This chapter should be cited as follows: This chapter was last updated:
Hindle, W, Mokbel, K, Glob. libr. women's med.,
(ISSN: 1756-2228) 2009; DOI 10.3843/GLOWM.10016
January 2009

The breast

Breast Cancer and the Obstetrician-Gynecologist

William H. Hindle, MD
Professor Emeritus, Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Founder, Breast Diagnostic Center, Women's and Children's Hospital, LAC+USC Medical Center, Los Angeles, California, USA
Kefah Mokbel, MB BS, MS, FRCS
Professor of Breast Cancer Surgery (The Brunel Institute of Cancer Genetics & Pharmacogenomics), Consultant Breast Surgeon at St. George's Hospital, Lead Breast Surgeon at The London Breast Institute of The Princess Grace Hospital, Reader in Breast Surgery (St. George's University of London), London, UK

INTRODUCTION

Breast cancer is the most common invasive (nonskin) cancer of women. For 2007, it is estimated that there will have been 178,480 invasive breast cancers and 62,030 new cases of in situ breast cancer diagnosed in women in the USA. In addition it is estimated that there will have been 40,460 female deaths from breast cancer in 2007.1 The incidence of breast cancer seems to have peaked in 1998 and the subsequent decline since then has been attributed to the saturation of breast cancer screening and the decrease in the use of hormone replacement therapy (HRT) since the publication of the Women's Health Initiative Study in 2002.2

The American Joint Committee on Cancer lists 24 different codable histologic types of breast malignancies (Table 1), of which seven are in situ and 17 are invasive (infiltrating).3 Each specific histologic type has its own unique characteristics, biologic behavior, and prognosis when treated. In addition, the optimum treatment varies with each specific histologic type. However, for invasive and in situ breast cancer, as many as 80% of the cases are of the ductal type. Color plates 1 through 16 show typical examples of the histology and cytology of normal breast tissue, fibrocystic changes, fibroadenoma, and invasive ductal carcinoma under low- and high-power magnification. (Color plates appear at the end of the chapter.)

 

Table 1. Codable histologic breast malignancies


In situ
 Carcinoma in situ, NOS*
 Comedocarcinoma, noninfiltrating
 Cribriform carcinoma in situ
 Intraductal carcinoma and lobular carcinoma in situ
 Intraductal carcinoma, noninfiltrating, NOS
 Lobular carcinoma in situ, NOS
 Noninfiltrating intraductal papillary adenocarcinoma
 Paget's disease and intraductal carcinoma of breast
 Paget's disease, mammary
Invasive
 Adenoid cystic carcinoma
 Carcinoma, NOS
 Carcinoma undifferentiated, NOS
 Carcinosarcoma, NOS
 Cribriform carcinoma, NOS
 Infiltrating duct carcinoma, NOS
 Inflammatory carcinoma
 Lobular carcinoma, NOS
 Medullary carcinoma, NOS
 Mucinous adenocarcinoma
 Paget's disease and infiltrating duct carcinoma of breast
 Phyllodes tumor, malignant
 Secretory carcinoma of breast
 Squamous cell carcinoma, NOS
 Tubular adenocarcinoma

*NOS = not otherwise specified.
(Adapted from American Joint Committee on Cancer: AJCC Cancer Staging Manual, p 236. 6th edn. New York, Springer, 2002.)

 

The incidence rate for breast cancer in women has increased steadily since 1977, as shown in comparison with other major invasive cancers in Figure 1.1 However, the incidence rate appears to have peaked in 1997, with a slight decrease since then. Figure 2 graphically depicts the contrasting mortality rates of the major invasive cancers.1 Possibly related to improved methods of treatment, the mortality rate for breast cancer has shown a continuous slightly downward trend of from 1940 to 1990. Probably caused by the widespread use of screening mammography, the mortality rate has decreased from 1990 to 1999. Hopefully, this trend of clinically meaningful decreasing mortality rates will continue as data for the years after 1999 become available. The 5-year survival rates by extent of breast cancer at the time of diagnosis are 86% for all stages, 97% for localized cancer, 78% for cancer with regional involvement, and 23% for metastatic cancer.2

Fig. 1. Trends of incidence rates of the major invasive cancers of women in the United States (1972–1999). (Jemal A, Murray T, Samuels A et al: Cancer statistics 2003. CA Cancer J Clin 53:5–26, 2003; p 13 with permission.)

Fig. 2. Trends of mortality rates of the major invasive cancers of women in the United States (1930–1999). (Jemal A, Murray T, Samuels A et al: Cancer statistics 2003. CA Cancer J Clin 53: 5–26, 2003; p 15 with permission.)

Obstetrician-gynecologists should strive to bring about the diagnosis of breast cancer before the cancer is palpable. This goal can be effectively achieved by annual screening mammography for women beginning at age 40 years.4 Mammography can perceive small (1- to 9-mm) nonpalpable breast cancers that have the optimum curability, with more than 90% 20-year disease-specific survival using current methods of treatment (Table 2).5 Palpable cancers have a less favorable outcome. Generally, survival from palpable breast cancer correlates inversely with increasing size.6 For example, 10-to 29-mm cancers have been reported to have 67% 15-year survival (Table 3).7

 

Table 2. 20-year breast cancer-specific survival: mammographic appearance vs. percentage survival


Mammographic appearance

Percentage survival
Stellate mass without calcifications100
Noncasting calcifications96
Circular mass without calcifications93
Casting calcifications60
All 1–9-mm tumors93

(Adapted by Patricia T. Kelly, PhD, from Tabar L, Vitak B, Chen HH, et al: The Swedish Two-County Trail twenty years later. Updated mortality results and new insights from long-term follow-up. Radiol Clin North Am 38:625–651, 2000.)
Tumors 1–9-mm without nodal involvement.

Table 3. 15-year breast cancer survival: correlation with tumor size


Tumor sizePercentage survival
10–14 mm86
15–19 mm72
20–29 mm67
30–39 mm46

(Adapted by Patricia T. Kelly, PhD, from Michaelson JS, Silverstein M, Wyatt J, et al: Predicting the survival of patients with breast carcinoma using tumor size. Cancer 95:713–723, 2002.)

