The breasts

 Are located in the upper chest wall

 Overlie the second to sixth ribs
 Extend from the lateral border of the sternum to the mid-axillary line.

 Each breast contains 12 to 20 lactiferous ducts which communicate with the nipple .

 Each lactiferous duct forms a lobe, which terminates in a terminal duct lobular unit (TDLU), where milk is made.

NIPPLE ANATOMY

 Each lactiferous duct enlarges, forming a lactiferous sinus.

 Lactiferous ducts: Cuboidal epithelium

 Nipple: Simple stratified squamous epithelium

 Milk is discharged from a collection of 12-20 large lactiferous ducts opening through pores in the nipple during lactation

The Terminal Duct Lobular Unit

 is a structural and functional unit of the breast
 one terminal duct (arrow) gives rise to a collection of smaller ductules
 each lobule terminating in an acinus
 lobule is the part of the breast that produces milk .

Intralobular Stroma vs Interlobular Stroma

Intralobular stroma
  refers to the connective tissue around the ductules within each lobule
 is a looser, more vascular and cellular connective tissue than the interlobular stroma.
 Contains: -fibroblasts
-IgA-secreting plasma cells
NB: Fibroadenomas and Phyllodes tumours are derived from the intralobular stroma.

Interlobular stroma:
 is the connective tissue found between the lobules.
 it is dense and collagenous and has fewer cells.

The Acinus
lined by an inner layer of columnar or cuboidal epithelium (secretory and absorptive)
an outer basal layer of myoepithelial cells.
Function of the epithelial and myoepithelial cells in the acinus:
1. EPITHELIAL CELLS:
 Also called the Luminal cells
 express the biologic markers
 ER, PR and E-cadherinand are responsible for the production and secretion of milk.

2. MYOEPITHELIAL CELLS:
 lie on the basement membrane
 assist in milk ejection during lactation.
 provide structural support to the lobules

Young vs Old Breast

As the breast ages, the interlobular stroma changes from dense fibrous tissue to adipose tissue. By mammogram, the breast becomes less dense.

Changes during pregnancy

Hormone effects before pregnancy

Estrogen: Stimulates ductal and alveolar cell growth, fat, and stroma

Prolactin: Stimulates alveolar cell proliferation and lobule differentiation for milk production. Also causes breast swelling during secretory phase
 POSTPARTUM/LACTATIONAL CHANGES

Progesterone: Stimulates and maintains lactogenesis & secretion

Oxytocin: Released by suckling reflex. Promotes expulsion of milk into ducts through action on myoepithelial cells.

Common Lesion Characteristics

Fibroadenoma Usually fine, round, mobile, non-tender
Cysts Usually soft to firm, round, mobile;often tender
Fibrocystic changes Nodular, rope-like;may be tender,
Cancer Irregular, stellate, firm, notclearly delineated from surrounding tissue

50 Cancer, until proven otherwise As above

ancy/ Lactating Lactating adenomas, cysts, mastitis& cancer As above

Fibroadenomas Cyst (“Blue dome cyst”)

 are neoplasms of intralobular stroma.

 are the most common mass-forming lesion found in the breast especially in young women.
 In young women: palpable circumscribed masses.
 in older women, they present as circumscribed or lobulated mammographic densities or clustered calcifications

PHYSICAL EXAM FINDINGS THAT FAVOUR A BENIGN MASS.

•Pain or tenderness (MORE suggestive of a plugged duct or infection)

•Milky discharge,

•The mass is round or oval shape,

•The mass has distinct edges,

•The mass is soft-firm,

•The mass has good mobility

PHYSICAL EXAM FINDINGS CONCERNING FOR MALIGNANCY

•Non-tender mass

•Bloody nipple discharge

•Unhealed lesions,

•New inversion of nipple,

•Mass >1cm,

•Irregular shape

•The mass is hard

•The mass is not mobile

•The mass has indistinct borders

Techniques Used
Core needle biopsy showing Invasive carcinoma. This is the preferred tissue sampling technique.

