more than 2.0 cm but not more than 5.0 cm across.

T3 StageT3: >5.0 cm

T4 StageTumor of any size with direct extension to (a) chest wall or (b) skin, only as described below T4a: The tumor is fixed to the chest wallT4b: The tumor is fixed to the skinT4c: T4a+T4bT4d: inflammatory carcinoma (red, swollen,and painful to the touch)T4 is divided into 4 groups.Inflammatory breast cancer is a cancer in which the overlying skin is red , swollen, and painful to the touch.The N stage (clinical regional LN NxRegional lymph nodes cannot be assessed (e.g., previously removed) .

N0: No cancer cells found in any LN.

N1: Metastasis to movable ipsilateral axillary LN.

N2: N2a:Met in ipsilateral axillary LN fixed or matted or to other structures, N2b:Met only in clinically apparenta ipsilateral internal mammary LN and in the absence of clinically evident axillary LN met.

N3: N3a:Met in ipsilateral infraclavicular LN. N3b: Met in ipsilateral internal mammary LN and axillary LN. N3c: Metastasis in ipsilateral supraclavicular LN.

N1. Cancer in nodes in the armpit but nodes not stuck to the structure.

The N stage (pathologic regional LNpNxRegional LN cannot be assessed (e.g., previously removed) pN0: No regional LN met histologically.

pN1: Met in 1 to 3 axillary LNpN2: Met in 4 to 9 axillary LNpN3: Met in 10 or more axillary LN

N1. Cancer in nodes in the armpit but nodes not stuck to the structure.pN2: Met in 4 to 9 axillary LN, or in clinically apparenta internal mammary lymph nodes in the absence of axillary lymph node metastasis p N2a:Metastases in ipsilateral axillary lymph nodes fixed or matted or to other structures, pN2b:Metastasis only in clinically apparenta ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis

pN3: Metastasis in 10 axillary LN, or in infraclavicular lymph nodes, or in clinically apparenta ipsilateral internal mammary LN in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes. pN3a;pN3b;pN3c.

The M stage (distant metastasis) Mx: Distant metastasis cannot be assessed M0: No distant metastasis M1Distant metastasis. M0: No sign of cancer spread. M1: Distant metastasis, Cancer has spread to another part of the body, apart from the breast and LN under the arm.

Stage and Grade The stage of breast cancer means how far it has grown and whether it has spread.

The grade means what the cancer cells look like under the microscope. Breast cancers can be grade 1 (Low grade or slow growing) grade 2( Intermediate grade ) grade 3 (High grade or fast growing)Stage 0. Tis, N0, M0.

Stage I. T1N0, M0. When the cancer has spread beyond a milk duct or lobe, but not outside the breast. The tumor size for this stage is equal to or less than 2 cm.The tumour is no more than 2 cm across (T1) The LNin the armpit are not affected The cancer has not spread

Staging of breast cancer Doctors divide breast cancer into four number stages. 'Staging' takes into account various factors, such as the size of the tumour, whether cancer cells have spread into the nearby lymph glands (lymph nodes), whether the cancer cells have receptors for hormones or other proteins, and whether the tumour has spread to any other part of the body. The word tumourmeans either a breast lump or the area of cancer cells found on a scan or mammogram.

The tests and scans you have when diagnosing your cancer give some information about the stage. The stage is important because it helps your breast cancer specialist to decide on the best treatment for you. Doctors also treat breast cancer according to its grade. They usually make decisions about treatment for breast cancer according to the TNM stageand the grade of the cancer.Stage II

This is divided into two groups

Stage IIA : T0,N1,M0; T1,N1,M0; T2,N0,M0; T1,N1,M0 : The tumour is less than 2 cm, the LN under the arm contain cancer but are not stuck to each other and the cancer has not spread. T0,N1,M0: Although no tumour is seen in the breast, the LN under the arm contain cancer cells but are not stuck together, and there is no sign of spread to other parts of the body. T2,N0,M0: The tumour is less than 5 cm, there are no cancer cells in LN in the armpit and the cancer has not spread.