Unfortunately, some cancers large enough to be palpable are not initially perceived on mammography. This probably occurs in less than 10% of cases.8 Increased mammographic density (Table 4) can obscure both nonpalpable and palpable breast cancers. Thus, women should have an annual clinical breast examination in addition to screening mammography. Ideally, the examination is performed before the mammogram so that the results of the examination are known by the radiologist/mammographer. Women with dense breasts should be preferably screened with full-field digital mammography rather than analogue mammography. The addition of ultrasound and/or MRI should be also considered in such subjects.

 

Table 4. The BI-RADS descriptive patterns of mammographic breast density


The breast is almost entirely fat
There are scattered fibroglandular densities that could obscure a lesion on mammography
The breast tissue is heterogeneously dense
This may lower the sensitivity of mammography
The breast tissue is extremely dense, which lowers the sensitivity of mammography

(American College of Radiology (ACR): Illustrated Breast Imaging Reporting and Data System (BI-RADS™), 3rd edn. Reston, VA, American College of Radiology, 1998.)

A conceptual mathematical model of the growth of a typical invasive ductal breast cancer is depicted in Figure 3.9 The growth of the cancer is based on a constant 100-day cell mass doubling time, which is the generally accepted mean rate of growth. However, estimated breast cancer doubling times have been reported in the range of 30–300 days and are not constant, but vary dependent on the specific cancer characteristics and host interaction. Nevertheless, the concept depicted is sound. There is a premammographic phase when the cancer is too small to be detected by any method currently available, followed by a preclinical phase when the cancer is too small to be palpable. Exactly when breast cancers metastasize is unknown, but the 90% 20-year disease-free survival of treated 1- to 9-mm mammographically detected cancers indicates that few had metastasized before the cancers reached a size of 1 cm. This concept underscores the importance of annual screening mammography, particularly in the 40- to 49-year-old group in which, clinically, some of the breast cancers grow aggressively with apparently shorter doubling times.

Fig. 3. Mathematical representation of the theoretical growth (size) of breast cancer plotted against time in years based on a constant cellular doubling time of 100 days. (Wertheimer MD, Costanza ME, Dodson TF et al: Increasing the effort toward breast cancer detection. JAMA 255: 1311 –1315, 1986; with permission.)

The American Cancer Society's 2007 guidelines for the early detection of breast cancer in asymptomatic women are annual mammography and clinical breast examination beginning at age 40 and clinical breast examination every 3 years for women ages 20–39.10 If a clinically suspicious breast lesion remains undiagnosed, the patient should be urgently referred to a breast specialist. If the patient has diagnosed breast cancer, optimum treatment is usually obtained at a dedicated breast center with a multidisciplinary treatment planning team (Table 5).

 

Table 5. A multidisciplinary treatment planning team should include the following oncologic breast specialists


Imaging
Medical oncology
Nursing/counseling
Pathology
Plastic surgery
Radiation therapy
Social service
Surgery

RISK FACTORS

Most women are concerned about the risk of breast cancer. Numerous epidemiologic studies have been published, but it is often difficult for patients, and even for physicians, to understand and appreciate the pertinent clinical meaning. Typically, a woman wants to know if she will get breast cancer, and that question is not answerable. An obstetrician-gynecologist can recommend that the patient read a clear understandable book, such as Assess Your True Risk of Breast Cancer by Patricia Kelly, PhD (An Owl Book, Henry Holt and Company, New York, NY, 2000). This book is also useful reading for obstetrician-gynecologists for insight into epidemiologic studies, statistics, relative risk, absolute risk, and statistical significance.

The clinically relevant risk factors for breast cancer are: (1) being a woman; (2) growing older; (3) gene mutations; (4) atypical ductal or lobular hyperplasia; (5) lobular carcinoma in situ (more accurately called lobular neoplasia, a tumor marker); and (6) atypical epithelial hyperplasia. Other epidemiologic risk factors are: (1) birth of first child after age 30; (2) consumption of an alcoholic beverage one or more times per day; (3) early onset of menstruation (menarche); (4) family history of breast cancer; (5) having had breast cancer; (6) increased mammographic density; (7) late ending of menstruation (menopause); (8) nulliparity; (9) postmenopausal estrogen and progestin therapy; (10) postmenopausal obesity; and (11) recent use of oral contraceptives. However, none of these epidemiologic risk factors alters clinical management. A summary of the published breast cancer relative risk data is in Table 6. Relative risk of less than 2–3 is an epidemiologic weak association without evidence of causality and, clinically, is likely to be a chance association, perhaps related to the multifactorial natural history and biologic behavior of breast cancers.

 

Table 6. Breast cancer relative risk factors grouped by magnitude


Relative risk < 2

Relative risk 2–4

Relative risk > 4
Early menarcheAge > 35 first birthGene mutation
Late menarche1st degree relative with breast cancerLobular carcinoma in situ
NulliparityRadiation exposureDuctal carcinoma in situ
Proliferative benign diseasePrevious breast cancerAtypical hyperplasia
Obesity  
Alcohol use  
Hormone replacement  

Summary of published levels of relative risks for breast cancer. (Brinkmann E, Morrow M: The surgeon's role in breast cancer chemoprevention. Breast Dis 12:103–112, 2001 [Table 1. p 105].)

 

Routine vigorous physical activity and maintenance of healthy body weight are associated with epidemiologic decreased risk of breast cancer.2

DIAGNOSIS: INVASIVE CANCER AND IN SITU CARCINOMA

Ductal carcinoma is the most common histologic type of breast cancer, accounting for as many as 80% of breast malignancies. Nonpalpable invasive ductal carcinoma is usually perceived on mammography. The typical findings are stellate solid mass or pleomorphic casting microcalcifications. However, a malignant solid mass may be circular and the calcifications may be noncasting. Ultrasound can be helpful in defining a malignant solid mass, particularly in a young woman or in any woman with mammographically dense breasts, but ultrasound is not effective in evaluating calcifications that are often not perceived on ultrasound. The definitive diagnosis of nonpalpable cancer is established by image-guided tissue core-needle biopsy, commonly with vacuum-assisted technique, or less commonly by imaging needle localization and open surgical biopsy for histologic diagnosis.

It is the patient herself who usually notices, often coincidentally, what she perceives as a mass. Then she presents to her physician, often an obstetrician-gynecologist, for confirmation that it is a palpable dominant mass and for diagnosis. A palpable dominant breast mass is defined as a three-dimensional distinct mass that is different from the remainder of the breast tissue and from the tissue of the other breast. The definitive diagnosis of the mass can be established by fine-needle aspiration cytology, tissue core-needle biopsy histology, or less commonly by open surgical biopsy.

