Breast ca solamist

BREAST CANCER
By solomon,(MD,R)

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 Epidemiology
 Breast cancer is the most common site-specific cancer in women and is the leading cause of
death from cancer for women aged 20 to 59 years
 It accounts for 29% of all newly diagnosed cancers in females and is responsible for 14% of
the cancer-related deaths in women
 There is a 10-fold variation in breast cancer incidence among different countries worldwide
 Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per
100,000 population), whereas Haiti has the lowest (2.0 deaths per 100,000 population)
 Breast cancer burden has well-defined variations by geography, regional lifestyle, and racial
or ethnic background

.
 African Americans also have a younger age distribution for breast cancer among women
<45 years of age,
 breast cancer incidence is highest among African Americans compared to other subsets of
the American population.
 African American women of all ages have notably higher incidence rates for estrogen
receptor negative tumors
 These same patterns of disease are seen in contemporary female populations of western,
sub-Saharan Africa, who are likely to share ancestry with African American women as a
consequence of the Colonial-era slave trade

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 Natural History
 Bloom and colleagues described the natural history of breast cancer based on the records of
250 women with untreated breast cancers who were cared for on charity wards in the
Middlesex Hospital, London, between 1805 and 1933
 median survival of this population was 2.7 years after initial diagnosis (Fig. 17-13).117
 The 5- and 10-year survival rates for these women were 18.0% and 3.6%, respectively
 Only 0.8% survived for 15 years or longer
 Autopsy data confirmed that 95% of these women died of breast cancer, whereas the
remaining 5% died of other causes
 Almost 75% of the women developed ulceration of the breast during the course of the
disease
 The longest surviving patient died in the nineteenth year after diagnosis

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 Primary Breast Cancer
 More than 80% of breast cancers show productive fibrosis that involves the epithelial and
stromal tissues
 With growth of the cancer and invasion of the surrounding breast tissues, the accompanying
desmoplastic response entraps and shortens Cooper’s suspensory ligaments to produce a
characteristic skin retraction
 Localized edema (peaud’orange) develops when drainage of lymph fluid from the skin is
disrupted
 With continued growth, cancer cells invade the skin, and eventually ulceration occurs
 As new areas of skin are invaded, small satellite nodules appear near the primary ulceration
 The size of the primary breast cancer correlates with disease-free and overall survival, but
there is a close association between cancer size and axillary lymph node involvement
 In general, up to 20% of breast cancer recurrences are local-regional, >60% are distant, and
20% are both local-regional and distant

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 Axillary Lymph Node Metastases
 As the size of the primary breast cancer increases, some cancer cells are shed into cellular spaces
and transported via the lymphatic network of the breast to the regional lymph nodes, especially
the axillary lymph nodes
 Lymph nodes that contain metastatic cancer are at first ill-defined and soft but become firm or
hard with continued growth of the metastatic cancer
 Eventually the lymph nodes adhere to each other and form a conglomerate mass
 Cancer cells may grow through the lymph node capsule and fix to contiguous structures in the
axilla, including the chest wall
 Typically, axillary lymph nodes are involved sequentially from the low (level I) to the central
(level II) to the apical (level III) lymph node groups
 Approximately 95% of the women who die of breast cancer have distant metastases
 Traditionally the most important prognostic correlate of disease-free and overall survival was
axillary lymph node status (see Fig. 17-14A)
 Women with node-negative disease had less than a 30% risk of recurrence, compared with as
much as a 75% risk for women with node-positive disease

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 Distant Metastases
 At the twentieth cell doubling, breast cancers acquire their own blood supply
(neovascularization)
 cancer cells may be shed directly into the systemic venous blood to seed the pulmonary
circulation via the axillary and intercostal veins or the vertebral column via Batson’s plexus
of veins, which courses the length of the vertebral column
 These cells are scavenged by natural killer lymphocytes and macrophages
 Successful implantation of metastatic foci from breast cancer predictably occurs after the
primary cancer exceeds 0.5 cm in diameter, which corresponds to the twenty-seventh cell
doubling
 For 10 years after initial treatment, distant metastases are the most common cause of death
in breast cancer patients
 For this reason, conclusive results cannot be derived from breast cancer trials until at least 5
to 10 years have elapsed

.
 60% of the women who develop distant metastases will do so within 60 months(5yrs) of
treatment
 metastases may become evident as late as 20 to 30 years after treatment of the primary
cancer
 Patients with estrogen receptor negative more likely to develop recurrence in the first 3 to 5
years
 Those with estrogen receptor positive tumors have a risk of developing recurrence which
drops off more slowly beyond 5 years than is seen with ER negative tumors
 Tumor size and nodal status remain powerful predictors of late recurrences

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 Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues,
and liver
 Brain metastases are less frequent
 There are factors which are associated with the risk of developing brain metastases
 For example, they are more likely to be seen in patients with
 triple receptor negative breast cancer (ER-negative, PR-negative and HER2-
negative) or
 patients with HER2-positive breast cancer who have received chemotherapy and
HER2-directed therapies

RISK FACTORS FOR BREAST CANCER
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 Hormonal and Nonhormonal Risk Factors
 Increased exposure to estrogen --increased risk for developing breast cancer
 Reducing exposure to estrogen is thought to be protective
 Factors that increase the number of menstrual cycles---are associated with increased risk
 early menarche, nulliparity, and late menopause
 older age at first live birth
 Finally, there is an association between obesity and increased breast cancer risk
 Major source of estrogen in postmenopausal women is the conversion of androstenedione to
estrone by adipose tissue
 Protective
 Moderate levels of exercise
 longer lactation period
 factors that decrease the total number of menstrual cycles
 The terminal differentiation of breast epithelium with a full-term pregnancy

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 Nonhormonal risk factors include radiation exposure
 Mantle radiation therapy for Hodgkin’s lymphoma have 75 times greater risk
 Survivors of the atomic bomb blasts in Japan have a very high incidence of breast cancer,
likely because of somatic mutations induced by the radiation exposure
 In both circumstances, radiation exposure during adolescence, a period of active breast
development, magnifies the deleterious effect.
 Study
 the risk of breast cancer increases as the amount of alcohol a woman consumes increases
 Alcohol ----increase serum levels of estradiol
 long-term consumption of foods with a high fat content contributes to an increased risk of breast
cancer by increasing serum estrogen levels

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 Risk Assessment Models
 The average lifetime risk of breast cancer for newborn U.S. females is 12%
 The longer a woman lives without cancer the lower her risk of developing breast cancer
 Thus, a woman aged 50 years has an 11% lifetime risk of developing breast cancer, and a
woman aged 70 years has a 7% lifetime risk of developing breast cancer
 Because risk factors for breast cancer interact, evaluating the risk conferred by
combinations of risk factors is difficult

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 Mammography screening program conducted in the 1970s
 Gail model most frequently used in the United States
 Incorporates ---6 parameters
 age,
 age at menarche,
 age at first live birth,
 the number of breast biopsy specimens,
 any history of atypical hyperplasia, and
 number of first-degree relatives with breast cancer
 It predicts the cumulative risk of breast cancer according to decade of life
 Gail revised model that includes
 body weight and
 mammographic density but excludes age at menarche

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 Risk Management
 Several important medical decisions
 These decisions include
 when to use postmenopausal hormone replacement therapy,
 at what age to begin mammography screening or incorporate magnetic resonance imaging (MRI)
screening,
 when to use tamoxifen to prevent breast cancer, and
 when to perform prophylactic mastectomy to prevent breast cancer
 Postmenopausal hormone replacement therapy controls the symptoms of estrogen
deficiency; namely, vasomotor symptoms such as hot flashes, night sweats and their
associated sleep deprivation, osteoporosis, and cognitive changes
 Use of combined estrogen and progesterone became standard for women who had not
undergone hysterectomy, because unopposed estrogen increases the risk of uterine cancer

.
 postmenopausal hormone replacement therapy ---breast cancer risk is threefold to fourfold
higher after >4 years of use
 estrogen + progesterone increased the incidence of breast cancer
 substantially greater for the combined estrogen + progesterone replacement therapy than
other types of hormone replacement therapy
 Breast Cancer Screening
 Routine use of screening mammography in women ≥50 years of age has been reported to
reduce mortality from breast cancer by 25%

.
 screening mammography in women<50 years of age is more controversial
 (a) breast density is greater and is less likely to detect early breast cancer
 (b) more false-positive test findings which results in unnecessary biopsy specimens; and
 (c) younger women are less likely to have breast cancer so fewer young women will benefit from
screening
 women between the ages of 40 and 49 years targeting mammography to women at higher
risk of breast cancer
 Current recommendations -- women undergo biennial mammographic screening between
the ages of 50 and 74 years

.
 The American Cancer Society (ACS) --recommend
 annual mammography for women beginning at age 40 years to continue as long as she is in good
health
 a clinical breast examination by a health professional annually
 Recommended by the ACS the use of MRI for breast cancer screening
 women with a 20% to 25% or greater lifetime risk using risk assessment tools
 based mainly on family history,
 BRCA mutation carriers,
 those individuals who have a family member with a BRCA mutation who have not been tested
themselves,
 individuals who received radiation to the chest between the ages of 10 to 30 years, and
 those individuals with a history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-
Ruvalcaba syndrome or those who have a first-degree relative with one of these syndromes

