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					BREAST
 HOUSSAM OSMAN
A BRIEF HISTORY OF BREAST CANCER THERAPY


   Tumor resection.
   Lymph node dissection
   Radiotherapy
   Chemotherapy
   Hormonal therapy
   Integrated therapy with breast conservative surgery.
EMBRYOLOGY AND FUNCTIONAL ANATOMY OF
             THE BREAST
Embryology:
 Develop from thickened ectoderm (mammary ridges, milk lines)
  extending from the base of the forelimb (future axilla) to the region of the
  hind limb (inguinal area).
 Male and female breasts are identical at birth. Proliferation start with
  puberty and development is completed with pregnancy.
 Congenital anomalies:
• Amastia : arrest in mammary ridge development.
• Polymastia : failure of normal regression.
• Polythelia, other congenital association.
• Inverted nipple : failure of a pit to elevate above skin level.
• Poland's syndrome .
• Turner's syndrome and Fleischer's syndrome.
• Witch's milk
Functional Anatomy :
 Location.
 Structure.
 Nipple – areola complex.
 Blood supply: internal mammary artery, posterior intercostal arteries,
  axillary artery, and lateral thoracic artery .
 Veins: internal thoracic vein, posterior intercostal veins, and axillary vein.
vertebral venous plexus of Batson.
  Lymphatic: the axillary vein group (lateral), the external mammary group (anterior
   or pectoral group), the scapular group (posterior or subscapular), the central group
   , the subclavicular group (apical), the interpectoral group (Rotter's).
Level I : located lateral to or below the lower border of the pectoralis minor muscle.
Level II : located superficial or deep to the pectoralis minor muscle.
Level III : located medial to or above the upper border of the pectoralis minor muscle.
                  PHYSIOLOGY OF THE BREAST
Breast Development and Function
   Estrogen initiates ductal development
   progesterone is responsible for differentiation of epithelium and for lobular
    development.
   Prolactin is the primary hormonal stimulus for lactogenesis in late pregnancy and
    the postpartum period. It upregulates hormone receptors and stimulates epithelial
    development.

Pregnancy, Lactation, and Senescence
   In response to estrogen and progesterone the breast tissues proliferate , skin
    darken, and Montgomery glands become more prominent.
   In late pregnancy prolactin stimulates the synthesis of milk with full expression of
    the lactogenic action after delivery of the placenta (low estrogen).
   Oxytocin initiates contraction of the myoepithelial cells resulting in compression of
    alveoli and expulsion of milk into the lactiferous sinuses.
   With menopause there is a decrease in the secretion of estrogen and
    progesterone by the ovaries and involution of the ducts and alveoli of the breast.
    The surrounding fibrous connective tissue increases in density, and breast tissues
    are replaced by adipose tissues
Gynecomastia
  enlarged breast in the male.
  Physiologic gynecomastia: the neonatal period, adolescence, and senescence.
   (excess of circulating estrogens in relation to circulating testosterone)
 In the nonobese male, breast tissue measuring at least 2 cm in diameter must be
   present before a diagnosis of gynecomastia may be made
 does not predispose the male breast to cancer.
 clinical classification of gynecomastia:
Grade I : Mild breast enlargement without skin redundancy
Grade IIa : Moderate breast enlargement without skin redundancy
Grade IIb : Moderate breast enlargement with skin redundancy
Grade III : Marked breast enlargement with skin redundancy and ptosis, which
   simulates a female breast
 The pathophysiologic mechanisms:
 I. Estrogen excess states
     A. Gonadal origin
     B. Nontesticular tumors
     C. Endocrine disorders
     D. Diseases of the liver—nonalcoholic and alcoholic cirrhosis
     E. Nutrition alteration states
  II. Androgen deficiency states
     A. Senescence
     B. Hypoandrogen states (hypogonadism)
     C. Renal failure
 III. Drug-related
 IV. Systemic diseases with idiopathic mechanisms
 Therapy.
    INFECTIOUS AND INFLAMMATORY DISORDERS
                 OF THE BREAST
Bacterial Infection :
    Staphylococcus aureus and Streptococcus species.
    related to lactation .
    US
    Abx and I&D.


Mycotic Infections :
    blastomycosis or sporotrichosis..
    Amphotrericin.