Ductal carcinoma in situ (DCIS) is most commonly nonpalpable and perceived on screening mammography as malignant calcifications, usually pleomorphic and of the casting type. The definitive diagnosis is usually established by stereotactic vacuum-assisted core biopsy or by open surgical biopsy with imaging needle localization. Tissue histology, usually of the entire lesion, is essential to be certain that there is not associated invasive ductal carcinoma.

Invasive lobular carcinoma spreads diffusely with a typical histologic Indian file pattern. Thus, invasive lobular carcinoma is often not apparent, either by palpation or by imaging, until the cancer is at an advanced stage. Lobular carcinoma in situ (LCIS) is thought to be a tumor marker with associated increased risk of eventual invasive carcinoma that usually is of the ductal type when it does occur and may even occur in the contralateral breast. The presence of high grade cytology and necrosis significantly increases the risk associated with LCIS.

REFERRAL AND CONTINUING FOLLOW-UP

If an obstetrician-gynecologist is not trained and experienced in an appropriate diagnostic technique, the patient with a palpable dominant breast mass or with mammography findings suspicious for malignancy (BI-RADS categories 4 and 5; Table 7)11 should be expeditiously referred to a breast center or a breast specialist if a breast center is not available. It is important to continue to follow-up the patient to be certain she is seen in referral and that a definitive diagnosis is established. If the patient delays or refuses the referral, her noncompliance should be clearly documented in her medical record and the patient informed, by certified mail if necessary, of the potentially life-threatening seriousness of her condition and inaction.

 

Table 7. The BI-RADS mammographic assessment categories


Category 0    Need additional imaging evaluation
Category 1Negative
Category 2Benign finding
Category 3Probably benign finding: short interval follow-up suggested
Category 4Suspicious abnormality: biopsy should be considered
Category 5Highly suggestive of malignancy: appropriate action should be taken

(American College of Radiology (ACR): Illustrated Breast Imaging Reporting and Data System (BI-RADS™), 3rd edn. Reston, VA, American College of Radiology, 1998.)

 

As a primary health care provider for women, the obstetrician-gynecologist should continue to be available to the patient, her spouse/partner, and her family for counseling, compassionate explanations of the diagnostic and treatment options, and caring and understandable answers to their questions and concerns.

TREATMENT OPTIONS

Equivalent long-term breast cancer survivals can be achieved by either breast-conserving therapy (lumpectomy, axillary lymph node dissection, and irradiation) or modified radical mastectomy.12 Radical mastectomy, which was The Standard for more than 70 years, is no longer indicated.13, 14

Breast-Conserving Surgery (BCS) 

Breast-conserving therapy is the preferred treatment for stages I and II (up to a size of 5 cm) breast cancer.15 Table 8 describes the American Joint Committee on Cancer staging of breast cancer.3 The absolute and relative contraindications for breast conserving therapy are listed in Table 9. The most common reason for selecting modified radical mastectomy instead of breast conserving therapy for stages I and II breast cancers is the patient's own choice. The medical contradictions are uncommon. Perhaps as many as 10% of women with stage I and 30% with stage II are not candidates for breast-conserving therapy.16 However, some of these unfavorable candidates and some women with cancers larger than stage II can benefit from pre-operative neoadjuvant chemotherapy or endocrine therapy, which can potentially decrease the size of the cancer and make a recommendation for breast-conserving therapy appropriate.17, 18

 

Table 8. TNM staging of breast cancer 2002


DEFINITION OF TNM
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.
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma in situ
Tis (DCIS)Ductal carcinoma in situ
Tis (LCIS)Lobular carcinoma in situ
Tis (Paget's)Paget's disease of the nipple with no tumor

Note: Paget's disease associated with a tumor is classified according to the size of the tumor.

T1Tumor 2 cm or less in greatest dimension
T1micMicroinvasion 0.1 cm or less in greatest dimension
T1aTumor more than 0.1 cm but not more than 0.5 cm in greatest dimension
T1bTumor more than 0.5 cm but not more than 1 cm in greatest dimension
T1cTumor more than 1 cm but not more than 2 cm in greatest dimension
T2Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3Tumor more than 5 cm in greatest dimension
T4Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below
T4aExtension to chest wall, not including pectoralis muscle
T4bEdema (including peau d'orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast
T4cBoth T4a and T4b
T4dInflammatory carcinoma

Regional lymph nodes (N)
Clinical
NXRegional lymph nodes cannot be assessed (e.g., previously removed)
N0No regional lymph node metastasis
N1Metastasis to movable ipsilateral axillary lymph node(s)
N2Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent* ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis
N2aMetastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
N2bMetastasis only in clinically apparent* ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis
N3Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparent* ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
N3aMetastasis in ipsilateral infraclavicular lymph node(s)
N3bMetastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3cMetastasis in ipsilateral supraclavicular lymph node(s)
Pathologic (pN)a
pNXRegional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study)
pN0No regional lymph node metastasis histologically, no additional examination for isolated tumor cells (ITC)

Note: Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters not greater than 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular methods but which may be verified on H&E stains. ITCs do not usually show evidence of malignant activity e.g., proliferation or stromal reaction.

pN0(i−)No regional lymph node metastasis histologically, negative IHC
pN0(i+)No regional lymph node metastasis histologically, positive IHC, no IHC cluster greater than 0.2 mm
pN0(mol−)No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)b
pN0(mol+)No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)b
pN1Metastasis in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent**
pN1miMicrometastasis (greater than 0.2 mm, none greater than 2.0 mm)
pN1aMetastasis in 1 to 3 axillary lymph nodes
pN1bMetastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent**
pN1cMetastasis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent.** (If associated with greater than 3 positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden)
pN2Metastasis in 4 to 9 axillary lymph nodes, or in clinically apparent* internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN2aMetastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm)
pN2bMetastasis in clinically apparent* internal mammary lymph nodes in the absence of axillary lymph node metastasis
pN3Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent* ipsilateral internal mammary lymph nodes 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
pN3aMetastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm), or metastasis to the infraclavicular lymph nodes
pN3bMetastasis in clinically apparent* ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent**
pN3cMetastasis in ipsilateral supraclavicular lymph nodes