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 MRI is an extremely sensitive screening tool
 not limited by the density of the breast tissue as mammography
 but its specificity is moderate leading to more false-positive events and the increased need for biopsy
 Chemoprevention
 Tamoxifen, a selective estrogen receptor modulator(antagonist at breast and agonist at uterus)
 The decrease is evident only in ER-positive breast cancers with no significant change in ER-
negative tumors
 There was no effect on mortality,
 The adverse events were similar in all 4 trials
 increased risk of endometrial cancer,
 thromboembolic events,
 cataract formation, and
 vasomotor disturbances in individuals receiving tamoxifen

.
 Tamoxifen therapy currently is recommended only for women
 who have a Gail relative risk of 1.66% or higher, who are aged 35 to 59,
 women over the age of 60 or
 women with a diagnosis of LCIS or
 atypical ductal or lobular hyperplasia
 In addition,
 deep vein thrombosis occurs 1.6 times as often,
 pulmonary emboli 3.0 times as often, and
 endometrial cancer 2.5 times as often in women taking tamoxifen
 The increased risk for endometrial cancer is restricted to early stage cancers in
postmenopausal women
 Cataract surgery is required almost twice as often among women taking tamoxifen

.
 The NSABP completed a second chemoprevention trial,designed to compare tamoxifen and
raloxifene for breast cancer risk reduction in high-risk postmenopausal women
 Raloxifene, use in managing postmenopausal osteoporosis suggested that it might be even more
effective at breast cancer risk reduction, but without the adverse effects of tamoxifen on the
uterus
 P-2 trial, the Study of Tamoxifen and Raloxifene (known as the STAR trial)
 P-2 trial showed the two agents were nearly identical in their ability to reduce breast cancer risk, but
raloxifene was associated with a more favorable adverse event profile
 An updated analysis revealed that raloxifene maintained 76% of the efficacy of tamoxifen in
prevention of invasive breast cancer with a more favorable side effect profile
 The risk of developing endometrial cancer was significantly higher with tamoxifen
use at longer follow-up
 Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS, raloxifene did
not have an effect on the frequency of these diagnoses

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 Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen in
reducing the incidence of contralateral breast cancers in postmenopausal women receiving
AIs for adjuvant treatment of invasive breast cancer
 MAP.3 trial was the first study to evaluate an AI as a chemopreventive agent in
postmenopausal women at high risk for breast cancer
 The trial randomized 4,560 women to exemestane 25 mg daily vs. placebo for five years
 After a median follow-up of 35 months, exemestane was shown to reduce invasive breast
cancer incidence by 65%
 Side effect profiles demonstrated more grade 2 or higher arthritis and hot flashes in patients
taking exemestane
 Recommendation=offer tamoxifen to women at increased risk for breast cancer or
raloxifene to postmenopausal women who are noted to be at increased risk

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 Risk-reducing Surgery
 A retrospective study of women at high risk for breast cancer found that prophylactic
mastectomy reduced their risk by >90%
 However, the effects of prophylactic mastectomy on the long-term quality of life are poorly
quantified
 For women with an estimated lifetime risk of 40%, prophylactic mastectomy added almost
3 years of life, whereas for women with an estimated lifetime risk of 85%, prophylactic
mastectomy added >5 years of life
 risk-reducing mastectomy was highly effective at preventing breast cancer in both BRCA1
and 2 mutation carriers
 Risk-reducing salpingo-oophorectomy was highly effective at reducing the incidence of
ovarian cancer and breast cancer in BRCA mutation carriers and was associated with a
reduction in breast cancer-specific mortality, ovarian cancer-specific mortality, and all-cause
mortality

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 BRCA Mutations
 BRCA1
 Up to 5% of breast cancers are caused by inheritance of germline mutations such as BRCA1
and BRCA2, which are inherited in an autosomal dominant fashion with varying degrees of
penetrance (Table 17-7)
 BRCA1 is located on chromosome arm 17q, spans a genomic region of approximately 100
kilobases (kb) of DNA, and contains 22 coding exons for 1863 amino acids
 Both BRCA1 and BRCA2 function as tumor suppressor genes, and for each gene, loss of
both alleles is required for the initiation of cancer
 Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell-
cycle control, and DNA damage repair pathways

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 Germline mutations in BRCA1 represent a predisposing genetic factor in as many
as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian
cancers
 Female mutation carriers have been reported to have up to a 85% lifetime risk
(for some families) for developing breast cancer and up to a 40% lifetime risk for
developing ovarian cancer
 The initial families reported had high penetrance and subsequently the average
lifetime risk has been reported to lie between 60%–70%
 Breast cancer susceptibility in these families appears as an autosomal dominant
trait with high penetrance
 Approximately 50% of children of carriers inherit the trait

.
 In general, BRCA1-associated breast cancers are
 Invasive ductal carcinomas,
 poorly differentiated,
 in the majority hormone receptor negative and have a triple receptor negative
(immunohistochemical profile: ER-negative, PR-negative and HER-2-negative) or
 basal phenotype (based on gene expression profiling)
 Distinguishing clinical features, such as
 an early age of onset compared with sporadic cases;
 a higher prevalence of bilateral breast cancer; and
 the presence of associated cancers in some affected individuals, specifically ovarian
cancer and possibly colon and prostate cancers

.
 The two most common mutations are 185delAG and 5382insC, which account for
10% of all the mutations seen in BRCA1
 These two mutations occur at a 10-fold higher frequency in the Ashkenazi Jewish
population than in non-Jewish caucasians
 BRCA2
 BRCA2 is located on chromosome arm 13q and spans a genomic region of
approximately 70 kb of DNA
 The biologic function of BRCA2 is not well defined, but like BRCA1, it is
postulated to play a role in DNA damage response pathways
 BRCA2 messenger RNA also is expressed at high levels in the late G1 and
S phases of the cell cycle


.
 The breast cancer risk for BRCA2 mutation carriers is close to 85%, and the lifetime ovarian
cancer risk, while lower than for BRCA1, is still estimated to be close to 20%
 Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a
high penetrance
 Approximately 50% of children of carriers inherit the trait
 Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an
estimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the
general male population
 BRCA2-associated breast cancers are
 invasive ductal carcinomas,
 more likely to be well differentiated and
 express hormone receptors than BRCA1-associated breast cancers

.
 BRCA2- distinguishing clinical features, as compared with sporadic cases,
 an early age of onset
 a higher prevalence of bilateral breast cancer, and
 the presence of associated cancers in some affected individuals, specifically ovarian,
colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers, as well as melanoma
 A number of founder mutations have been identified in BRCA2
 The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2% and accounts
for 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi
women

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 Identification of BRCA Mutation Carriers
 Identifying hereditary risk for breast cancer is a four-step process
 (a) obtaining a complete, multigenerational family history,
 (b) assessing the appropriateness of genetic testing for a particular patient,
 (c) counseling the patient, and
 (d) interpreting the results of testing
 Genetic testing should not be offered in isolation, but only in conjunction with patient
education and counseling, including referral to a genetic counselor
 A thorough and accurate family history is essential to this process, and the maternal and
paternal sides of the family are both assessed, because 50% of the women with a BRCA
mutation have inherited the mutation from their fathers

.
 A method for calculating carrier probability such as the Manchester scoring system and
BODICEA -used to offer referral to a specialist genetic clinic
 A hereditary risk of breast cancer is considered if
 a family includes Ashkenazi Jewish heritage;
 a first-degree relative with breast cancer before age 50;
 a history of ovarian cancer at any age in the patient or first- or second-degree relative
with ovarian cancer;
 breast and ovarian cancer in the same individual;
 two or more first- or second-degree relatives with breast cancer at any age;
 patient or relative with bilateral breast cancer; and
 male breast cancer in a relative at any age

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 BRCA Mutation Testing
 Appropriate counseling for the individual being tested for a BRCA mutation is
strongly recommended, and documentation of informed consent is
required
 The test that is clinically available for analyzing bBRCA mutations is gene
sequence analysis
 Cancer Prevention for BRCA Mutation Carriers
 Risk management strategies for BRCA1 and BRCA2 mutation carriers include the
following:
 1. Risk-reducing mastectomy and reconstruction
 2. Risk-reducing salpingo-oophorectom
 3. Intensive surveillance for breast and ovarian cancer
 4. Chemoprevention

.
 Although removal of breast tissue reduces the likelihood that BRCA1 and BRCA2 mutation
carriers will develop breast cancer, mastectomy does not remove all breast tissue and
women continue to be at risk because a germline mutation is present in any remaining
breast tissue
 For postmenopausal BRCA1 and BRCA2 mutation carriers who have not had a mastectomy,
it may be advisable to avoid hormone replacement therapy, because no data exist regarding
the effect of the therapy on the penetrancen of breast cancer susceptibility genes
 Present screening recommendations for BRCA mutation carriers who do not undergo risk-
reducing mastectomy include
 clinical breast examination every 6 months and
 mammography every 12 months beginning at age 25 years,
because the risk of breast cancer in BRCA mutation carriers increases after age 30 years
 Recently focused on the use of MRI for breast cancer screening in high-risk individuals and
known BRCA mutation carriers
 MRI appears to be more sensitive at detecting breast cancer in younger women with dense
breasts