Stage IIB: T2,N1,M0; T3,N0,M0T2,N1,M0 : The tumour is less than 5 cm and the LN under the arm contain cancer cells but are not stuck to each other, and the cancer has not spread or T3,N0,M0 : The tumour is bigger than 5 cm across, there are no cancer cells in the lymph nodes in the armpit and the cancer has not spreadLike Stage I, Stage II is considered an early stage of breast cancer. Tumors can range from 2 cm to more than 5 cm. They may or may not have spread to the axillary lymph nodes.Stage II breast cancerThis is divided into two groups

Stage IIIStage IIIA: T0,N2,M0; T1,N2,M0; T2,N2,M0;T3,N1,M0;T3,N2,M0. Although no tumour is seen in the breast, the lymph nodes under the arm contain cancer cells and are stuck together, but there is no sign of cancer spread or The tumour is 5 cm or less, the lymph nodes in the armpit contain cancer cells and are stuck to each other, but the cancer has not spread elsewhereor The tumour is more than 5 cm, the lymph nodes in the armpit contain cancer cells and may be stuck together, but there is no further spread.

Stage IIIB: T4,N0,M0; T4,N1,M0; T4,N2,M0.The tumour is fixed to the skin or chest wall, the lymph nodes may or may not contain cancer cells, but there is no further spread.

Stage IIIC: Ant T, N3, M0. The tumour can be any size and has spread to lymph nodes in the armpit and under the breast bone, or to nodes above or below the collarbone, but there is no further spread.Stage III (A-C). This is considered a locally advanced form of breast cancer. It has spread to the axillary lymph nodes, to tissues near the breast (such as the skin or chest wall) or to lymph nodes inside the chest wall. Tumors can range from smaller than 2 inches (5 cm) to larger than 2 inches.

Stage IVStage IV. Ant T, any N, M1.Metastatic cancer, which is cancer that has spread to other more distantorgans of the body. Frequent metastatic sites for breast cancer are the bones, lungs, liver or brain. Stage IV is also the classification given to inflammatory breast cancer or breast cancer that has spread to the lymph nodes in the neck near the collarbone.

The tumour can be any size The lymph nodes may or may not contain cancer cells The cancer has spread or metastasised to other parts of the body such as the lungs, liver or bonesSurvival rate and prognosis factorsStage Survival rate at 8 year(%)Stage 90Stage 70Stage 40Stage 10Stage Classifications for Early Stage DiseaseStage 0TisN0M0Stage IT1N0M0Stage IIAT0N1M0T1N1M0T2N0M0Stage IIB T2N1M0

Singletary SE, et al. J Clin Oncol. 2002;20:3576-3577.In 2003, the American Joint Committee on Cancer (AJCC) revised the staging system for breast cancer. Prior to the revisions, stage II (IIA and IIB) was considered to be early stage disease. Most breast cancer clinicians now consider stage IIB disease to be a form of locally advanced and large primary breast cancer. The new staging system includes information on the number of nodes with metastases. Clinical stage II disease includes the presence of movable ipsilateral axillary metastases. However, if more than four lymph nodes with metastases are found during pathologic evaluation, patients are considered to have stage III breast cancer. This change was made because it was determined that the prognosis is directly proportional to the absolute number of lymph nodes with metastases. The survival rate for women with more than four lymph nodes with metastases is similar to that for women with stage III breast cancer, as defined by the previous staging system.

Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on cancer staging system for breast cancer. J Clin Oncol. 2002;20:3576-3577.