Distant metastasis (M)
MXDistant metastasis cannot be assessed
M0No distant metastasis
M1Distant metastasis

STAGE GROUPING
Stage 0TisN0M0Stage IIBT2N1M0Stage IIIBT4N0M0
Stage IT1*N0M0 T3N0M0 T4N1M0
Stage IIAT0N1M0Stage IIIAT0N2M0 T4N2M0
 T1*N1M0 T1*N2M0Stage IIICAny TN3M0
 T2N0M0 T2N2M0Stage IVAny TAny NM1
     T3N1M0    
     T3N2M0    

*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.
aClassification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node dissection is designated (sn) for “sentinel node,” e.g., pN0(i+) (sn).
bRT-PCR: reverse transcriptase/polymerase chain reaction.
**Not clinically apparent is defined as not detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.
*T1 includes T1mic
Note: Stage designation may be changed if post-surgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.
(American Joint Committee on Cancer: AJCC Cancer Staging Manual, pp 227–228, 6th edn. New York, Springer, 2002.)

 

 

Table 9. Medical contraindications to breast-conserving therapy


Absolute
  Pregnancy, because of contraindicated radiation therapy
  Two or more cancers in different breast quadrants
  Diffuse “malignant” microcalcifications
  Prior radiation therapy to the breast area
  Persistent surgical margins involved with cancer
Relative
  Collagen vascular disease
  Multiple gross cancers in one quadrant
  Diffuse indeterminate calcifications
  A large cancer in a small breast
  Large pendulous breast, because of difficulties with radiation therapy

(Adapted from Morrow M, Strom EA, Bassett LW, et al: Standard for breast conserving therapy in the management of invasive breast carcinoma. CA Cancer J Clin 52:277–300, 2002.)

 

An open surgical biopsy of a suspicious dominant mass should be performed with the same careful technique as lumpectomy for known cancer.19 Otherwise, re-excision of the area of the tumor bed is usually necessary.20 As many as 50% of women referred to a cancer center who had their cancer diagnosed by open surgical biopsy required re-excision of the area of the biopsy because the biopsy margins were positive (cut across cancer).20 Definitive diagnosis of cancer by fine-needle aspiration cytology or tissue core-needle biopsy histology should eliminate the need for most re-excisions if the open surgical biopsy follows National Surgical Adjuvant Breast and Bowel Project (NSAPB) technique for lumpectomy.19

Axillary lymph node clearance involves removal of the levels I,II and III lymph nodes (Table 10 shows the description of the levels of axillary lymph nodes). If the patient has known invasive cancer associated with pathological axillary nodes, then axillary lymph node dissection can be performed at the same time as her lumpectomy. Sentinel node biopsy (SNB) using the dual localization (radioactive isotope tracer and blue dye) approach has recently become the gold standard technique of evaluating the axilla in patients with clinically node-negative invasive breast cancer. THE SNB can be evaluated intraoperatively by frozen section or molecular analysis and immediate axillary node clearance is performed if the SNB is positive for malignancy. The technique of SNB however requires special equipment and a learning curve of experience for the surgeon (Fig. 4). Although the sentinel node biopsy is well-established,21, 22, 23 however, the technique is currently available in a limited number of breast centers worldwide. Advantages of the SNB include a lower risk of developing lymphedema (a major complication of axillary lymph node clearance that requires prolonged treatment, often with limited success) and shorter hospitalization.

Table 10. Description of the surgical levels of axillary lymph nodes


Level I: Lateral to the lateral border of the pectoralis minor muscle
Level II:Under the insertion of the pectoralis minor, between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter's) node
Level III:Medial to the medial border of the pectoralis minor muscle, including the nodes designated as apical

(Adapted from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th edn, p 224. New York, Springer, 2002.)


Fig. 4.  This photograph demonstrates the procedure of patent blue dye injection in the left breast for SNB identification in a woman with a screen-detected breast cancer. The radioactive isotope tracer was already injected. 








Radiation therapy (irradiation) is an essential component of breast-conserving therapy and is usually performed in an oncologic radiation therapy center. The radiation oncologist directs the technique and dosage of the therapy, which is individualized to the particular medical circumstances of each breast cancer patient. Usually a total dose of whole breast irradiation of 4500–5000 centigrays is administered in fractions using opposed tangential fields. The course of irradiation is usually administered in daily fractions (5 days per week) for 3–6 weeks. A boost dose of irradiation to the tumor bed increases the target dosage to 6000–6500 centigrays. Careful individualized radiation therapy planning and modern equipment minimize the adverse effects of irradiation, particularly the uncommon but devastating long-term sequellae.24 Radiation therapy has been demonstrated to control the local recurrence of invasive breast cancer surgically treated with lumpectomy.14, 25

A state-of-the-art (as of 2002) comprehensive clinical review of breast-conserving therapy for invasive breast cancer, authored by multidisciplinary authorities, has been published.26 This work provides details and documentation for obstetrician-gynecologists in clinical practice who seek further information about breast-conserving therapy.

Modified Radical Mastectomy

Modified radical mastectomy (total mastectomy and axillary lymph node dissection) removes the entire breast, including the overlying skin and the axillary lymph nodes, usually levels I and II, en bloc. The major modification is the preservation of the pectoralis major muscle, which facilitates improved wound healing and, potentially, allows reconstruction. Modified radical mastectomy is performed for stages I and II breast cancer for which breast-conserving therapy is contraindicated (see Table 9), for selected cancers larger than stage II, and for patient preference when equal therapeutic results and breast cancer survival can be achieved with either breast-conserving therapy or modified radical mastectomy.