.
 MRI does lead to the detection of benign breast lesions that cannot easily be distinguished
from malignancy, and these false-positive events can result in more interventions, including
biopsy specimens
 The current recommendations from the American Cancer Society are for annual MRI in
women with a 20% to 25% or greater lifetime risk of developing breast cancer, including
women with a strong family history of breast or ovarian cancer and women who were
treated for Hodgkin’s disease in their teens or early twenties
 There is insufficient evidence to recommend the use of tamoxifen uniformly for BRCA1
mutation carriers
 Cancers arising in BRCA1 mutation carriers are usually high grade and are most often
hormone receptor negative
 Approximately 66% of BRCA1-associated DCIS lesions are estrogen receptor negative,
which suggests early acquisition of the hormone-independent phenotype

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 NSABP P1 trial there was a 62% reduction in the incidence of breast cancer in
BRCA2 carriers, similar to the overall reduction seen in the P1 trial
 Tamoxifen appears to be more effective at preventing estrogen receptor-positive
breast cancers
 The risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers ranges from 20%
to 40%, which is 10 times higher than that in the general population
 In women with a documented BRCA1 or BRCA2 mutation, consideration for
bilateral risk-reducing salpingo-ophorectomy should be between the ages of 35
and 40 years at the completion of childbearing
 Removing the ovaries reduces the risk of ovarian cancer and breast cancer when
performed in premenopausal BRCA mutation carriers
 Hormone replacement therapy is discussed with the patient at the time of
oophorectomy

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 The Cancer Genetics Studies Consortium recommends
 Yearly transvaginal ultrasound timed to avoid ovulation and
 annual measurement of serum cancer antigen 125 levels beginning at age 25 years
 The best screening modalities for ovarian carcinoma in BRCA mutation carriers
who have opted to defer prophylactic surgery
 Other hereditary syndromes associated with an increased risk of breast cancer
include
 Cowden disease (PTEN mutations, in which cancers of the thyroid, GI tract, and benign
skin and subcutaneous nodules are also seen),
 Li-Fraumeni syndrome (p53 mutations, also associated with sarcomas, lymphomas, and
adrenocortical tumors), and
 syndromes of breast and melanoma

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 HISTOPATHOLOGY OF BREAST CANCER
 Cancer cells are
 in situ or
 invasive depending on whether or not they invade through the basement membrane
 Multicentricity refers to the occurrence of a second breast cancer outside the breast
quadrant of the primary cancer (or at least 4 cm away)
 multifocality refers to the occurrence of a second cancer within the same breast quadrant
as the primary cancer (or within 4 cm of it)
 Multicentricity occurs60% to 90% of women with LCIS, and 40% to 80% of DCIS
 LCIS occurs bilaterally in 50% to 70% of cases and 10% to 20% of cases of DCIS

.

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 Lobular Carcinoma In Situ
 LCIS originates from the terminal duct lobular units and develops only in the
female breast
 It is characterized by distention and distortion of the terminal duct lobular units
by cells which are large but maintain a normal nuclear: cytoplasmic ratio
 Cytoplasmic mucoid globules are a distinctive cellular feature
 LCIS may be observed in breast tissues that contain microcalcifications, but the
calcifications associated with LCIS typically occur in adjacent tissues
 This neighborhood calcification is a feature that is unique to LCIS and contributes
to its diagnosis

.
 The average age at diagnosis is 45 years, which is approximately 15 to 25 years younger
than the age at diagnosis for invasive breast cancer
 LCIS has a distinct racial predilection, occurring 12 times more frequently in white women
than in African American women
 Invasive breast cancer develops in 25% to 35% of women with LCIS
 Invasive cancer may develop in either breast, regardless of which breast harbored the initial
focus of LCIS, and is detected synchronously with LCIS in 5% of cases
 In women with a history of LCIS, up to 65% of subsequent invasive cancers are ductal, not
lobular, in origin
 For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer
rather than as an anatomic precursor
 Individuals should be counseled –
 risk of developing breast cancer and risk reduction strategies, including observation with
screening, chemoprevention, and risk-reducing bilateral mastectomy

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 Ductal Carcinoma In Situ
 DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers
 7% in all biopsy tissue specimens
 The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for
progression to an invasive cancer
 Histologically, DCIS is characterized by a proliferation of the epithelium that lines the
minor ducts, resulting in papillary growths within the duct lumina
 The papillary growths (papillary growth pattern) eventually coalesce and fill the duct
lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer
cells, which show hyperchromasia and loss of polarity (cribriform growth pattern)

.
 Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and
distend the ducts (solid growth pattern)
 With continued growth, these cells outstrip their blood supply and become necrotic (comedo
growth pattern)
 Calcium deposition occurs in the areas of necrosis and is a common feature seen on
mammography
 DCIS is now frequently classified based on nuclear grade and the presence of necrosis
 The risk for invasive breast cancer is increased nearly fivefold in women with DCIS
 The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the
DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of
invasive ductal carcinoma (Fig. 17-15A and B)

.
 Invasive Breast Carcinoma
 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
 About 80% 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 classification
 1. Paget’s disease of the nipple
 2. Invasive ductal carcinoma—Adenocarcinoma with productive fibrosis
(scirrhous, simplex, NST), 80%
 3. Medullary carcinoma, 4%
 4. Mucinous (colloid) carcinoma, 2%
 5. Papillary carcinoma, 2%
 6. Tubular carcinoma, 2%
 7. Invasive lobular carcinoma, 10%
 8. Rare cancers (adenoid cystic, squamous cell, apocrine)

.
 Paget’s disease of the nipple
 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
 usually is associated with extensive DCIS and may be with an invasive cancer
 A palpable mass may or may not be present
 A nipple biopsy specimen 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 cells) in the
rete pegs of the epithelium
 may be confused with superficial spreading melanoma
 Differentiation from pagetoid intraepithelial melanoma is based on the presence of S-100
antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget’s
disease
 Surgical therapy for Paget’s disease may involve lumpectomy or mastectomy, depending on the
extent of involvement of the nipple-areolar complex and the presence of DCIS or invasive
cancer in the underlying breast parenchyma

.
 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 up to 25%
of screen-detected cases and
 up to 60% of symptomatic cases
 occurs most frequently in perimenopausal or postmenopausal women in the fifth to
sixth decades of life as a solitary, firm mass
 from the SEER database, 75% of ductal cancers showed estrogen receptor expression

.
 Medullary carcinoma
 is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a frequent
phenotype of BRCA1 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:
 (a) a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells;
 (b) large pleomorphic nuclei that are poorly differentiated and show active mitosis; and
 (c) a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation
 Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the
periphery of the cancer, and <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
 Over 90% 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 microscopic 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
 In a large series from the SEER database 87% of papillary cancers have been reported
to express estrogen receptor
 McDivitt and colleagues noted that these tumors 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
 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 mammographic
screening and usually is diagnosed in the perimenopausal or early menopausal periods
 Under low-power magnification, a haphazard array of small, randomly arranged tubular elements
is seen
 In a large SEER database 94% of tubular cancers were reported to express
estrogen receptor
 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
 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. 17-17)
 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 carcinomas
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 mammographic features, invasive lobular
carcinoma may be difficult to detect
 Over 90% of lobular cancers express estrogen receptor

.
 DIAGNOSIS OF BREAST CANCER
 In~30% of cases, the woman discovers a lump in her breast
 Other less frequent presenting signs and symptoms of breast cancer include
 (a) breast enlargement or asymmetry;
 (b) nipple changes, retraction, or discharge;
 (c) ulceration or erythema of the skin of the breast;
 (d) an axillary mass; and
 (e) musculoskeletal discomfort
 However, up to 50% of women presenting with breast complaints have no physical signs of
breast pathology
 Breast pain usually is associated with benign disease

.
 If a young woman (≤45 years) presents with a palpable breast mass and equivocal
mammographic findings, ultrasound examination and biopsy are used to avoid a delay in
diagnosis
 Examination
Inspection
 inspects the woman’s breast with her arms by her side, with her arms straight up in the air,
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
(peaud’orange), nipple or skin retraction, or erythema
 With the arms extended forward and in a sitting position, the woman leans forward to
accentuate any skin retraction

.
 Palpation
 As part of the physical examination, the breast is carefully palpated
 With the patient in the supine position , examine all quadrants of the breast from the
sternum laterally to the latissimus dorsi muscle and from the clavicle inferiorly to the upper
rectus sheath
 performs the examination with the palmar aspects of the fingers, avoid grasping or pinching
motion
 The breast may be cupped or molded to check for retraction
 A systematic search for lymphadenopathy then is performed
 examination of the axilla
 By supporting the upper arm and elbow, stabilizes the shoulder girdle
 Using gentle palpation, assesses all three levels of possible axillary lymphadenopathy
 Careful palpation of supraclavicular and parasternal sites also is performed
 A diagram of the chest and contiguous lymph node sites is useful for recording location,
size, consistency, shape, mobility, fixation, and other characteristics

.
 Imaging Techniques
 Mammography
 Conventional mammography delivers a radiation dose of 0.1 cGy per study
 By comparison, chest radiography delivers 25% of this dose
 However, there is no increased breast cancer risk associated with the radiation dose
delivered with screening mammography
 Screening mammography is used to detect unexpected breast cancer in asymptomatic
women
 In this regard, it supplements history taking and physical examination