Locally Advanced Breast Cancer LABCThis means the cancer has not spread to another part of the body but may be:

Bigger than 5 cm across Growing into the skin or muscle of the chest Present in the lymph nodes in the armpit, and these lymph nodes are either stuck to each other, or other structures ( N2)Prognostic Factors that Influence SurvivalYounger age at diagnosisTumor size at diagnosisNumber of nodes with metastasisHistologic grade of primary tumorHormone and HER2 receptor statusAmerican Cancer Society. Breast Cancer Facts and Figures 2003-2004.Risk factors are used to predict the prognosis for a patient and to guide treatment decisions. Relative survival rates decrease as the time after diagnosis increases. In a study reported by Michaelson et al., survival rates were 87% at five years after diagnosis, 77% at 10 years, and 52% at 20 years. Women under age 40 with breast cancer have slightly lower survival rates than older women, which may be due to more aggressive tumors and less responsiveness to hormone therapy. Survival decreases with the increasing size of tumors and five-year survival is lower for patients who have a more advanced stage of disease at the time of diagnosis. The prognosis is better for women with ER-positive or PR-positive tumors than for women with hormone-negative tumors.

American Cancer Society. Breast Cancer Facts and Figures 2003-2004. Available at: www.cancer.org/downloads/STT/CAFF2003BrFPWSecured.pdf. Accessed September 25, 2004.Michaelson JS, Silverstein M, Wyatt J, et al. Predicting the survival of patients with breast carcinoma using tumor size. Cancer. 2002;95:713-723.

Surgical options in breast cancerBreast-Conserving Surgery (BCS): an operation to remove the cancer but not the breast itself. some of the lymph nodes that may be removed. and radiation therapy is usually given after surgery for six to eight weeks.

Segmental mastectomy: also called a partial mastectomy or quadrantectomy. to remove more breast tissue than with a lumpectomy. The cancerous area and a surrounding margin of normal tissue are removed.

You may have any of these treatments, or all of them, depending on your situation. It is impossible to generalise about breast cancer treatment because there are so many different sets of circumstances. Your doctor will take many different factors into account when deciding how to treat you. This is also referred to as breast conserving therapy. The surgeon removes the cancerous area and a surrounding margin of normal tissue. A second incision may be made in order to remove the lymph nodes. This treatment aims to maintain a normal breast appearance when the surgery is over.After the lumpectomy, a five- to eight-week course of radiation therapy is often used to treat the remaining breast tissue. The majority of women who have small, early-stage breast cancers are excellent candidates for this treatment approach.Women who are not usually eligible for a lumpectomy include those who have already had radiation therapy to the affected breast, have two or more areas of cancer in the same breast that are too far apart to be removed through one incision, or have cancer that was not completely removed during the lumpectomy surgery.Surgical options in breast cancer (cont.)Total mastectomy: also called a simple mastectomy. to remove the whole breast that has cancer .

Modified radical mastectomy: to remove the whole breast that has cancer, many of the lymph nodes under the arm, the lining over the chest muscles, and sometimes, part of the chest muscles. Auchincloss (left the pectoral muscle behind) and Patey (1848) (remove the pectoralis minor muscles).

Radical mastectomy (rarely done): Halsted and Meyer reported (1894) . to remove the breast that has cancer, chest wall muscles under the breast, and complete dissection of axillary LD levels I to III, the long thoracic n. and the thoracodosal neurovascular bundle.

Surgical options in breast cancerProphylactic mastectomy: is preventive removal of the breast to lower the risk of breast cancer in high-risk people.

Prophylactic ovary removal. is a preventive surgery that lowers the amount of estrogen in the body, making it harder for estrogen to stimulate the development of breast cancer.

Breast reconstruction. is the rebuilding of the breast after mastectomy and sometimes lumpectomy. Reconstruction can take place at the same time as cancer-removing surgery, or months to years later. Some women decide not to have reconstruction and opt for a prosthesis instead.

Axillary Lymph Node DissectionGoalsAccurate stagingRegional controlSurvival advantage?

No benefit in removing healthy lymph nodes

Is complete node dissection necessary for staging?

The goals of axillary lymph node dissection are to provide accurate staging information and to remove node disease that may cause later difficulty with regional control of disease. The procedure is controversial among oncologists, but it is likely that the survival advantage conferred by the removal of node disease is small. There is no benefit in removing healthy lymph nodes.