Hidradenitis Suppurativa :
    chronic inflammatory condition that originates within the accessory areolar glands
     of Montgomery or within the axillary sebaceous glands.
    Antibiotic therapy with incision and drainage. Excision may be required which may
     necessitate coverage with flaps or STSG.
Mondor's Disease
   thrombophlebitis involves the superficial veins of the anterior chest wall and
    breast.
   present as a tender, cord-like structure.
   ? Biopsy
   anti-inflammatory medications, warm compresses, restriction of motion, and
    brassiere support of the breast. When symptoms persist or are refractory to
    therapy, excision of the involved vein segment is appropriate.
 COMMON BENIGN DISORDERS AND DISEASES
           OF THE BREAST
ANDI:

Early reproductive years (age 15–25)
Normal                        Disorder                            Disease
Lobular development           Fibroadenoma              Giant fibroadenoma
Stromal development           Adolescent hypertrophy    Gigantomastia
Nipple eversion               Nipple inversion          Subareolar abscess
                                                        Mammary duct fistula
Later reproductive years (age 25–40)
Normal                        Disorder                          Disease
Cyclical changes of           Cyclical mastalgia                Incapacitating
    menstruation                                                mastalgia
Nodularity
Epithelial hyperplasia        Bloody nipple discharge
  of pregnancy
Involution (age 35–55):

Normal                    Disorder                       Disease
Lobular involution        Macrocysts
                          Sclerosing lesions

Duct involution
–Dilatation               Duct ectasia              Periductal mastitis
–Sclerosis                Nipple retraction

Epithelial turnover       Epithelial hyperplasia   Epithelial hyperplasia
                                                       with atypia
Cancer Risk Associated with Benign Breast Disorders and In Situ Carcinoma of
   the Breast:



Nonproliferative lesions of the breast                       No increased risk
Sclerosing adenosis                                          No increased risk
Intraductal papilloma                                        No increased risk
Florid hyperplasia                                           1.5 to 2-fold
Atypical lobular hyperplasia                                 4-fold
Atypical ductal hyperplasia                                  4-fold
Ductal involvement by cells of atypical ductal hyperplasia   7-fold
Lobular carcinoma in situ                                    10-fold
Ductal carcinoma in situ                                     10-fold
Classification of benign breast disorders:

Nonproliferative disorders of the breast :
• Cysts and apocrine metaplasia
• Duct ectasia :dilated subareolar ducts, palpable , thick nipple discharge.
• Calcifications
• Fibroadenoma and related lesions

Proliferative breast disorders without atypia
• Sclerosing adenosis
• Radial and complex sclerosing lesions
• Ductal epithelial hyperplasia
• Intraductal papillomas

Atypical proliferative lesions
• Atypical lobular hyperplasia (ALH)
• Atypical ductal hyperplasia (ADH)
Treatment of Selected Benign Breast Disorders and Diseases:
Cysts:
   Aspiration
   If the mass did not disappear or if the fluid is blood stained -> US, needle biopsy,
    and possible excisional biopsy.
Fibroadenoma:
   ultrasound examination with core-needle biopsy.
   Counseling
   Excision.
Sclerosing disorders:
   mimic cancer.
   Excisional biopsy and histologic examination are frequently necessary to exclude
    the diagnosis of cancer
Periductal mastitis:
   Aspiration
   If no pus -> Abx
   Purulent -> surgery
            RISK FACTORS FOR BREAST CANCER

Hormonal and Nonhormonal Risk Factors :
 Estrogen:
↑ : early menarche, nulliparity, and late menopause, older age at first live birth,
   obesity.
↓ : exercise, longer lactation period, full-term pregnancy .
 Nonhormonal: radiation exposure, alcohol, high fat diet.


Risk-Assessment Models :
   The average lifetime risk of breast cancer for newborn U.S. females is 12%.
   Two risk-assessment models are currently used to predict the risk of breast cancer.
Risk Management :
  Postmenopausal hormone replacement therapy.
  screening mammography in women age 50 years and older reduces mortality from
   breast cancer by 33%.
 Tamoxifen:
*Gail relative risk of 1.70 or greater -> reduce the incidence of breast cancer by 49%.
*DVT, PE, endometrial CA, cataract.


BRCA Mutations:
 BRCA-1 and BRCA-2, autosomal dominant, tumor-suppressor genes.
 BRCA-1 :
*chromosome 17q
*90% lifetime risk for developing breast cancer and up to a 40% lifetime risk for
    developing ovarian cancer.
*invasive ductal carcinomas, are poorly differentiated, and are hormone receptor–
    negative.
 BRCA-2:
chromosome 13q
The breast cancer risk for BRCA-2 mutation carriers is close to 85% and the lifetime
    ovarian cancer risk
 Identifying carriers:
(1) obtaining a complete, multigenerational family history.
(2) assessing the appropriateness of genetic testing for a particular patient
(3) counseling the patient
(4) interpreting the results of testing
 Cancer prevention measures:
    *Prophylactic mastectomy and reconstruction;
    *Prophylactic oophorectomy and hormone replacement therapy;
    *Intensive surveillance for breast and ovarian cancer; and
    *Chemoprevention.
    EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST
                     CANCER

Epidemiology:
    the most common site-specific cancer in women and is the leading cause of death
     from cancer for women age 40 to 44 years.
    increase in incidence and decrease in mortality rate.
    The 5- and 10-year survival rates for these women were 18.0 and 3.6%,
     respectively.