.
 With screening mammography, two views of the breast are obtained
 The craniocaudal (CC) view (Fig. 17-20A and B) and
 The mediolateral oblique (MLO) view (Fig. 17-20 C and D)
 The MLO view images the greatest volume of breast tissue, including the upper outer
quadrant and the axillary tail of Spence
 The CC view provides better visualization of the medial aspect of the breast and permits
greater breast compression
 Diagnostic mammography is used to evaluate women with abnormal findings such as a
breast mass or nipple discharge

.
 In addition to the MLO and CC views, a diagnostic examination may use views that better define
the nature of any abnormalities, such as the 90-degree lateral and spot compression views
 The 90-degree lateral view is used along with the CC view to triangulate the exact location of an
abnormality
 Spot compression may be done in any projection by using a small compression device, which is
placed directly over a mammographic abnormality that is obscured by overlying tissues
 The compression device minimizes motion artifact, improves definition, separates overlying
tissues, and decreases the radiation dose needed to penetrate the breast
 Magnification techniques (×1.5) often are combined with spot compression to better resolve
calcifications and the margins of masses
 Mammography also is used to guide interventional procedures, including needle localization and
needle biopsy
 Specific mammographic features that suggest a diagnosis of breast cancer include a solid mass
with or without stellate features, asymmetric thickening of breast tissues, and clustered
microcalcifications

.
 The presence of fine, stippled calcium in and around a suspicious lesion is
suggestive of breast cancer and occurs in as many as 50% of nonpalpable cancers
 These microcalcifications are an especially important sign of cancer in younger
women, in whom it may be the only mammographic abnormality
 33% reduction in mortality for women after screening mammography
 Mammography was more accurate than clinical examination for the detection of
early breast cancers, providing a true-positive rate of 90%
 Only 20% of women with nonpalpable cancers had axillary lymph node
metastases, compared with 50% of women with palpable cancers

.
 Current guidelines of the NCCN suggest that normal-risk women ≥20 years of age should have a
breast examination at least every 3 years
 Starting at age 40 years, breast examinations should be performed yearly and a yearly mammogram
should be taken
 The benefits from screening mammography in women ≥50 years of age has been noted to be
between 20% and 25% reduction in breast cancer mortality
 Ductography
 The primary indication for ductography is nipple discharge, particularly when the fluid contains
blood
 Radiopaque contrast media is injected into one or more of the major ducts and mammography is
performed
 A duct is gently enlarged with a dilator and then a small, blunt cannula is inserted under sterile
conditions into the nipple ampulla
 With the patient in a supine position, 0.1 to 0.2 mL of dilute contrast media is injected and CC and
MLO mammographic views are obtained without compression
 Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-22
 Cancers may appear as irregular masses or as multiple intraluminal filling defects

.
 Ultrasonography.
 Second only to mammography in frequency of use for breast imaging,
ultrasonography is an important method of resolving equivocal mammographic
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. 17-23)
 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. 17-25) 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

.
 Its findings are highly reproducible and it has a high patient acceptance rate, but
it does not reliably detect lesions that are ≤1 cm in diameter
 Ultrasonography can also be utilized to image the regional lymph nodes in
patients with breast cancer (Fig. 17-26)
 The sensitivity of examination for the status of axillary nodes ranges from 35% to
82% and specificity ranges from 73% to 97%
 The features of a lymph node involved with cancer include cortical thickening,
change in shape of the node to more circular appearance, size larger than 10
mm, absence of a fatty hilum and hypoechoic internal echoes

.
 Magnetic Resonance Imaging
 In the circumstance of negative findings on both mammography and physical examination,
the probability of a breast cancer being diagnosed by MRI is extremely low
 MRI study of the contralateral breast in women with a known breast cancer has shown a
contralateral breast cancer in 5.7% of these women
 MRI can also detect additional tumors in the index breast (multifocal or multicentric
disease) that may be missed on routine breast imaging and this may alter surgical decision
making
 Some clinical scenarios where MRI may be useful include
 the evaluation of a patient who presents with nodal metastasis from breast cancer without an
identifiable primary tumor;
 to assess response to therapy in the setting of neoadjuvant systemic treatment;
 to select patients for partial breast irradiation techniques; and
 evaluation of the treated breast for tumor recurrence

.
 Breast Biopsy
Nonpalpable Lesions
 Image-guided breast biopsy specimens are frequently required to diagnose nonpalpable lesions
 Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques
are used when no mass is present (microcalcifications or architectural distortion only)
 The combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-
needle aspiration (FNA) biopsy achieves almost 100% accuracy in the preoperative diagnosis of
breast cancer
 However, although FNA biopsy permits cytologic evaluation, core-needle permits the analysis of
breast tissue architecture and allows the pathologist to determine whether invasive cancer
is present
 This permits the surgeon and patient to discuss the specific management of a breast cancer before
therapy begins
 Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single
surgical procedure can be planned based on the results of the core biopsy
 The advantages of core-needle biopsy include a low complication rate, minimal scarring, and a
lower cost compared with excisional breast biopsy

.
 Palpable Lesions
 FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting
 A 1.5-in, 22-gauge needle attached to a 10-mL syringe or a 14 gauge core biopsy needle is used
 For FNA, use of a syringe holder enables the surgeon performing the FNA biopsy to control the
syringe and needle with one hand while positioning the breast mass with the opposite hand
 After the needle is placed in the mass, suction is applied while the needle is moved back and
forth within the mass
 Once cellular material is seen at the hub of the needle, the suction is released and the needle is
withdrawn
 The cellular material is then expressed onto microscope slides
 Both air-dried and 95% ethanol–fixed microscopic sections are prepared for analysis
 When a breast mass is clinically and mammographically suspicious, the sensitivity and
specificity of FNA biopsy approaches 100%

.
 BREAST CANCER STAGING AND BIOMARKERS
 Breast Cancer Staging
 The clinical stage of breast cancer is determined primarily through physical
examination of the skin, breast tissue, and regional lymph nodes (axillary,
supraclavicular, and internal mammary)
 clinical determination of axillary lymph node metastases has an accuracy of only
33%
 Ultrasound (US) is more sensitive than physical examination alone in determining
axillary lymph node involvement during preliminary staging of breast carcinoma
 Fine-needle aspiration (FNA) or core biopsy of sonographically indeterminate or
suspicious lymph nodes can provide a more definitive diagnosis than US alone
 Pathologic stage combines the findings from pathologic examination of the
resected primary breast cancer and axillary or other regional lymph nodes

.
 Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases
were possible after resection and pathologic analysis of 10 or more level I and II axillary lymph
nodes
 A frequently used staging system is the TNM (tumor, nodes, and metastasis) system
 Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary
lymph node metastases (see Fig. 17-14B)
 Others have shown an association between tumor size, axillary lymph node metastases, and
disease-free survival
 One of the most important predictors of 10- and 20-year survival rates in breast cancer is the
number of axillary lymph nodes involved with metastatic disease
 Routine biopsy of internal mammary lymph nodes is not generally performed
 In the context of a ‘triple node’ biopsy approach either the internal mammary node or a low axillary
node when positive alone carried the same prognostic weight
 When both nodes were positive the prognosis declined to the level associated with apical node
positivity
 A double node biopsy of the low axillary node and either the apical or the internal mammary node
gave the same maximum prognostic information as a triple node biopsy

.
 With the advent of sentinel lymph node dissection and the use of preoperative
lymphoscintigraphy for localization of the sentinel nodes, surgeons have again
begun to biopsy the internal mammary nodes but in a more targeted manner
 The 7th edition of the AJCC staging system does allow for staging based on
findings from the internal mammary sentinel nodes
 Drainage to the internal mammary nodes is more frequent with central and
medial quadrant cancers
 Clinical or pathologic evidence of metastatic spread to supraclavicular lymph
nodes is no longer considered stage IV disease, but routine scalene or
supraclavicular lymph node biopsy is not indicated

.
 Biomarkers
 Breast cancer biomarkers are of several types
 Risk factor biomarkers are those associated with increased cancer risk
 These include
 familial clustering and inherited germline abnormalities,
 proliferative breast disease with atypia, and
 mammographic densities.
 Exposure biomarkers are a subset of risk factors that include
 measures of carcinogen exposure such as DNA adducts
 Surrogate endpoint biomarkers
 are biologic alterations in tissue that occur between cancer initiation and development
 These biomarkers are used as endpoints in short term chemoprevention trials and
 include histologic changes, indices of proliferation, and genetic alterations leading to
cancer
 Prognostic biomarkers provide information regarding cancer outcome irrespective of therapy,
 whereas predictive biomarkers provide information regarding response to therapy

.
 Candidate prognostic and predictive biomarkers and biologic targets for breast cancer
include
 (a) the steroid hormone receptor pathway;
 (b) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER-
2)/neu, epidermal growth factor receptor (EGFR), transforming growth factor, platelet-derived growth factor,
and the insulin-like growth factor family;
 (c) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67;
 (d) indices of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index;
 (e) the mammalian target of rapamycin (mTOR) signaling pathway;
 (f) tumor-suppressor genes such as p53;
 (g) the cell cycle, cyclins, and cyclin-dependent kinases;
 (h) the proteasome;
 (i) the COX-2 enzyme;
 (j) the peroxisome proliferator-activated receptors (PPARs); and
 (k) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio

