BREAST PATHOLOGY

OBJECTIVES:

 Reviewing breast architectures

 listing examples of developmental abnormalities
 enumerate the breast presenting symptoms of pathological significance
 state the inflammatory breast lesions
 define and classify the breast benign proliferative lesions
 citing the breast cancer epidemiological facts and risk factors
 listing the morphological features and variants of breast cancer
 state the stromal breast tumors
 evaluate the role of early breast cancer detection and the way to achieve
that

Normal anatomy and cellular constituents

 two major structures (ducts and lobules),

 two types of epithelial cells (luminal and myoepithelial),
 two types of stroma (interlobular and intralobular).
 Each element is the source of both benign and malignant lesions
 Six to 10 major duct orifice open onto the skin surface at the nipple
 Successive branching of the large ducts eventually leads to the terminal duct
lobular unit
 In adult women, the terminal duct branches into a grapelike cluster of small
acini to form a lobule.
 Only with the onset of pregnancy does the breast become completely mature
and functional. Lobules increase progressively in number and size. By the end
of the pregnancy the breast is composed almost entirely of lobules separated
by relatively scant stroma
 Disorders of Development:

 Milk Line Remnants: extends from the axilla to the perineum.

Supernumerary nipples or breasts result from the persistence of epidermal
thickenings disorders that affect the normally situated breast rarely arise in
these heterotopic, hormone-responsive foci, which most commonly come to
attention as a result of painful premenstrual enlargements
 Accessory Axillary Breast Tissue: extends into the subcutaneous tissue of the
chest wall or the axillary fossa (the “axillary tail of Spence”), outside of the
area clinically identified as breast tissue
 Congenital Nipple Inversion: Congenitally inverted nipples are usually of
little significance since they correct spontaneously during pregnancy, or can
sometimes be everted by simple traction should be distinguished from
acquired retraction that may associate cancer.

Clinical Presentations of Breast Diseases

 Pain (mastalgia or mastodynia):
o cyclic:- premenstrual edema
o non-cyclic:
- ruptured cyst
- infection
- physical injury
- only 10% of cancer are painful
 Palpable masses :
o normal nodularity (or “lumpiness”)
o cysts,
o fibroadenomas,
o invasive carcinomas
Only 10% of breast masses in women younger than age 40 are malignant as
compared with 60% of masses in women older than age 50.
 Nipple discharge :
o Milky discharges (galactorrhea) elevated prolactin levels
o Bloody or serous discharges are most commonly due to large duct
papillomas and cysts,
o During pregnancy, a bloody discharge can result from the rapid growth
and remodeling of the breast
o it is associated with carcinoma in 7% of women younger than age 60
but in 30% of older women.
 Inflammatory Disorders:
Acute Mastitis:

bacterial mastitis typically occurs during the first month of breastfeeding

due to cracks and fissures in the nipples. Staphylococcus aureus or, less commonly,
streptococci invade the breast tissue. If not treated the infection may spread to the
entire breast. Rarely, surgical drainage is required.

Duct Ectasia:
palpable periareolar mass that is often associated with thick, white nipple secretions
and occasionally with skin retraction This disorder tends to occur in the fifth or sixth
decade of life, usually in multiparous women.

Duct ectasia. Chronic inflammation and fibrosis surround an ectatic duct filled with
inspissated debris. The fibrotic response can produce a firm irregular mass that
mimics invasive carcinoma on palpation or mammogram.:

Fat Necrosis:
painless palpable mass, skin thickening or retraction, or mammographic densities or
calcifications. About half of affected women have a history of breast trauma or prior
surgery.