The primary breast cancer:
    productive fibrosis that involves the epithelial and stromal tissues. .
    (peau d'orange).
    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.
    up to 20% of breast cancer recurrences are locoregional, more than 60% are
     distant, and 20% are both locoregional and distant.
Axillary lymph node metastases:
   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.
   The most important prognostic correlate for disease-free and overall survival.


Distant metastases:
   Hematogenously 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.
   the most common cause of death in breast cancer patients.
   bone, lung, pleura, soft tissues, and liver.
          HISTOPATHOLOGY OF BREAST
                   CANCER
Carcinoma In Situ:
•   Basement membrane involvement
•   Diagnosis necessitates the analysis of multiple microscopy sections to exclude
    invasion
•   Multicentricity; occurrence of a second breast cancer outside the breast quadrant
    of the primary cancer
•   Multifocality; occurrence of a second cancer within the same breast quadrant as
    the primary cancer
•   2 types:
     • Lobular carcinoma in situ
     • Ductal carcinoma in situ
Lobular Carcinoma in Situ (LCIS):
•   Multicentricity; 60 to 90% of cases
•   Bilaterally in 50 to 70% of cases
•   The age at diagnosis is 44 to 47 years
•   12 times more frequently in white women than in African American women
•   Cytoplasmic mucoid globules; distinctive cellular feature
•   Neighborhood calcification
•   Invasive breast cancer develops in 25 to 35% of cases;
     – either breast, regardless of which breast harbored the initial focus of LCIS
     – 65% of subsequent invasive cancers are ductal, not lobular in origin
•   A marker of increased risk for invasive breast cancer rather than an anatomic
    precursor
Ductal Carcinoma in Situ (DCIS):
•   Multicentricity; 40 to 80% of cases
•   Bilaterally in 10 to 20% of cases
•   Accounts for 5% of male breast cancers
•   Early development; no cancer cell cytological features
•   Mammography: Calcium deposition occurs in the areas of necrosis
•   Classified based on nuclear grade and the presence of necrosis (comedo,
    noncomedo..etc)
•   Fivefold increase in the risk of invasive breast cancer (ipsilateral breast, same
    quadrant)
•   An anatomic precursor of invasive ductal carcinoma
Invasive Breast Carcinoma :
I. Paget's disease of the nipple
II. Invasive ductal carcinoma
    A.     Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80%
    B.     Medullary carcinoma 4%
    C.     Mucinous (colloid) carcinoma 2%
    D.     Papillary carcinoma 2%
    E.     Tubular carcinoma (and ICC) 2%

III. Invasive lobular carcinoma 10%
           (signet-ring cell carcinoma)

IV. Rare cancers (adenoid cystic, squamous cell, apocrine)
              DIAGNOSING BREAST CANCER

History and Physical Examination
Imaging Techniques:
• Mammography
    – Screening mammography ;
        • unexpected, asymptomatic
    – Diagnostic mammography (more views)
        • false-positive rate of 10%
        • false-negative rate of 7%
   – Xeromammography
• Ductography
    – Primary indication: nipple discharge
• Ultrasonography
• Magnetic Resonance Imaging (MRI)
   – Strong family history of breast cancer
   – MRI of the contralateral breast in women with a known breast cancer
      (5.7% positive)
Breast Biopsy:
• Nonpalpable Lesions
   – Image-guided
   – Fine-needle aspiration (FNA) biopsy
       • cytologic evaluation
   – Core-needle biopsy
       • alternative to open biopsy
       • low complication rate, avoidance of scarring, and a lower cost.
   – Open biopsy
       • breast tissue architecture
       • invasive cancer is present
• Palpable Lesions
   – Fine-needle aspiration (FNA) biopsy
   – Core-needle biopsy (sampling error)
  BREAST CANCER STAGING AND BIOMARKERS
Breast Cancer Staging :
 TNM:
TX                        Primary tumor cannot be assessed
T0                        No evidence of primary tumor
Tis                       Carcinoma in situ
T1                        2 cm or less
T2                        more than 2 cm but not more than 5 cm
T3                        more than 5 cm
T4                        direct extension to (a) chest wall or (b) skin
NX                        cannot be assessed
N0                        No regional lymph node metastasis
N1                        movable ipsilateral axillary lymph node
N2                        ipsilateral axillary lymph nodes fixed or matted
MX                        cannot be assessed
M0                        No distant metastasis
M1                        Distant metastasis
 Staging:
Stage 0      Tis     N0      M0