.
 Steroid Hormone Receptor Pathway
 Estrogens, estrogen metabolites, and other steroid hormones such as progesterone all have been shown to
have an effect
 Breast cancer risk is related to estrogen exposure over time
 In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone
increases the risk of breast cancer by 26% compared to placebo
 Patients with hormone receptor-positive tumors survive two to three times longer after a diagnosis of
metastatic disease than do patients with hormone receptor-negative tumors
 Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered
candidates for hormonal therapy
 Tumors positive for estrogen or progesterone receptors have a higher response rate to endocrine therapy
than tumors that do not express estrogen or progesterone receptors
 Tumors positive for both receptors have a response rate of >50%, tumors negative for both receptors
have a response rate of <10%, and tumors positive for one receptor but not the other have an
intermediate response rate of 33%

.
 Growth Factor Receptors and Growth Factors
 Overexpression of EGFR in breast cancer correlates with estrogen receptor–negative status
and with p53 overexpression
 Similarly, increased HER-2/neu growth factor receptor in breast cancer is associated with
mutated p53, Ki-67 overexpression, and estrogen receptor– negative status
 HER-2/neu is a member of the EGFR family of growth factor receptors in which ligand
binding results in receptor homodimerization and tyrosine phosphorylation by tyrosine
kinase domains within the receptor
 Tyrosine phosphorylation is followed by signal transduction, which results in changes in
cell behavior

.
 HER-2/neu is both an important prognostic factor and a predictive factor in breast cancer
 When overexpressed in breast cancer, HER-2/neu promotes enhanced growth and
proliferation, and increases invasive and metastatic capabilities
 patients with HER-2/neu–overexpressing breast cancer have poorly differentiated tumors
with high proliferation rates, positive lymph nodes, decreased hormone receptor expression,
and an increased risk of recurrence and death due to breast cancer
 Routine testing of the primary tumor specimen for HER-2/neu expression should be
performed on all invasive breast cancers
 Patients whose tumors overexpress HER-2/neu are candidates for anti–HER-2/neu therapy
 Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against
HER-2/neu

.
 Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is an
active and well-tolerated option for first-line treatment of women with HER-2/neu–
overexpressing metastatic breast cancer
 More recently, adjuvant trials demonstrated that trastuzumab also was highly effective in the
treatment of women with early-stage breast cancer when used in combination with
chemotherapy
 Patients who received trastuzumab in combination with chemotherapy had between a 40%–
50% reduction in the risk of breast cancer recurrence and approximately a third reduction in
breast cancer mortality compared with those who received chemotherapy alone


.
 Indices of Proliferation
 PCNA is a nuclear protein associated with a DNA polymerase whose expression increases
in phase G1 of the cell cycle, reaches its maximum at the G1/S interface, and then decreases
through G2
 Good correlation is noted between PCNA expression and
 (a) cell-cycle distributions seen on flow cytometry based on DNA content, and
 (b) uptake of bromodeoxyuridine and the proliferation-associated Ki-67 antigen
 PCNA and Ki-67 expression are positively correlated with p53 overexpression, high S-
phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast
cancer specimens, and are negatively correlated with estrogen receptor content
 Ki67 was included with three other widely measured breast cancer markers (ER, PR, and
HER2)

.
 Indices of Angiogenesis
 Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes
cancer progression through several different mechanisms, including delivery of oxygen and
nutrients and the secretion of growth promoting cytokines by endothelial cells
 VEGF induces its effect by binding to transmembrane tyrosine kinase receptors
 Overexpression of VEGF in invasive breast cancer is correlated with increased microvessel
density and recurrence in node-negative breast cancer
 When bevacizumab was added to paclitaxel chemotherapy, median progression-free
survival increased to 11.3 months from the 5.8 months seen in patients who received
paclitaxel alone

.
 Indices of Apoptosis
 Alterations in programmed cell death (apoptosis), which may be triggered by p53-
dependent or p53-independent factors
 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for
apoptosis, with some members functioning as inhibitors of apoptosis and others as
promoters of apoptosis
 Bcl-2 is the only oncogene that acts by inhibiting apoptosis rather than by
directly increasing cellular proliferation
 The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in
the presence of wild-type (normal) p53 and/or AP-1/
fos
 The bax:bcl-2 ratio and the resulting formation of either bax-baxhomodimers, which
stimulate apoptosis, or bax–bcl-2 heterodimers, which inhibit apoptosis, represent an
intracellular regulatory mechanism with prognostic and predictive implications

.
 In breast cancer, overexpression of bcl-2 and a decrease in the bax:bcl-2 ratio correlate with
high histologic grade, the presence of axillary lymph node metastases, and reduced disease-
free and overall survival rates
 Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor
response to chemotherapy, and decreased overall survival

.
 OVERVIEW OF BREAST CANCER THERAPY
 Once a diagnosis of breast cancer is made, the type of therapy offered to a
breast cancer patient is determined by the stage of the disease, the biologic
subtype and the general health status of the individual


.
 In Situ Breast Cancer (Stage 0)
 Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with early
invasion
 Expert pathologic review is required in all cases
 Bilateral mammography is performed to determine the extent of the in situ cancer and to exclude a
second cancer
 Because LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive
disease, the current treatment options for LCIS include observation, chemoprevention, and bilateral total
mastectomy
 The goal of treatment is to prevent or detect at an early stage the invasive cancer that subsequently
develops in 25% to 35% of these women
 There is no benefit to excising LCIS, because the disease diffusely involves both breasts in many cases
and the risk of developing invasive cancer is equal for both breasts
 The use of tamoxifen as a risk reduction strategy should be considered in women with a diagnosis of
LCIS

.
 Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one
quadrant) usually require mastectomy
 For women with limited disease, lumpectomy and radiation therapy are generally recommended
 For non palpable DCIS, needle localization or other image-guided techniques are used to guide the surgical
resection
 Specimen mammography is performed to ensure that all visible evidence of cancer is excised
 Adjuvant tamoxifen therapy is considered for DCIS patients with ER-positive disease
 The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy
 Women treated with mastectomy have local recurrence and mortality rates of <2%
 There is no randomized trial comparing mastectomy vs. breast conserving surgery and
 none of the randomised trials of breast conserving surgery with or without radiotherapy for DCIS were
powered to show a difference in mortality
 Ductal carcinoma in situ (DCIS) (females), to reduce the risk for invasive breast cancer: 20 mg once daily for 5 years
 Breast cancer risk reduction (pre- and postmenopausal high-risk females): Oral: 20 mg once daily for 5 years

.
 Women treated with lumpectomy and adjuvant radiation therapy have a local recurrence
rate that is increased compared to mastectomy
 About 45% of these recurrences will be invasive cancer when radiation therapy is not used
 The B-17 trial--rates of both ipsilateral noninvasive and invasive recurrences were
significantly lower in patients who received radiation
 Silverstein and colleagues have been proponents of avoiding radiation therapy in selected
patients with DCIS who have widely negative margins after surgery
 They reported that
 When greater than 10 mm margins were achieved, there was no additional benefit from radiation therapy
 When margins were between 1- to 10-mm there was a relative risk of local recurrence
of 1.49, compared to 2.54 for those with margins less than 1 mm

.
 The Eastern Cooperative Oncology Group (ECOG) initiated a prospective registry trial
(ECOG 5194) to identify those patients who could safely undergo breast conserving surgery
without radiation
 Eligible patients were those with
 low or intermediate grade DCIS measuring 2.5 cm or less who had negative margins of
at least 3 mm
 high grade DCIS who had tumors measuring 1 cm or less with a negative margin of at
least 3 mm
 At a median follow-up of 6.2 years, patients with low or intermediate grade DCIS had
an in-breast recurrence rate of 6.1% while those with high grade DCIS had a recurrence
rate of 15.3%
 Approximately 4% of patients developed a contralateral breast cancer during follow-up
in both the low/intermediate and high grade groups

.
 The Radiation Therapy Oncology Group (RTOG) trial with “good risk” DCIS and randomized
them to lumpectomy vs. lumpectomy with whole breast irradiation
 The local recurrence rate at 5 years was 0.4% for patients randomized to receive radiation and
3.2% for those who did not receive radiation
 NSABP B-24 trial reported a significant reduction in local recurrence after 5 years of
tamoxifen in women with ER-positive DCIS
 Based on this some guidelines have advocated that all patients (women with ER-positive
DCIS without contraindications to tamoxifen therapy) should be offered tamoxifen following
surgery and radiation therapy for a duration of 5 years
 Five years of tamoxifen is not uniformly prescribed across the world as adjuvant therapy
following breast conserving surgery and radiation therapy for DCIS