Breast Reconstruction

Most women who require or request mastectomy are candidates for breast reconstruction.16 This option should be presented to the patient when she is making her treatment choice. If she is interested in reconstruction, she should be referred, before scheduling her definitive surgery, to a plastic surgeon experienced in the techniques of both prosthetic reconstruction and autologous tissue reconstruction. Both prosthetic and autologous tissue reconstructions can be immediate (during the same operation as the modified racial mastectomy) or delayed (performed at a later date). Immediate or delayed breast reconstruction following conventional non-skin sparing mastectomy (NSSM) often results in prominent scars on the new breast and a paddle of skin that is of a different color and texture. Skin-sparing mastectomy (SSM) preserves most of the overlying skin during an immediate breast reconstruction (IBR) thus leading to a superior aesthetic outcome. It also reduces the need for contralateral breast adjustment in order to achieve symmetry. In selected cases, the nipple-areola complex can be also preserved. Breast reconstruction can be achieved using a breast prosthesis, the latissimus dorsi (LD) myocutaneous flap (usually plus a breast prosthesis) (Fig. 5; Fig. 6), deep inferior epigastric perforator (DIEP) free flap, transverse rectus abdominis myocutaneous (TRAM) flap, or superior/inferior gluteal artery perforator (S-GAP or I-GAP) free flaps.  The choice of the reconstruction method depends upon the patient's body habitus, co-morbidity, smoking history, size and shape of her breasts, her preference and the surgeon's experience. TRAM is the most common autologous tissue reconstruction. Data from 1994 to 1995 reveal that only 8.3% of mastectomy patients had breast reconstruction.16 This low utilization is influenced by: (1) patient age and comorbidity; (2) income; (3) geographic location; (4) type of hospital; and (5) tumor size (for example, women aged 50 or younger had a more than four-fold higher rate of reconstruction than older women); (6) the need for postmastectomy RT and (7) the availability of surgical expertise.

Fig. 5. This 47-year-old woman had left standard skin-sparing mastectomy and immediate reconstruction using the LD flap and implant. She subsequently had nipple reconstruction and tattooing.


 

Fig. 6. This 35 year old woman had bilateral nipple-preserving SSM and immediate reconstruction with implants.




RADIATION THERAPY

Radiation therapy (RT) is an essential component of breast-conserving surgery (BCS) and has been described. Indications for post-mastectomy RT include involvement of more than three nodes, positive surgical margins and/or tumors larger than 5 cm. Although radiation therapy is effective in local control of breast cancer, the long-term (10-year and 20-year) morbidity especially ischemic heart disease remains a concern.24  Modern techniques of accurate planning and radiation delivery will reduce long-term complications. Partial breast irradiation which can be given intra-operatively or post-operatively through special catheters following BCS seems to be a promising alternative to whole-breast RT in selected cases and is currently under investigation.

Radiation therapy, or irradiation, is a common component of the treatment of stages III and IV, often called advanced breast cancer. The exact irradiation technique and dosage is individualized to each case. Irradiation of the axilla should be avoided whenever possible in view of the high rate of complications such as lymphedema and restriction of shoulder movement. Radiation therapy can be also used to treat local recurrences and metastases such as bony and brain deposits.

ADJUVANT SYSTEMIC THERAPY

Adjuvant systemic therapy for breast cancer began with various surgical hormonal ablations, such as oophorectomy and adrenalectomy. In the 1960s, various single-agent chemotherapies were used and reported. Clinical trails were performed in the 1970s. Multidrug chemotherapy, often called polychemotherapy, was found to be more effective than the single-drug therapies.17, 27, 28

Chemotherapy

In 2005, the Early Breast Cancer Trialists Collaborative Group updated their meta-analysis of 194 unconfounded clinical trials of multidrug therapies.29 Combinations of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and later of cyclophosphamide, doxorubicin (Adriamycin is the proprietary name of doxorubicin), and 5-fluorouracil (CAF) achieved significant reductions in the 5 year breast cancer recurrence rates and the 15 year mortality rates. Allocation to about 6 months of anthracycline-based polychemotherapy (e.g., with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p = 0.0001 for recurrence, 2p < 0.00001 for breast cancer mortality) more effective than CMF chemotherapy.29 Anthracyline and/or taxane based regimens are the most frequently used chemotherapy protocols in the adjuvant setting. Taxanes are particularly indicated for node positive breast cancer.29

Table 11 lists classifications of systemic therapeutic agents with examples. The recommendations for adjuvant therapy for node-negative breast cancer are given in Table 12. The recommendations for adjuvant therapy for node-positive breast cancer are given in Table 13. Molecular signatures such as Oncotype DX and Mammaprint are increasingly being used to refine chemotherapy recommendations in premenopausal women with node negative ER+ve breast cancer smaller than 2 cm. For example a recurrence score of 18 or less (range 0–100) indicates that the potential benefit from adjuvant chemotherapy is too small to justify its use in such cases.

 

Table 11. Systemic chemotherapeutic agents in use for breast cancer with examples


Antimetabolites
  Methotrexate
  5-Fluorouracil
Alkylating agents
  Cyclophosphamide
Antitumor antibiotics
  Doxorubicin (an anthracycline)
Mitotic spindle inhibitors (taxanes)
  Paclitaxel
  Docetaxel

(Adapted from Russell CR: Adjuvant systemic therapy for breast cancer. In Hindle WH, (ed): Breast Care, a Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999.)

 

 

Table 12. Recommendations for Adjuvant Therapy for Node-Negative Breast Cancer


Condition

Standard therapyConsideration
<1 cm, ER+, low histologic gradeTamoxifen or none 
1–2 cm, ER+, low histologic grade  
PremenopausalChemotherapy and/or tamoxifen Aromatase inhibitors can be considered after ovarian ablation
Postmenopausal Aromatase inhibitors or tamoxifen 
>2 cm or ER−  
Premenopausal  
 ER+Chemotherapy followed by tamoxifenAomatase inhibitors can be considered after ovarian ablation
 ER−Chemotherapy 
Postmenopausal  
 ER+Aromatase inhibitors or tamoxifenChemotherapy should be considered
 ER−Chemotherapy 


(Russell CR: Adjuvant systemic therapy for breast cancer. In Hindle WH (ed): Breast Care, a Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999.)

NB. Herceptin for 18 months should be considered in all patients with HER-2 positive tumors who also require chemotherapy.

 

 

Table 13. Recommendations for adjuvant therapy for node-positive breast cancer


Estrogen receptor statesStandard therapyConsideration
Premenopausal  
 ER+Chemotherapy followed by tamoxifenAromatase inhibitors after ovarian ablation is an alternative to tamoxifen
 ER−Chemotherapy 
Postmenopausal  
 ER+Chemotherapy and/or aromatase inhibitors or tamoxifenConsider extended adjuvant endocrine therapy
 ER−Chemotherapy 


(Russell CR: Adjuvant systemic therapy for breast cancer. In Hindle WH, (ed): Breast Care, a Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999.)

NB. Herceptin should be considered in all patients with HER-2 positive breast cancer requiring chemotherapy.