Sentinel nodeThe sentinel nodes are the first nodes through which lymphatic fluid flows from a tumor. In other words, the sentinel nodes are like the gatekeepers to the rest of the lymph nodes.

The sentinel nodes are the first nodes through which lymphatic fluid flows from a tumor. In other words, the sentinel nodes are like the gatekeepers to the rest of the lymph nodes.The Lymph Node Mapping with Sentinel Node Biopsy procedure- commonly called Sentinel Node Biopsy - helps doctors discover which lymph nodes need to be removed and whether cancer cells have spread to these nodes. Here's how the procedure works.Often, the first step is a visit to Nuclear Medicine where a radioactive tracer is injected around the tumor site.Then during surgery, the surgeon injects a blue dye around the tumor site. The lymph fluid will carry the dye and tracer as it drains to the lymph nodes.

Sentinel Lymph Node Biopsy as a Substitute for Axillary Lymph Node DissectionStandard practice in U.S.A. and EuropeProven accurate method for detection of clinically occult node metastasesCan be used to detect lymph node metastases in patients with a clinically negative axillaTechnique requires multidisciplinary participation and validation

Sentinel Node Biopsy

isosulfan blue dye (Lymphazurin) is injected in a similar fashion

The surgeon then looks for the node with the blue dye or scans with a special gamma probe to find the node with the highest tracer count. This is the sentinel node.Often, the first step is a visit to Nuclear Medicine where a radioactive tracer is injected around the tumor site.Then during surgery, the surgeon injects a blue dye around the tumor site. The lymph fluid will carry the dye and tracer as it drains to the lymph nodes.The surgeon then looks for the node with the blue dye or scans with a special gamma probe to find the node with the highest tracer count. This is the sentinel node.

The dye or radioactive tracer creates a "map" of the nodes, showing which nodes to remove. In some cases, only the blue dye may be used to find the sentinel nodes.

Once the sentinel lymph nodes have been "mapped," the surgeon can remove those specific nodes - the Sentinel Node Biopsy. After the biopsy is done, the pathologist can do an in-depth analysis in the lab to see if the nodes contain cancer cells.The blue dye may cause the breast skin to stain blue for several days. It may also cause the urine to look greenish for about 24 hours while it is excreted by the kidneys. In rare cases, the patient may experience an allergic reaction to the dye.

Sentinel Node Biopsy may add some time to a patient's surgery, but it will not increase recovery time. Furthermore, there are few serious side effects to Sentinel Node Biopsy. Due to the information from the Sentinel Node Biopsy, some patients may not need to have additional lymph nodes removed. In that case, there is less time in surgery.

Breast cancers suitable for conservation surgerySingle clinical and mammographic lesionTumor 4 cmNo local advancement (T1, T2 < 4 cm), extensive nodal involvement (No, N1), or metastases (M0)Tumor > 4 cm in a large breast

Radiation Therapyis mandatory following breast-conserving surgery. Whole-breast radiation following breast-conserving surgery reduces chance of local recurrence by about two-thirds.

Is considered appropriate for patients at high risk of recurrence after mastectomy such as (T 5 cm, N(+) 4, involvement of the pectoralis muscle)

Systemic Adjuvant Therapy

Aim to prevent or delay distant metastases.ChemotherapyHormonal therapyTargeted therapy

Is based on two principles: Fisrtthere is a burst of mitotic activity in met sites after a primary tumor is removed; secondly, breast cancer is a systemic disease characterized by widespread early occult met, which usually antedates diagnosis.

Tamoxifen is beneficial for ER-positive breast cancer.

The benefit of tamoxifen and chemotherapy is additive, but must be given sequentiallyData from the Early Breast Cancer Trialists Collaborative Group meta-analysis has shown that tamoxifen reduces the risk of recurrence and improves survival in patients with ER-positive or ER-unknown early stage breast cancer. Cytotoxic chemotherapy has also been demonstrated to confer benefit, but has a greater impact for younger patients compared with older patients. Combined treatment with both endocrine therapy and chemotherapy is additive in terms of reducing the risk of recurrence and improving survival.