.
 Early Invasive Breast Cancer (Stage I, IIA, or IIB)
 There have been six prospective randomized trials comparing breast conserving surgery to
mastectomy in early stage breast cancer and all have shown equivalent survival rates regardless
of the surgical treatment type
 NSABP B-06, which is the largest of all the breast conservation trials, compared total
mastectomy to lumpectomy with or without radiation therapy in the treatment of women with
stage I and II breast cancer
 After 5- and 8-year follow-up periods, the disease-free (DFS), distant disease-free, and overall
survival (OS) rates for lumpectomy with or without radiation therapy were similar to those
observed after total mastectomy
 However, the incidence of ipsilateral breast cancer recurrence was higher in the group not
receiving radiation therapy
 These findings supported the use of lumpectomy and radiation therapy in the treatment of stage I
and II breast cancer and this has since become the preferred method of treatment for women with
early stage breast cancer who have unifocal disease and who are not known BRCA mutation
carriers

.
 subgroups of patients who may not benefit from the addition of radiation therapy is older
patients who may have a shorter life expectancy due to medical comorbidities
 Two randomized trials have shown that in selected patients with small, low-grade tumors,
lumpectomy alone without radiation therapy may be appropriate
 The Cancer and Leukemia Group B (CALGB) C9343 trial enrolled women over the age of
70 with T1N0 breast cancer
 There were fewer local recurrences with radiation (1% vs. 4%, P<0.001), there were no
differences in DFS and OS
 Radiation can be avoided in early-stage breast cancer patients over the age of
70 when they are diagnosed with T1, N0, ER-positive breast cancer

.
 Accelerated partial breast irradiation (APBI) is also an option for carefully selected patients
with DCIS and early stage breast cancer
 Since the majority of recurrences after breast conservation occur in or adjacent to the tumor
bed there has been interest in limiting the radiation to the area of the primary tumor bed
with a margin of normal tissue
 APBI is delivered in an abbreviated fashion (twice daily for 5 days) and at a lower total
dose compared with the standard course of 5 to 6 weeks of radiation (50 Gray with or
without a boost) in the case of whole breast irradiation
 shortened course of treatment may increase the feasibility of breast conservation for some
women and may improve radiation therapy compliance

.
 TARGIT study --intraoperative breast irradiation (IORT) or external beam radiotherapy (EBRT)
 Median follow-up of 2.4 years use of IORT had a recurrence rate of 3.3% vs. 1.3% with EBRT, a 2% increased recurrence risk
 The American Society for Radiation Oncology (ASTRO) developed guidelines for the use of APBI outside of clinical trials
 ASTRO guidelines describe patients
 “suitable” for APBI to include
 women 60 years of age or older with a unifocal,
 T1,
 ER-positive tumor with no lymphovascular invasion, and
 margins of at least 2 mm
 “cautionary” -there is uncertainty about the appropriateness of APBI, includs
 invasive lobular histology,
 a tumor size of 2.1 cm to 3 cm,
 ER-negative disease,
 focal lymphovascular invasion, or
 margins less than 2 mm
 unsuitable for APBI includes those with
 T3 or T4 disease,
 ER-negative disease,
 multifocality, multicentricity,
 extensive LVI, or positive margins

.
 Currently, mastectomy with axillary staging and breast conserving surgery with
axillary staging and radiation therapy are considered equivalent treatments for
patients with stage I and II breast cancer
 Breast conservation is considered for all patients because of the important
cosmetic advantages and equivalent survival outcomes
 Not advised in women who are known BRCA mutation carriers due to the high
lifetime risk for development of additional breast cancers
 Relative contraindications to breast conservation therapy include
 (a) prior radiation therapy to the breast or chest wall,
 (b) persistently positive surgical margins after reexcision,
 (c) multicentric disease, and
 (d) scleroderma or lupus erythematosus

.
 For most patients with early-stage disease, reconstruction can be performed
immediately at the time of mastectomy
 Immediate reconstruction allows for skin-sparing, thus optimizing cosmetic
outcomes
 Skin-sparing mastectomy with immediate reconstruction has been popularized
over the past decade as reports of low local-regional failure rates have been
reported and reconstructive techniques have advanced
 There is a growing interest in the use of nipple-areolar sparing mastectomy
 Patients who are planned for postmastectomy radiation therapy are not ideal
candidates for nipple-sparing mastectomy because of the effects of radiation on
the preserved nipple


.
 Immediate reconstruction can be performed using implants or autologous tissue;
tissue flaps commonly used include the transverse rectus abdominis
myocutaneous flap, deep inferior epigastric perforator flap, and latissimus dorsi
flap (with or without an implant)
 If postmastectomy radiation therapy is needed, a tissue expander can be placed
at the time of mastectomy to save the shape of the breast and reduce the
amount of skin replacement needed at the time of definitive reconstruction
 The expander can be deflated at the initiation of radiation therapy to allow for
irradiation of the chest wall and regional nodal basins
 Removal of the tissue expander and definitive reconstruction, usually with
autologous tissue, can proceed 6 months to 1 year after completion of radiation
therapy

.
 Axillary lymph node dissection (ALND)
 Axillary lymph node status has traditionally been an important determinant in staging and
prognosis for women with early stage breast cancer
 was utilized for axillary staging and regional control by removing involved lymph nodes
 Randomized trials evaluating immediate ALND vs delayed fashion ALND performed (once
clinically palpable axillary disease became evident) have not shown any detriment in survival
 With increased mammographic screening and detection of smaller, node-negative breast
cancers, it became clear that routine use of ALND for axillary staging was not necessary in up to
75% percent of women with operable breast cancer presenting with a negative axilla at the time
of screening
 Lymphatic mapping and sentinel lymph node (SLN) dissection were initially developed for
assessment of patients with clinically node negative melanoma
 Given the changing landscape of newly diagnosed breast cancer patients with a clinically node-
negative axilla, surgeons quickly began to explore the utility of SLN dissection as a replacement
for ALND in axillary staging

.
 randomized trials -if SLN dissection could replace ALND
 The ALMANAC trial
 primary operable breast cancer to SLN dissection vs. standard axillary surgery
 The incidence of lymphedema and sensory loss, drain usage, length of hospital stay, and
time to resumption of normal day-today activities for the SLN group was significantly
lower than with the standard axillary treatment
 The NSABP B-32 trial compared -clinically node negative +SLN dissection followed by ALND
vs SLN dissection with ALND only if a SLN was positive for metastatic disease
 A total of 5,611 patients were randomized with
 SLN identification rate of 97%, and a false-negative rate of 9.7%
 A total of 26% of these clinically node-negative patients had a positive SLN
 Over 60% of patients with positive SLNs had no additional positive lymph
nodes within the ALND specimen
 The B-32 trial and other randomized trials demonstrated no difference in DFS, OS, and
local-regional recurrence rates between patients with negative SLNs who had SLN
dissection alone compared with those who underwent ALND

.
 Most important, patients who had SLN dissection alone were found to have
decreased morbidity (arm swelling and range of motion) and improved quality of
life vs. patients who underwent ALND
 The American College of Surgeons Oncology Group (ACOSOG) initiated the Z0010
and Z0011 trials -to evaluate the incidence and prognostic significance of occult
metastases (identified in the bone marrow and SLNs ) of early-stage clinically
node-negative and the utility of ALND in clinical T1-2, N0 breast cancer with 1 or
2 positive SLNs for patients treated with breast conserving surgery and whole
breast irradiation (WBI)
 Z0010-The investigators concluded that routine use of immunohistochemistry to
detect occult disease in SLNs is not warranted
 Zoo11-there was no difference between patients randomized to ALND and SLN
only in terms of OS, DFS

.
 Z0010 trial
 infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%
 At 6 months following surgery, axillary paresthesias were noted in 8.6% of patients,
decreased range of motion in the upper extremity was reported in 3.8%, and 6.9% of
patients had a change in the arm circumference of >2 cm on the ipsilateral side, which was
reported as lymphedema
 Younger patients were more likely to report paresthesias, whereas increasing age and body
mass index were more predictive of lymphedema
 Z0011 trial, patients undergoing SLN dissection with ALND had
 more wound infections, seromas, and paresthesias than those women undergoing SLN dissection alone
 Lymphedema at one year after surgery was reported by 13% in the SLN plus ALND but only 2% in the SLN
dissection alone group
 Arm circumference measurements were greater at one year in patients undergoing SLN dissection plus
ALND

.
 NCCN guidelines now state that there was no OS difference for patients with 1 or 2
positive SLNs treated with breast conserving surgery who underwent completion ALND vs.
those who had no further axillary surgery
 In patients who present with axillary lymphadenopathy that is confirmed to be metastatic
disease on FNA or core biopsy, SLN dissection is not necessary and patients can proceed
directly to ALND or be considered for preoperative systemic therapy
 Adjuvant chemotherapy for patients with early-stage invasive breast cancer is considered
for patients with
 node-positive cancers, patients with cancers that are >1 cm, and patients with node-
negative cancers of >0.5 cm when adverse prognostic features are present
 Adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear
grade, high histologic grade, HER-2/neu overexpression or amplification, and negative
hormone receptor status
 Adjuvant endocrine therapy is considered for women with hormone receptor-positive
cancers, and use of an aromatase inhibitor is recommended if the patient is
postmenopausal