 

Breast cancer chemotherapy is complex and is being continuously updated. It is critical that the chemotherapy be individualized and adapted to each patient's particular circumstances. The choice of specific medications used and the dosage and treatment schedule are the purview of the patient's medical oncologist. The actual treatment plan varies with the clinical experience and familiarity of the medical oncologist with a multitude of different chemotherapy options. Furthermore, if the patient's medical situation qualifies, then current chemotherapy clinical trials are often available under local, regional, or national institutional guidelines. The role of the obstetrician-gynecologist is that of supportive follow-up and availability for the patient's consultation.

Hormonal Therapy

Tamoxifen is the most commonly used hormonal therapy. Unless the patient has had a hysterectomy, an obstetrician-gynecologist is directly involved in the follow-up of a woman using tamoxifen. Multiple studies have shown that tamoxifen has an estrogenic effect on the endometrium, with more than a two-fold increased incidence of endometrial carcinoma in women using tamoxifen. Therefore, women using tamoxifen need to be followed-up by the same guidelines as women using unopposed estrogen therapy. Any abnormal uterine bleeding should urgently be investigated and an endometrial biopsy performed for diagnosis. If there is no abnormal uterine bleeding, a woman using tamoxifen should be followed-up in the routine manner with annual mammograms, clinical breast examinations, and pelvic examinations. It is important that a woman using tamoxifen know that the occurrence of any abnormal uterine bleeding is a critical indication for an urgent appointment with her obstetrician-gynecologist.

Oncologists for women with DCIS, node-negative invasive carcinoma, node-positive invasive carcinoma, and metastatic invasive carcinoma often prescribe tamoxifen 20 mg daily as a single or divided dose.30, 31, 32 Recent clinical trials have shown that aromatase inhibitors (anastrozole, letrozole and exemestane) are superior to Tamoxifen in postmenopausal women with ER+ invasive breast cancer in adjuvant, neoadjuvant and metastatic settings.33 Adjuvant hormonal therapy is usually given for 5 years, because there is evidence of no further benefit after 5 years of treatment.30 In postmenopausal women with ER+ invasive breast cancer who have already completed 5 years of tamoxifen, adjuvant endocrine therapy may be extended with an aromatase inhibitor such as letrozole for further 4 years especially if the tumor was node positive (extended adjuvant).33 Furthermore, switching endocrine therapy from Tamoxifen to an aromatase inhibitor after 2–3 years seems to be superior to taking tamoxifen alone for 5 years in such patients.33 Tamoxifen may be also indicated for the prevention of breast cancer in selected women at high risk of developing ER+ breast cancer and women with identified BRCA-1 and/or BRCA-2 genetic mutations.34, 35 However, BRCA gene mutations probably account for only 5% of all breast cancers.36

The nonneoplastic side-effects of tamoxifen compared with placebo therapy are given in Table 14. Tamoxifen therapy has additional benefits of reducing postmenopausal osteoporotic bone loss, reduction of hip, spine, and wrist fractures, and reduction in cholesterol and low-density lipoproteins. Compared with tamoxifen, aromatase inhibitors are less likely to cause endometrial cancer and DVT but are more likely to cause bone fractures (due to increased bone loss) and hypercholesterolemia.37 There is insufficient evidence to support the routine use of adjuvant endocrine therapy in patients with pure DCIS.38 

 

Table 14. Side-effects of tamoxifen compared with placebo therapy


 Percent of patients reporting the symptom
ToxicityPlacebo (n = 1439)Tamoxifen (n = 1422)
Hot flashes

46.2

62.4*

Fluid retention

28.6

30.9*

Vaginal discharge

14.2

28.4*

Irregular menses

17.6

23.6*

Nausea

22.6

23.3*

Skin rash

14.3

17.7*

Diarrhea

12.9

9.8*

Vascular thrombi

0.2

1.5*


*Statistically significant difference.
(Russell CR: Adjuvant systemic therapy for breast cancer. In Hindle WH, (ed): Breast care, a Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999.)

Tamoxifen belongs to a group of medications called selective estrogen receptor modulators (SERMs). Other SERMs undergoing investigation are droloxifene, idoxifene, raloxifene, tibolone, and toremifene. Only tamoxifen is Food and Drug Administration (FDA)-approved for the treatment of breast cancer. Raloxifene is FDA-approved for the prevention of osteoporosis. Preliminary investigations suggest that raloxifene is as effective as tamoxifen for the prevention of both DCIS and invasive breast cancer. In addition, it appears that raloxifene does not have an estrogenic effect on the endometrium, as does tamoxifen. Breast cancer clinical trials of raloxifene are underway, and if the results are as conclusive as those for tamoxifen, then FDA approval of raloxifene for the treatment of breast cancer will be sought.

Biological Therapy

HER-2 over-expression is implicated in the pathogenesis of breast cancer and represents a key marker and determinant of patient outcome. Herceptin (Trastuzumab, TZ) is a recombinant humanized monoclonal antibody which targets HER-2. Introduction into clinical practice has significantly improved the natural history of HER-2 over-expressing tumors and has altered the standard of care for these women. The clinical utility of TZ was first established in the management of HER-2 over-expressing metastatic breast cancer (MBC), with improvements recognized in both the quality and quantity of life. Prospective randomized controlled trials have consistently demonstrated the efficacy of TZ for early breast cancer (EBC) in the adjuvant setting with significant improvements in disease free and overall survival. Emerging roles for TZ include neo-adjuvant therapy and the treatment of progressive disease. TZ is well-tolerated and safe, however, associated cardiac dysfunction remains a significant clinical concern. Appropriate patient selection and monitoring for cardiac dysfunction are required.39

Other examples of biological therapy include bevacizumab and lapatinib. The former is a recombinant humanized monoclonal antibody against vascular endothelial growth factor and has been approved as first-line therapy for metastatic breast cancer (mBC). Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) tyrosine kinases. It was approved by the FDA in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER-2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and herceptin.

DUCTAL CARCINOMA IN SITU

Ductal carcinoma in situ (DCIS) is a heterogeneous disease, in terms of its radiological characteristics, histological morphology and molecular attributes. This diversity is reflected in its natural history and influences optimal treatment strategy.  Before the advent and use of mammography, DCIS accounted for approximately 2% of the diagnosed breast malignancies. In 2007, the incidence of diagnosed DCIS is estimated to be somewhat more than 25% of that of invasive carcinoma.1 In a breast center with a large volume of screening mammography, DCIS can account for more than 30% of the diagnosed malignancies. Plates 17 and 18 show the histological features of low- and high-grade DCIS.