Fine needle aspirate: FNA preparations consist of a suspension of cells or cell clusters. In FNAs, the diagnosis is based on the cytologic features.
However, without the architecture obtained with a core biopsy, this technique is not commonly used.

Breast Cancer

Invasive carcinoma: palpable mass and elicit a stromal reaction/desmoplastic response which is often what makes the breast masses palpable

2. Ductal carcinoma in situ (DCIS): Mammograms are also important for detecting DCIS (calcifications) since most DCIS cases do not form palpable
lesions.

3. Lobular carcinoma in situ (no longer classified as a carcinoma)

Risk Factors
Age of menarche: Early age= increased risk

•Presence of deleterious genes such as BRCA1 and BRCA2

•Age of first live birth: Late first pregnancy = increased risk

•Number of first degree relatives with breast cancer

•Number of previous breast biopsies

•Any breast biopsy showing atypical hyperplasia

•Race: Non-Hispanic white women have the highest rates of breast cancer .

High Risk Lesions

 DCIS (Ductal carcinoma in situ)

 LCIS (Lobular carcinoma in situ) (According to latest AJCC, LCIS is no longer regraded as carcinoma)

 ADH (Atypical ductal hyperplasia)

 ALH (Atypical lobular hyperplasia)

DCIS: A Clonal population of epithelial cells within the ductal system.
The process is in situ, i.e. the cells are confined within the basement membrane.

DCIS is characterized based

on 3 major histologic criteria:
Architecture, Nuclear grade & necrosis.
1.Architecture:
•Comedo, Cribriform, Papillary, micropapillary, solid (without necrosis), etc..
2.Nuclear Grade
•low( microcalcification) , intermediate, or high
3.Necrosis:
•Present vs. absent

Comedo subtypes of DCIS are automatically classified

as high grade.
Low grade DCIS is more likely to express ER

High grade DCIS : -over-express HER2/neu

-show necrosis

LCIS:
-A Clonal population of epithelial cells within the ductal/lobular system.
-Characterized by a solid proliferation of monomorphic cells with low to intermediate grade
nuclei.
-Often show pagetoid spread.
-The process is in situ, i.e. the cells are confined within the basement membrane.
(Note that cells tend to be discohesive in ALH and LCIS) due to lack of E-Cadherin.

Microinvasionis defined as invasion less than or equal to 0.1 cm in size. Like invasive
carcinoma, it is associated with a stromal desmoplastic reaction.
Adjuvant endocrine therapy
•For ER+ disease, tamoxifen (an Estrogen receptor antagonist) treatment is also
recommended. Sometimes, ER-negative disease can also be treated with Tamoxifen.

Lobular proliferations (LCIS, ALH & invasive lobular carcinoma) generally show loss
of E-cadherin
E-cadherin is normally present on luminal cells but absent in ALH, LCIS and invasive
lobular carcinoma. It’s expression is retained in DCIS and ADH and can therefore be
used as a tool to distinguish ductal proliferations from lobular proliferations.
OPTIONS FOR MEDICAL MANAGEMENT OF LCIS
1. Chemopreventive therapy:
-on estrogen receptor antagonists (e.g. Tamoxifen) or aromatase inhibitors and followed with
regular surveillance
2. Surveillance alone without medical therapy may also be an option (especially if there is a
contraindication to tamoxifen) However, surveillance must last for the patient's lifetime,
because the increased risk of breast cancer persists indefinitely
3. Alternative surgical approach: -availability of tamoxifen, prophylactic bilateral
mastectomies were regularly performed on women with a diagnosis of LCIS
-bilateral mastectomies for LCIS are generally reserved for patients with other strong
contributory risk factors (eg, strong family history, BRCA1, 2 mutations, prior hx of breast
ca, etc)

CLINICAL PRESENTATION OF INVASIVE CARCINOMA

1.Palpable mass.
2.Axillary lymph node metastases
3.Dimpling, due to fixation to the chest wall or skin
4.Nipple retraction
5.Lymphatic involvment can result in blockage of the local are of lymph drainage, causing
lymphedema, skin thickening, and peau d'orange ,etc.
6.MammographyRadiodense mass. Most commonly, irregular or ill-defined.