.
 Option: 5 years of an aromatase inhibitor or two years of tamoxifen followed by 3
years of an aromatase inhibitor (the so called, ‘switch’ regime);
 The majority of clinicians appear to favor 5 years of an aromatase inhibitor,
especially with increasing risk of recurrence
 HER-2/neu status is determined for all patients with newly diagnosed invasive
breast cancer and when positive, systemic therapy recommendations
 Trastuzumab is the only HER-2/neu–targeted agent that is currently approved for
use in the adjuvant setting
 The FDA approved trastuzumab use as part of a treatment regimen containing
doxorubicin, cyclophosphamide, and paclitaxel for treatment of HER-2/neu–
positive, node-positive breast cancer
 Subsequently, giving trastuzumab concurrently with docetaxel and carboplatin
appeared as effective as giving trastuzumab following an anthracycline containing
regimen

.
 Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB)
 Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but
have no clinically detected distant metastases
 most of these patients will already have distant metastasis which is often highlighted by
radiological evidence when bone scans, PET &/or CT scans are performed
 Even when they are negative, elevated serum tumor markers may be another indicator that
distant spread has already occurred
 Neoadjuvant therapy followed by modified radical mastectomy, post-operative radiotherapy
and endocrine therapy vs. primary endocrine therapy followed by sequential therapy on
progression of disease showed no difference in either overall survival or uncontrolled local
disease at death
 Preoperative (also known as neoadjuvant) chemotherapy should be considered for locally
advanced stage III breast cancer, especially those with estrogen receptor negative tumors
 For selected clinically indolent estrogen receptor positive, locally advanced tumors, primary
endocrine therapy may be considered, especially if the patient has other co-morbid conditions

.
 breast-conserving surgery can be used for appropriately selected patients with
locally advanced breast cancer who achieve a good response with preoperative
chemotherapy
 For patients with stage IIIA disease who experience minimal response to
chemotherapy and for patients with stage IIIB breast cancer, preoperative
chemotherapy can decrease the local-regional cancer burden enough to permit
subsequent modified radical mastectomy to establish local-regional control
 In both stage IIIA and IIIB disease, surgery is followed by adjuvant radiation
therapy

.
 Internal Mammary Lymph Nodes
 Metastatic disease to internal mammary lymph nodes may be occult, may be evident on chest
radiograph or CT scan, or may present as a painless parasternal mass with or without skin
involvement
 There is no consensus regarding the need for internal mammary lymph node radiation therapy
in women who are at increased risk for occult involvement (cancers involving the medial
aspect of the breast, axillary lymph node involvement) but who show no signs of internal
mammary lymph node involvement
 Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly
involved internal mammary lymph nodes

.
 Distant Metastases (Stage IV)
 Treatment is not curative but may prolong survival and enhance a woman’s quality of
life
 Endocrine therapies that are associated with minimal toxicity are preferred to
cytotoxic chemotherapy in estrogen receptor positive disease
 Appropriate candidates for initial endocrine therapy include women with hormone
receptor-positive cancers who do not have immediately life threatening disease (or
‘visceral crisis’)
 This includes women with bone / soft tissue and limited visceral metastases
 Symptoms per se (e.g., breathlessness) are not in themselves an indication for
chemotherapy
 For example, breathlessness due to a pleural effusion -percutaneous drainage and if
the breathlessness is relieved the patient should be commenced on endocrine therapy
 whereas if the breathlessness is due to lymphangitic spread then chemotherapy would
be the treatment of choice

.
 Systemic chemotherapy is indicated for women with hormone receptor-negative cancers,
‘visceral crisis’, and hormone-refractory metastases
 Anatomically localized problems that will benefit from individualized surgical or radiation
treatment, such as
 brain metastases,
 pleural effusion,
 pericardial effusion,
 biliary obstruction,
 ureteral obstruction,
 impending or existing pathologic fracture of a long bone,
 spinal cord compression, and
 painful bone or soft tissue metastases
 Bisphosphonates, which may be given in addition to chemotherapy or endocrine therapy, should
be considered in women with bone metastases
 Stage Iv, women who undergo resection of the primary tumor have improved survival over those
who do not

.
 Local-Regional Recurrence
 Women treated previously with mastectomy undergo surgical resection of the local-regional
recurrence and appropriate reconstruction
 Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given
if the chest wall has not previously received radiation therapy or if given the time from previous
treatment there is scope for further radiation therapy, particularly if this is palliative
 Women treated previously with a breast conservation procedure undergo a mastectomy and
appropriate reconstruction
 Chemotherapy and antiestrogen therapy are considered
 Breast Cancer Prognosis
 The overall 5-year relative survival
 by geographic areas was 89.2%
 by race was reported to be 90.4% for white women and 78.7% for black women
 localized disease (61% of patients) is 98.6%;
 for patients with regional disease (32% of patients), 84.4%; and
 for patients with distant metastatic disease (5% of patients), 24.3%

.
 SURGICAL TECHNIQUES IN BREAST CANCER THERAPY
 Excisional Biopsy with Needle Localization
 Excisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing
breast tissue
 Needle core biopsy is the preferred diagnostic method and excisional biopsy should be reserved for
those cases where the needle biopsy results are discordant with the imaging findings or clinical
examination
 In general circumareolar incisions can be used to access lesions which are subareolar or within a short
distance of the nipple-areolar complex
 Elsewhere in the breast, incisions should be placed which are in the lines of tension in the skin that are
generally concentric with the nipple-areola complex
 In the lower half of the breast, the use of radial incisions typically provides the best outcome

.
 When the tumor is quite distant from the central breast, the biopsy incision can be excised
separately
from the primary mastectomy incision, should a mastectomy be required
 Radial incisions in the upper half of the breast are not recommended because of possible
scar contracture resulting in displacement of the ipsilateral nipple-areola complex
 Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-
areolar complex downward
 The specimen should be x-rayed to confirm the lesion has been excised with appropriate
margins
 Cosmesis may be facilitated by approximation of the surgical defect using 3-0 absorbable
sutures
 A running subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures
is performed
 Wound drainage is usually not required

.
 Sentinel Lymph Node Dissection
 primarily used to assess the regional lymph nodes in women with early breast cancers who are
clinically node negative by physical examination and imaging studies
 This method also is accurate in women with larger tumors (T3 N0), but nearly 75% of these
women will prove to have axillary lymph node metastases on histologic examination and
wherever possible it is better to identify them preoperatively as this will allow a definitive
procedure for known axillary disease
 Accurate for staging of the axilla after chemotherapy in women with clinically node-negative
disease at initial presentation
 Meta-analysis of 449 cases of SLN biopsy in clinically lymph node negative
 reported a sensitivity of 93% giving a false negative rate of 7% with a negative predictive value
of 94% and an overall accuracy of 95%

.
 Clinical situations where SLN dissection is not recommended include
 inflammatory breast cancers,
 palpable axillary lymphadenopathy and biopsy proven metastasis,
 DCIS without mastectomy, or
 prior axillary surgery
 Although limited data are available, SLN dissection appears to be safe in pregnancy when
performed with radioisotope alone
 combination of intraoperative gamma probe detection of radioactive colloid and intraoperative
visualization of blue dye (isosulfan blue dye or methylene blue) is more accurate for
identification of SLNs than the use of either agent alone
 Some surgeons use preoperative lymphoscintigraphy, although it is not required for
identification of the SLNs

.
 On the day before surgery, or the day of surgery, the radioactive colloid is injected either in
the breast parenchyma around the primary tumor or prior biopsy site, into the subareolar
region, or subdermally in proximity to the primary tumor site
 It is not recommended that the blue dye be used in a subdermal injection because this can result in
tattooing of the skin (isosulfan blue dye) or skin necrosis (methylene blue)
 In women who have undergone previous excisional biopsy, the injections are made in the
breast parenchyma around the biopsy cavity but not into the cavity itself
 Anaphylactic reactions have been documented and some groups administer a regimen of
antihistamine, steroids, and a histamine H-2 receptor antagonist preoperatively as a
prophylactic regimen to prevent allergic reactions
 The use of radioactive colloid is safe, and radiation exposure is very low
 Sentinel node dissection can be performed in pregnancy with the radioactive colloid without
the use of blue dye

.
 A hand-held gamma counter is used to transcutaneously identify the location of the SLN
 This can help to guide placement of the incision
 A 3- to 4-cm incision is made in line with that used for an axillary dissection, which is a curved
transverse incision in the lower axilla just below the hairline
 After dissecting through the subcutaneous tissue, the surgeon dissects through the axillary fascia,
being mindful to identify blue lymphatic channels
 Following these channels can lead directly to the SLN and limit the amount of dissection through the
axillary tissues
 The gamma probe is used to facilitate the dissection and to pinpoint the location of the SLN
 As the dissection continues, the signal from the probe increases in intensity as the SLN is approached
 The SLN also is identified by visualization of blue dye in the afferent lymph vessel and in the lymph
node itself
 Before the SLN is removed, a 10-second in vivo radioactivity count is obtained
 After removal of the SLN, a 10-second ex vivo radioactive count is obtained, and the node is then
sent to the pathology laboratory for either permanent- or frozen-section
analysis

.
 The lowest false-negative rates for SLN dissection have been obtained when all
blue lymph nodes and all lymph nodes with counts >10% of the 10-second ex vivo
count of the SLN are harvested (“10% rule”)
 Based on this, the gamma counter is used before closing the axillary wound to
measure residual radioactivity in the surgical bed
 A search is made for additional SLNs if the counts remain high
 This procedure is repeated until residual radioactivity in the surgical bed is less
than 10% of the 10-second ex vivo count of the most radioactive SLN and all blue
nodes have been removed
 Studies have demonstrated that 98% of all positive SLNs will be recovered
with the removal of four SLNs, therefore it is not necessary to remove greater
than four SLNs for accurate staging of the axilla