Until the acceptance of breast conserving therapy for invasive cancer, the treatment of DCIS was total mastectomy without axillary node dissection. Adjuvant chemotherapy is not indicated for DCIS. Most cases of localized DCIS are currently treated with lumpectomy (with tumor-free margins) followed by adjuvant radiation therapy.12, 25 Extensive and/or multicentric lesions are treated with total mastectomy (+/- immediate breast reconstruction) combined with the SNB in case there is an occult invasive malignancy. The SNB may be also considered in selected high risk cases treated with BCS (e.g., large high grade lesions +/- mass on imaging).38 Tamoxifen may be indicated in selected cases following BCS.34, 37, 38. Without RT following BCS, the risk of local recurrence is approximately 1% per year; however, approximately 50% of the recurrences are invasive carcinoma. There is no consensus as to the optimum treatment of DCIS, particularly for low-grade lesions less than 1 cm and those with clear surgical margins. Adjuvant RT may be safely omitted in selected cases of BCS for small low-grade lesions treated with adequate local excision.38 The details and specific treatment of the spectrum of DCIS continues to be debated by authorities in the field. A state-of-the-art (as of 2008), comprehensive, clinical review of the management of DCIS authored by leading experts has been recently published.38. The authors of this report highlight that a significant proportion of DCIS lesions behave in a clinically benign fashion and do not progress to invasive disease and therefore, a reliable identification of these patients could allow treatment to be less radical or safely omitted. Management should be tailored to the individual within the context of a multidisciplinary team. Approaches such as biological profiling and molecular analysis represent an opportunity to improve our understanding of the tumor biology of this condition and rationalize its treatment.38

 

 

 

CHEMOPREVENTION AND SURVEILLANCE

Based on an almost 50% decreased incidence of contralateral breast cancer during the study period demonstrated in the NSABP clinical trial,31 a prevention trial for women at high risk for breast cancer was undertaken. The results of the NSABP P-1 prevention trial documented a 45% reduction in clinically diagnosed breast cancer for women treated with tamoxifen 20 mg daily for 5 years.35 The incidence of estrogen receptor-positive cancers was reduced by 67%.33 Long-term clinical trails, such as for 15–20 years, will be required to confirm that the cancers were indeed prevented; that is, they did not occur. It is possible that the cancers did not become large enough to be diagnosable during the 5 years of tamoxifen therapy. The fact that most breast cancers are present for many years before the time of mammographic and clinical diagnosis (see Fig. 3) makes the expected outcome of long-term studies uncertain. Knowing the endpoint of disease-specific survival would be the most informative. Raloxifene was also reported to decrease the incidence of breast cancer as a secondary end-point in clinical trials. In the Study of Tamoxifen and Raloxifene (STAR) trial, postmenopausal women at increased risk of breast cancer received either tamoxifen (20 mg/day) or raloxifene (60 mg/day) over 5 years.40 There were an equal number of cases of invasive breast cancer in women assigned to tamoxifen and raloxifene. There were fewer cases of DCIS in the tamoxifen group than in the raloxifene group. There were fewer cases of uterine cancer and thromboembolic events with raloxifene than with tamoxifen. There is no evidence however that chemoprevention with tamoxifen or raloxifen improves survival and therefore their overall use for this indication has been limited. Aromatase inhibitors haven been recently reported to decrease the incidence of ER +ve cancer in the contralateral breast by 75% (greater reduction than tamoxifen). There is no evidence however that chemoprevention with tamoxifen or raloxifene improves survival and therefore their overall use for this indication has been limited. Aromatase inhibitors have been recently reported to decrease the incidence of ER +ve cancer in the contralateral breast by 75% (greater reduction than tamoxifen). Anastrozole and tamoxifen as chemopreventative agents are being currently investigated in a randomized controlled trial (IBIS II).

There are data to support the importance of routine annual obstetrician-gynecologists follow-up, including mammography, clinical breast examination, and pelvic examination, for women with breast cancer. Postmenopausal uterine bleeding should be expeditiously evaluated because, particularly for women using tamoxifen, the possibility of endometrial cancer is a significant concern.

ESTROGEN AND ESTROGEN/PROGESTIN THERAPY

Because the breasts are a component of the female reproductive system and their development and physiologic function (lactation) requires the coordinated and balanced action of female (and other) hormones, controversy continues as to the role of estrogen and progesterone in the initiation and promotion of breast cancer. Furthermore, with women's fear of breast cancer and the media's dramatization of breast cancer-related news, obstetrician-gynecologists will be called on to respond and put seemingly urgent latest news in perspective.

Human estrogen was identified in 1929 and used clinically in 1938. Conjugated equine estrogen (CEE), which is the most commonly prescribed estrogen in the United States, was marketed in 1942; subsequently, more than 3700 studies have reported on CEE. Figure 7 graphically summarizes the risk estimates of breast cancer for ever-users compared with never-users of estrogen replacement therapy (ERT).41 Figure 8 is a similar graph of risk estimates of breast cancer comparing ever-users with never-users of hormone replacement therapy (HRT).41 Figure 9 summarizes the relative risks for breast cancer deaths with HRT.42 Although there are occasional outliers, most of the mean values have wide confidence intervals, and few reach epidemiologic statistical significance. No obvious trends are apparent. The results of The Women's Health Initiative Study, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50–79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993–1998, were published in 2002. The study showed that the use of HRT was associated with an increased risk of developing breast cancer. Surprisingly however, it demonstrated that HRT had no protective effect on the cardiovascular system but to the contrary, it could even promote the development of a cardiovascular event.43 Therefore it is currently recommended that HRT use is  avoided when possible and it is used in lowest possible dose for the shortest possible period when indicated.

Fig. 7. Risk estimates for incident breast cancer: ever-users compared with never-users of estrogen replacement therapy (unopposed estrogen). (Bush TL, Whiteman M, Flaws JA: Hormone replacement therapy and breast cancer: A qualitative review. Obstet Gynecol 98: 498–508, 2001; with permission.)

Fig. 8. Risk estimates for incident breast cancer: ever-users compared with never-users of hormone replacement therapy (estrogen plus progestin). (Bush TL, Whiteman M, Flaws JA: Hormone replacement therapy and breast cancer: A qualitative review. Obstet Gynecol 98: 498–508, 2001; with permission.)