Gross appearance:
Most tumors: Firm to hard, with irregular
borders .
Less frequently -well-circumscribed border ,
softer consistency
BRCA1 AND BRCA2 MUTATIONS
BRCA1 Cancer predisposing mutations
-Found on chromosome 17q21
-functions to repair double stranded DNA breaks that occur due to damage.
-mutation have risks for cervix, uterus, fallopian tube, primary peritoneum, pancreas,
esophageal, stomach, and prostate cancers,
Found in 1/500 to 1/1000 people in general population.

BRCA2 Cancer predisposing mutations

-Found on chromosome 13q12
-Mutations (can be frameshift, deletions, insertions, nonsense mutations, etc..) produce a
truncated protein with loss of function.
Mutation have risks for cervix, uterus, fallopian tube, primary peritoneum, pancreas,
esophageal, stomach, and prostate cancers,
NB: BRCA2carriers are at increased risk of prostate and pancreatic cancer

Tumor types:

Invasive ductal Carcinoma

-forms solid tumour nests and ductal structures
-show loss of E-Cadherin expression

Invasive Lobular Carcinoma

-invade the stroma as single non-cohesive cells,
-described as “Indian filing
-show loss of E-Cadherin expression.
-signet rings cells

Infiltrating lobular carcinomas

-are multicentric,bilateral
-low grade
-well-differentiatedand ER
-arise in older women
-metastasize to meninges, peritoneum, or GI tract and less frequently to lungs.

Tubular carcinoma:
-well differentiated
-invasive carcinoma
-small malignant cells arranged in single-layer tubules.
-a very good prognosis with only 5-10% metastasizing to lymph nodes.

Medullary carcinoma
-syncytial sheets of pleomorphic tumour cells
-a prominent lymphoplasmacytic infiltrate within the surrounding stroma.
-have a soft, fleshy appearance grossly
-shows a significant increase in incidence in BRCA1 carriers.
-tend to be triple negative (ER-, PR-, HER2/neu-)
Benign lesions that may mimic invasive carcinomas
Radial Sclerosing Lesion
 (Radial Scar)
 Sclerosing Adenosis

Pathologic Staging and prognosis:

–Lymph node involvement (determines prognosis)

–Tumour size (determines prognosis)

•Histologic Grade: Well vs. mod. Poorly differentiated(determines prognosis)

•Presence of lymphovascular invasion/LVI(determines prognosis and risk of local

recurrence)

•Tumor type (determine prognosis, multifocality, risk of local recurrence, site and patterns
of recurrence)

•Association with DCIS

•Margins(determine risk of local recurrence)

•Hormonereceptorsand HER-2 expression

•Presence or absence of chest wall invasion (determines prognosis, recurrence risk,

In the absence of known systemic metastasis, lymph node status is the single most
important prognostic indicator.

Lymph Node Status is the single MOST important indicator of prognosis (in the absence
of documented systemic metastasis)
Number of positive lymph nodes correlates with decreased disease-free survival (DFS)
and overall survival.
The presence or absence of lymphovascular invasion (LVI) in a tissue section is not used in
the staging or grading of breast cancer,, but it is still considered an indicator of worse
prognosis
 Invasive Carcinoma: Histologic Grade

Histologic Grade can be described in terms of the Modified Blue Richardson (MBR)
Scoring system, which is based on combining the scores for three criteria:
 Tubule formation
 mitotic count
 nuclear grade.