.
 Results from the NSABP B-32 trial showed that the false negative rate for SLN dissection is
influenced by tumor location, type of diagnostic biopsy, and number of SLNs removed at
surgery
 The authors reported that tumors located in the lateral breast were more likely to have a false-
negative SLN
 This may be explained by difficulty in discriminating the hot spot in the axilla when the
radioisotope has been injected at the primary tumor site in the lateral breast
 Those patients who had undergone an excisional biopsy before the SLN procedure were
significantly more likely to have a false-negative SLN
 This report further confirms that surgeons should use needle biopsy for diagnosis whenever
possible and reserve excisional biopsy for the rare situations in which needle biopsy findings
are non diagnostic or discordant

.
 Finally, removal of a larger number of SLNs at surgery appears to reduce the false-negative
rate
 In B-32, the false-negative rate was reduced from 17.7% to 10% when two SLNs were
recovered and to 6.9% when three SLNs were removed
 In the B-32 trial, SLNs were identified outside the level I and II axillary nodes in 1.4% of
cases
 This was significantly influenced by the site of radioisotope injection
 When a subareolar or periareolar injection site was used, there were no instances of SLNs
identified outside the level I or II axilla, compared with a rate of 20% when a peritumoral
injection was used
 This supports the overall concept that the SLN is the first site of drainage from the
lymphatic vessels of the primary tumor
 Internal mammary node drainage on preoperative lymphoscintigraphy was associated with
worse distant disease-free survival in early-stage breast cancer

.
 Breast Conservation
 Breast conservation involves resection of the primary breast cancer with a margin of normal-appearing
breast tissue, adjuvant radiation therapy, and assessment of regional lymph node status
 Resection of the primary breast cancer is alternatively called segmental mastectomy, lumpectomy, partial
mastectomy, wide local excision, and tylectomy
 For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to total
mastectomy because BCT produces survival rates equivalent to those after total mastectomy while
preserving the breast
 Six prospective randomized trials have shown that overall and disease-free survival rates are similar with
BCT and mastectomy,
 however three of the studies showed higher local-regional failure rates in patients undergoing BCT
 In two of these studies, there were no clear criteria for histologically negative margins
 Addition of radiation reduces recurrence by half and improves survival at year 15 by about a sixth
 When all of this information is taken together, BCT is considered to be oncologically equivalent to
mastectomy

.
 BCT appears to offer advantages with regard to quality of life and aesthetic outcomes
 BCT allows for preservation of breast shape and skin as well as preservation of sensation, and
provides an overall psychologic advantage associated with breast preservation
 BCS is currently the standard treatment for women with stage 0, I, or II invasive breast cancer
 Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy
without assessment of regional lymph nodes
 When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola
complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of
the breast
 Radial incisions are preferred when the tumor is in the lower aspect of the breast
 Skin excision is not necessary unless there is direct involvement of the overlying skin by the
primary tumor
 The breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate
to achieve a cancer-free margin
 Significant controversy exists on the appropriate margin width for BCT

.
 Specimen x-ray should routinely be performed to confirm the lesion has been excised and that
there appears to be an appropriate margin
 Specimen orientation is performed by the surgeon
 Additional margins from the surgical bed are taken as needed to provide a histologically
negative margin
 Requests for determination of ER, PR, and HER-2 status are conveyed to the pathologist
 It is the surgeon’s responsibility to ensure complete removal of cancer in the breast
 Ensuring surgical margins that are free of breast cancer will minimize the chances of local
recurrence and will enhance cure rates
 Local recurrence of breast cancer after conservation surgery is determined primarily by the
adequacy of surgical margins
 Cancer size and the extent of skin excision are not significant factors in this regard

.
 It is the practice of many North American and European surgeons to undertake re-excision
when residual cancer within 2 mm of a surgical margin is determined by histopathologic
examination
 If clear margins are not obtainable with re-excision, mastectomy is required
 SLN is performed before removal of the primary breast tumor
 When indicated, intraoperative assessment of the sentinel node can proceed while the
segmental mastectomy is being performed
 The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at
a later time to improve the overall aesthetic outcome
 The use of oncoplastic techniques range from a simple re-shaping of breast tissue to local
tissue rearrangement to the use of pedicled flaps or breast reduction techniques

.
 Oncoplastic techniques are of prime consideration when:
 (a) a significant area of breast skin will need to be resected with the specimen to achieve negative
margins;
 (b) a large volume of breast parenchyma will be resected resulting in a significant defect;
 (c) the tumor is located between the nipple and the inframammary fold, an area often associated
with unfavorable cosmetic outcomes; or
 (d) excision of the tumor and closure of the breast may result in mal positioning of the nipple
 Mastectomy and Axillary Dissection
 A skin-sparing mastectomy removes all breast tissue, the nipple-areola complex, and scars from any
prior biopsy procedures
 There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence rates
reported with standard mastectomy, when skin-sparing mastectomy is used for patients with Tis to T3
cancers

.
 A total (simple) mastectomy without skin sparing removes all breast tissue, the nipple-areola complex,
and skin
 An extended simple mastectomy removes all breast tissue, the nipple-areola complex, skin, and the
level I axillary lymph nodes
 A modified radical (‘Patey’) mastectomy removes all breast tissue, the nipple-areola complex, skin,
and the levels I, II and III axillary lymph nodes
 The pectoralis minor which was divided and removed by Patey may be simply divided, giving
improved access to level III nodes, and then left in-situ or occasionally the axillary clearance can
be performed without dividing pectoralis minor
 The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the
pectoralis major and pectoralis minor muscles, and the level I, II, and III axillary lymph nodes
 The use of systemic chemotherapy and hormonal therapy as well as adjuvant radiation therapy for
breast cancer have nearly eliminated the need for the radical mastectomy

.
 Nipple-areolar sparing mastectomy has been popularized over the last decade especially for
risk-reducing mastectomy in high risk women
 For those patients with a cancer diagnosis, many consider factors for eligibility:
 tumor located more than 2–3 cm from the border of the areola,
 smaller breast size,
 minimal ptosis,
 no prior breast surgeries with periareolar incisions,
 body mass index less than 40 kg/m2,
 no active tobacco use,
 no prior breast irradiation, and
 no evidence of collagen vascular disease

.
 For a variety of biologic, economic, and psychosocial reasons, some women
desire mastectomy rather than breast conservation
 Women who are less concerned about cosmesis may view mastectomy as the most
expeditious and desirable therapeutic option because it avoids the cost and
inconvenience of radiation therapy
 Some women whose primary breast cancers cannot be excised with a reasonable
cosmetic result or those who have extensive microcalcifications are best treated
with mastectomy
 Similarly women with large cancers that occupy the subareolar and central
portions of the breast and women with multicentric primary cancers also undergo
mastectomy

.
 Modified Radical Mastectomy
 Preserves the pectoralis major muscle with removal of level I, II, and III (apical) axillary lymph nodes
 The operation was first described by David Patey,
 He had removed the pectoralis minor muscle allowing complete dissection of the level III axillary lymph
nodes while preserving the pectoralis major and the lateral pectoral nerve
 A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral nerve,
which courses in the lateral neurovascular bundle of the axilla and usually penetrates the pectoralis minor
to supply the lateral border of the pectoralis major
 Anatomic boundaries of the modified radical mastectomy are
 Laterally ---the anterior margin of the latissimus dorsi muscle,
 Medially ----the midline of the sternum,
 Superiorly ----the subclavius muscle, and
 Inferiorly--the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold

.
 Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and
telasubcutanea
 Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the
overlying breast tissue are elevated off the underlying musculature, which allows for the
complete removal of the breast (Fig. 17-36)


.
 Subsequently, an axillary lymph node dissection is performed
 The most lateral extent of the axillary vein is identified and the areolar tissue of the lateral
axillary space is elevated as the vein is cleared on its anterior and inferior surfaces
 The areolar tissues at the junction of the axillary vein and the anterior edge of the latissimus
dorsi muscle, which include the lateral and subscapular lymph node groups (level I), are
cleared
 Care is taken to preserve the thoracodorsal neurovascular bundle
 The dissection then continues medially with clearance of the central axillary lymph node
group (level II)
 The long thoracic nerve of Bell is identified and preserved as it travels in the investing fascia
of the serratus anterior muscle
 Every effort is made to preserve this nerve, because permanent disability with a winged
scapula and shoulder weakness will follow denervation of the serratus anterior muscle

.
 Patey divided the pectoralis minor and removed it to allow access right up to the apex of the
axilla
 The pectoralis minor muscle is usually divided at the tendinous portion near its insertion
onto the coracoid process (Fig. 17-37 inset), which allows dissection of the axillary vein
medially to the costoclavicular (Halsted’s) ligament
 Finally, the breast and axillary contents are removed from the surgical bed and are sent for
pathologic assessment
 In Patey’s modified radical mastectomy he removed the pectoralis minor muscle
 Many surgeons now divide only the tendon of the pectoralis minor muscle at its insertion
onto the coracoid process while leaving the rest of the muscle intact, which still provides
good access to the apex of the axilla

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