Stage I      T1      N0      M0

Stage IIA    T0      N1      M0
             T1      N1      M0
             T2      N0      M0
Stage IIB    T2      N1      M0
             T3      N0      M0

Stage IIIA   T0      N2      M0
             T1      N2      M0
             T2      N2      M0
             T3      N1      M0
             T3      N2      M0
Stage IIIB   T4      N0      M0
             T4      N1      M0
             T4      N2      M0
Stage IIIC   any T   N3      M0

Stage IV     any T   any N   M1
 Traditional Prognostic and Predictive Factors for Invasive Breast Cancer:

Tumor Factors                               Host Factors
Nodal status                                Age
Tumor size                                  Menopausal status
Histologic/nuclear grade                    Family history
Lymphatic/vascular invasion                 Previous breast cancer
Pathologic stage                            Immunosuppression
Hormone receptor status                     Nutrition
DNA content (ploidy, S-phase fraction)      Prior chemotherapy
Extensive intraductal component             Prior radiation therapy
      OVERVIEW OF BREAST CANCER THERAPY

In Situ Breast Cancer (Stage 0):
   Bilateral mammography is performed to determine the extent of the in situ cancer
    and to exclude a second cancer.
   LCIS: observation with or without tamoxifen.
   DCIS:
    *widespread disease (two or more quadrants)-> require mastectomy.
    *limited disease-> lumpectomy and radiation therapy are recommended.
    *Low-grade DCIS of the solid, cribriform, or papillary subtype, which is less than
           0.5 cm in diameter, may be managed by lumpectomy alone.
    *Nonpalpable -> needle localization techniques to guide the surgical resection.
    *Adjuvant tamoxifen therapy is considered for all DCIS patients.
Early Invasive Breast Cancer (Stage I, IIa, or IIb) :
     mastectomy with assessment of axillary lymph node status and breast
      conservation (lumpectomy with assessment of axillary lymph node status and
      radiation therapy) are considered equivalent.
     Axillary lymphadenopathy or metastatic disease in a sentinel axillary lymph node
      necessitates an axillary lymph node dissection.
     contraindications to breast conservation therapy include :
(1)   prior radiation therapy to the breast or chest wall.
(2)   involved surgical margins or unknown margin status following re-excision.
(3)   multicentric disease.
(4)   scleroderma or other connective-tissue disease.
     Adjuvant chemotherapy for early invasive breast cancer is considered for all node-
      positive cancers, all cancers that are larger than 1 cm in size, and node-negative
      cancers larger than 0.5 cm in size when adverse prognostic features are present.
     Tamoxifen therapy is considered for hormone receptor–positive women with
      cancers that are larger than 1 cm in size.
     . HER2/neu expression is determined for all newly diagnosed patients with breast
      cancer and may be used to provide prognostic information, predict the relative
      efficacy of various chemotherapy regimens, and predict benefit from Herceptin in
      women with metastatic or recurrent breast cancer.
Advanced Locoregional Regional Breast Cancer (Stage IIIa or IIIb):
   surgery is integrated with radiation therapy and chemotherapy.
   operable stage IIIa : modified radical mastectomy, followed by adjuvant chemotherapy,
    followed by adjuvant radiation therapy. Neoadjuvant can be considered.
   inoperable stage IIIa and for stage IIIb: neoadjuvant chemotherapy is used to decrease
    the locoregional cancer burden and may permit subsequent surgery to establish
    locoregional control. In this setting, surgery is followed by adjuvant chemotherapy and
    adjuvant radiation therapy.


Internal Mammary Lymph Nodes:
   Systemic chemotherapy and radiation therapy are used in the treatment of grossly
    involved internal mammary lymph nodes.


Distant Metastases (Stage IV) :
   hormonal therapy for women with hormone receptor–positive cancers; women with
    bone or soft tissue metastases only; and women with limited and asymptomatic
    visceral metastases.
   Systemic chemotherapy is indicated for women with hormone receptor–negative
    cancers, symptomatic visceral metastases, and hormone refractory metastases.
   anatomically localized problems may benefit from individualized surgical treatment
Locoregional Recurrence:
   Women with a previous mastectomy undergo surgical resection of the locoregional
    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.
   Women with previous breast conservation undergo a mastectomy and appropriate
    reconstruction. Chemotherapy and antiestrogen therapy are considered.
    NONSURGICAL BREAST CANCER THERAPIES
Radiation Therapy :
   used for all stages of breast cancer.
   reduce the risk of local recurrence.