Fig. 9. Relative risks for breast cancer death with hormone replacement therapy use (estrogen plus progestin). (Nanda K, Bastian LA, Schulz K: Hormone replacement therapy and the risk of death from breast cancer: A systematic review. Am J Obstet Gynecol 186: 325–334, 2002; with permission.)

 

CONCLUSION

Obstetrician-gynecologists play an important role in the detection of breast abnormalities, the diagnosis of breast cancer, and the continuing follow-up of women treated for breast cancer. They should see that breast cancer screening for women aged 40 years and older includes annual mammograms and clinical breast examinations. Furthermore, obstetrician-gynecologists should be a readily available source to their patients of accurate information and caring counsel about breast cancer and breast-related concerns.

If a woman presents with a dominant breast mass that remains undiagnosed or does not respond to treatment, she should be expeditiously referred to a breast specialist for triple assessment (clinical examination, breast imaging and needle biopsy). The American College of Obstetricians and Gynecologists guidelines for referral are: (1) explain to the patient that she needs further care; (2) provide names of qualified physicians from whom the patient can receive care; (3) answer the patient's questions; and (4) document these steps and include a detailed description of the clinical findings in the medical record.44 This is sound advice.

All women with a newly diagnosed breast cancer should be referred to and managed in designated breast cancer centers that adopt a multi-disciplinary and evidence-based approach to management.

COLOR PLATES

Plate 1. Normal breast histology, low power (original magnification ×40). Normal breast components are present, including terminal ductal lobular units imbedded in fibrous and adipose tissue. Fat cells compose the majority of the breast tissue volume. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 2. Normal breast histology, high power (original magnification ×200). A single layer of ductal cells sparsely encircled by elongated myoepithelial cells forms the acini within surrounding fibrous tissue. A well-demarcated terminal duct lobular unit is seen on the left. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 3. Normal breast cytology, low power (original magnification ×40). The smear is characteristically hypocellular with small cohesive clusters of adipose tissue (center right) and of ductal cells (center left). (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 4. Normal breast cytology, high power (original magnification ×200). The benign ductal cells are compact, uniform, and cohesive in a tight cluster. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 5. Fibrocystic changes, histology, low power (original magnification ×40). Microcysts and mild degrees of epithelial ductal hyperplasia are seen with increased fibrosis in the surrounding stroma. Many of the microcysts are lined by the typical apocrine metaplasia of ductal cells (solid arrow). (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 6. Fibrocystic changes, histology, high power (original magnification ×200). Apocrine metaplasia (solid arrow) of ductal cells is prominent with characteristic abundant eosinophilic cytoplasm (on the left). A central duct (hollow arrow) shows mild epithelial hyperplasia. A dilated duct or microcyst lined with the usual ductal epithelium is seen on the right. The surrounding stroma is fibrotic. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 7. Fibrocystic changes, cytology, low power (original magnification ×40). Scattered clusters of dense fibrous tissue and of apocrine (ductal) cells are seen. Large histiocytes (foam cells) are present in a clear background. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 8. Fibrocystic changes, cytology, high power (original magnification ×400). Dense fibrous tissue often predominates in a smear. Foamy histiocytes (at the right) are frequently seen. Benign ductal cells should be identified elsewhere in the smear to confirm the benign nature of the lesion. In this picture, there are numerous, small, brown red blood cells in the background. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 9. Fibroadenoma, histology, low power (original magnification ×40). There is a well-demarcated border (solid arrow) separating the solid fibroadenoma from the normal breast tissue. The fibroadenoma has the characteristic elongated branching glandular pattern of ductal cells surrounded by pale hypocellular stroma. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 10. Fibroadenoma, histology, high power (original magnification ×400). The elongated slit-like glands contain a single layer of uniform ductal epithelial cells with occasional outer small (compared with ductal cells) elongated myoepithelial cells. The surrounding stroma is formed of finely arranged collagen bundles with interspersed small (compared with ductal cells) fibrocytes. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 11. Fibroadenoma, cytology, low power (original magnification ×40). There are numerous monolayer clusters of extremely cohesive ductal epithelial cells with antler-like formations. The background is filled with scattered, single, small, naked (without cytoplasm), elongated (bipolar) nuclei. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 12. Fibroadenoma, cytology, high power (original magnification ×200). The epithelial monolayer clusters are composed of uniform, small, evenly spaced ductal cells that are delineated sharply at the cluster edge. A fragment of characteristically cellular stroma and numerous scattered myoepithelial cell naked nuclei (bipolar/elongated shape without attached cytoplasm) are present. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 13. Invasive ductal carcinoma, histology, low power (original magnification ×40). This tumor is composed of infiltrating ductal carcinoma and areas of in situ ductal carcinoma (solid arrow) with typical necrotic centers within the intact duct. Dilated ducts lined by proliferating epithelial cells, which are delimited by the basement membrane, characterize the in situ component. The invasive component (hollow arrow) presents as small aggregates of malignant cells and single malignant cells infiltrating through the stroma. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 14. Invasive ductal carcinoma, histology, high power (original magnification ×200). Invasive clusters of enlarged, irregularly shaped, hyperchromatic ductal epithelial cells are infiltrating the benign stroma. A portion of a duct containing in situ ductal carcinoma is present in the upper right corner of the picture. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 15. Invasive ductal carcinoma, cytology, low power (original magnification ×40). The entire smear is covered with abundant, poorly cohesive, malignant ductal cells with a dirty background of blood and necrotic debris. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)

Plate 16. Invasive ductal carcinoma, cytology, high power (original magnification ×200). Numerous poorly cohesive (dyshesive) clusters of malignant ductal cells as well as abundant, characteristic single, malignant cells are present. The malignant ductal cell nuclei are enlarged and irregularly sized with prominent macronucleoli. (Florentine B, Felix JC: Fine-needle aspiration cytology of the breast and Felix JC. Pathology of the female breast. In Hindle WH, (ed): Breast Care, A Clinical Guidebook for Women's Health Care Providers. New York, Springer, 1999; with permission; between pages 116 and 117: photographically enlarged ×20%.)


Plate 17: Low-grade DCIS

Plate 18: High-grade DCIS with necrosis

Plate 19: Micrometastasis in a sentinel node.

Plate 20: Isolated tumor cells in a sentinel node.

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