Grade I: score 3, 4, or 5: (Well-Differentiated)

Grade II: score 6, 7: (Moderately differentiated)
Grade III: score 8, 9: (Poorly differentiated)

Features Well-differentiated Moderately differentiated Poorly differentiated (Grade 3)

(Grade 1) (Grade 2)
Tubule formation Prominent Tubules Fewer tubules, solid clusters, single Rare tubules.
infiltrating cells
Nuclei Small, round, monomorphic Greater nuclear pleomorphism Enlarged, irregular & hyperchromatic
Mitotic figures Rare mitoses Present Numerous mitoses
Proliferation - - High
Tumour necrosis - - Necrosis present

MASTECTOMY PROCEDURE
Most common type of mastectomy (Skin removed)
Skin sparing mastectomy (less common)
Only nipple areolar complex removed. Remaining skin preserved

Sentinel lymph node biopsy

The sentinel node is the first node to which lymphatic drainage occurs. It is presumed be the
first site of metastasis

LYMPHATIC DRAINAGE FOR BREAST LESIONS:

•AXILLARY (Most common)
•INTERNAL MAMMARY
•SUPRACLAVICULAR

Lymphedema is a complication of full axillary dissections.

Systemic Therapy for invasive breast carcinoma

Historically, the decision to use systemic therapy for invasive carcinoma was based
predominantly on pathologic stage and prognostic data. Therefore, traditionally:
-If node positive, all got chemotherapy
-If Node negative and Tumor size <1cm : No chemotherapy
-If Node negative and Tumor size > 1cm, then additional factors, such lymphovascular
invasion (LVI) were used to determine whether to give chemotherapy

Biologic characteristics of the tumor (esp. ER, PR and HER2 status) also play a
significant role in clinical management:

-HER2+tumors can now be treated with Herceptin

-ER+ HER2-tumors get most response from hormonal therapies (e.g. tamoxifen)

-Oncotype Dx can be used to decide whether chemotherapy should be added to a regimen..

This test can be used to predict which patients will benefit by adding chemotherapy to
hormonal therapy.

-Triple-negative tumors are more likely to be treated with chemotherapy due to their worse
prognosis (even if the lymph nodes are negative)
HormoneTherapy Description Usesand adverse effects.
Tamoxifen A selective oestrogen Treatment of ER+ invasive and in situ breast carcinomas
receptor modular that Also used as a chemopreventive agent.
competitively binds Used in Pre-and post menopausal women.
oestrogen receptors; In
breast cancer, it acts as
an oestrogen antagonist
by preventing
proliferation of ER+
tumour cells. In bone, it
acts as an ER agonist,
leading to decreased bone
turnover and increased
bone density. It also acts
as a partial agonist in the
endometrium.
Adverse effect: May increase risk of endometrial cancer; hot flashes & flushing.

Aromataseinhibitors: Inhibitsconversion of Used in ER+ or hormone receptor unknown breast

Anastrozole [Arimidex], androgens to estrogen in Cancer in postmenopausal women.
letrozole. the periphery. Not
recommended for pre-
menopausal women,
since the decreased
estrogen causes the
pituitary to secrete more
gonadotropins,
stimulating the ovaries to
increase estrogen
production, thus
balancing the effects of
the inhibitors
Adverse effects:Hot flashes; nausea; vomiting . Increased osteoporosis CV disease risk.

Trastuzumab Monoclonal antibody Used to treat Primaryand metastatic breast cancer

(Herceptin)
Adverse effect: Cardiac toxicity
against HER-2 that binds +/-chemotherapy
to neoplastic cells
overexpressing HER-2
and mediates antibody-
dependent cytotoxicity
and destruction of tumour
cells

-ER+ HER2-tumors get most response from hormonal therapies (e.g. tamoxifen)
-Oncotype Dx can be used to decide whether chemotherapy should be added to a regimen..
This test can be used to predict which patients will benefit by adding chemotherapy to
hormonal therapy.

-Triple-negative tumors are more likely to be treated with chemotherapy due to their worse
prognosis (even if the lymph nodes are negative)