Adjuvant chemotherapy:
   reduce in the odds of recurrence and of death in women age 70 years or younger
    with stage I, IIa, or IIb breast cancer.
   age 70 years or older, adjuvant chemotherapy is recommended those with blood
    vessel or lymph vessel invasion, high nuclear grade, high histologic grade,
    HER2/neu overexpression, and negative hormone receptor status.


Neoadjuvant chemotherapy:
   For operable advanced locoregional breast cancer .
   inoperable stage IIIa and for stage IIIb breast cancer, neoadjuvant chemotherapy is
    used to decrease the locoregional cancer burden.
Chemotherapy for distant metastases:
   women with hormone receptor–negative cancers with symptomatic visceral
    metastasis or with hormone refractory cancer may receive systemic chemotherapy.


Antiestrogen Therapy :
   all women with in situ cancer, reduce in the incidence of invasive breast cancer.
   Node-negative women with hormone receptor–positive breast cancers that are 1
    to 3 cm in size.
   Node-positive women and for all women with a cancer that is more than 3 cm in
    size.
   Can be added to the neoadjuvant therapy regimen for women with advanced
    locoregional breast cancer, especially for women with hormone receptor–positive
    cancers.


Anti-HER2/Neu Antibody Therapy :
   Patients with cancers that overexpress HER2/neu .
               SPECIAL CLINICAL SITUATIONS

Nipple Discharge:
• Unilateral
    Suggestive of cancer:
        • Spontaneous
        • Localized to a single duct
        • 40 years or more
        • Bloody
        • Associated with a mass
• Bilateral
    Suggestive of a benign condition:
        • Multiductal in origin
        • 39 years or less
        • Milky or blue green in color
Axillary Lymph Node Metastases with Unknown Primary Cancer :

•   Consistent with a breast cancer metastasis; 90% occult breast cancer

•   Axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer
    patients

•   Metastatic disease cannot be excluded; fine-needle biopsy and/or open biopsy of
    an enlarged axillary lymph node

•   Metastatic cancer found; immunohistochemical analysis
Breast Cancer During Pregnancy:

•   1 of every 3000 pregnant women (axillary lymph node metastases are present in
    up to 75% of them)
•   Average age is 34 years
•   Less than 25% of the breast nodules developing during pregnancy and lactation
    will be cancerous
•   Ultrasonography and needle biopsy (decreased sensitivity of mammography
    during pregnancy)
•   30% of the benign conditions encountered will be unique to pregnancy and
    lactation
•   First and second trimesters: modified radical mastectomy
•   Third trimester: lumpectomy with axillary node dissection
•   Radiation & Chemotherapy are considered in special situations
Male Breast Cancer:

•   Less than 1% of all breast cancers
•   North Americans and the British (Jewish and African American)
•   Preceded by gynecomastia in 20% of men
•   Radiation exposure, estrogen therapy, testicular feminizing syndromes,
    Klinefelter's syndrome (XXY)
•   Peak incidence in the sixth decade of life
•   85%: Infiltrating NST
•   15%: DCIS
•   Modified radical mastectomy (adjuvant radiotherapy and chemotherapy can be
    considered)
•   Men do worse (advanced stage of their cancer at the time of diagnosis)
Phyllodes Tumors :

•   Benign, borderline, or malignant
•   Borderline tumors have a greater potential for local recurrence
•   Sharply demarcated from the surrounding breast tissue
•   Always monoclonal (fibroadenomas are either polyclonal or monoclonal)
•   Small: excised with a 1-cm margin of normal-appearing breast tissue
•   Large phyllodes tumors may require mastectomy
•   Axillary dissection is not recommended
Inflammatory Breast Carcinoma:

•   Stage IIIb
•   Less than 3% of breast cancers
•   Skin changes:
     – brawny induration
     – erythema with a raised edge
     – edema (peau d'orange)
•   Mistaken for a bacterial infection of the breast
•   75% have palpable axillary lymphadenopathy
•   Distant metastases at diagnosis in 25% of white women
•   Surgery +/- radiation therapy
•   Neoadjuvant chemotherapy
Rare Breast Cancers :

•   SQUAMOUS CELL (EPIDERMOID) CARCINOMA

•   ADENOID CYSTIC CARCINOMA

•   APOCRINE CARCINOMA

•   SARCOMAS

•   LYMPHOMAS

				
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