Granulomatous Mastitis:
Granulomatous lobular mastitis is an uncommon disease that only occurs in parous
women. The granulomas are closely associated with lobules, suggesting that the
disease may be caused by a hypersensitivity reaction to antigens expressed during
lactation. Treatment with steroids is sometimes effective.
Benign Epithelial Lesions:
(1) nonproliferative breast changes,
(2) proliferative breast disease,
(3) atypical hyperplasia

Non-proliferative Breast Changes (Fibrocystic Changes):

It is not associated with an increased risk of breast cancer. There are three principal
morphologic changes:
(1) cystic change, often with apocrine metaplasia: form by the dilation of lobules
and in turn may coalesce to form larger cysts. cells may underwent metaplastic
apocrine cells that mimic normal apocrine glands.
(2) fibrosis,: chronic inflammation and fibrosis contribute to the palpable nodularity.
(3) adenosis: increase in the number of acini per lobule. It is a normal feature of
pregnancy. In nonpregnant women, adenosis can occur as a focal change.
 fibrocystic changes: grossly
showed cysts. Microscopically
sowed cystic changes,
apocrine metaplasia and
stromal fibrosis

Proliferative Breast Disease Without Atypia:

Lesions characterized by proliferation of epithelial cells, without atypia, are
associated with a small increase in the risk of subsequent carcinoma in either breast.
They are predictors of risk but unlikely to be true precursors of carcinoma.

Epithelial hyperplasia. The lumen

is filled by a heterogeneous, mixed
population of luminal and
myoepithelial cell types

Sclerosing Adenosis. There are an increased number of acini that are compressed and
distorted in the central portion of the lesion histologic pattern that at times closely
mimics invasive carcinoma

Proliferative Breast Disease with Atypia:

Atypical hyperplasia is a clonal proliferation having some, but not all, of the
histologic features that are required for the diagnosis of carcinoma in situ. It is
associated with a moderately increased risk of carcinoma and includes two forms,
1. atypical ductal hyperplasia
2. atypical lobular hyperplasia
 atypical ducatal hyperplasia:
similar to hyperplasia but cells
showed atypia (pleomorphism)
yet it is focal and inadequate to
be considered as carcinoma in
situ.

Clinical Significance of Benign Epithelial Changes

Proliferative disease is associated with a 1.5- to two-fold increased risk, while
proliferative disease with atypia confers a four- to five-fold increased risk. Both
breasts are at increased risk, although the risk to the ipsilateral breast may be slightly
higher.
Risk reduction can be achieved surgical intervention or treatment with estrogen
antagonists, such as tamoxifen. However, fewer than 20% of women with atypical
hyperplasia develop breast cancer, and therefore many choose careful clinical and
radiologic surveillance overintervention:

Carcinoma of the Breast:

Carcinoma of the breast is the most common non-skin malignancy in women and
is second only to lung cancer as a cause of cancer deaths. A woman who lives to
age 90 has a one in eight chance of developing breast cancer based on the expression
of estrogen receptor and HER2 can be divided into three major biologic subgroups:
 Estrogen receptor (ER)-positive, HER2-negative (50% to 65% of tumors)
 HER2-positive (10% to 20% of tumors, which may either be ER-positive or
ER-negative)
 ER-negative, HER2-negative (10% to 20% of tumors).
A cancer is called estrogen-receptor-positive (or ER+) if it has receptors for
estrogen. This suggests that the cancer cells, like normal breast cells, may receive
signals from estrogen that could promote their growth. The cancer is progesterone-
receptor-positive (PR+) if it has progesterone receptors. Again, this means that the
cancer cells may receive signals from progesterone that could promote their growth.
These groups show striking differences with regard to patient characteristics,
pathologic features, treatment response, and outcome.
HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB)
family. Amplification or over-expression of this oncogene has been shown to play an
important role in the development and progression of certain aggressive types of breast
cancer. In recent years the protein has become an important biomarker and target of
therapy for approximately 30% of breast cancer patients
Risk Factors:
The major risk factors are related to hereditary factors, lifetime exposure to estrogen
and, to a lesser extent, environmental or lifestyle factors. Among the large number of
identified risk factors are the following:

Breastfeeding. The longer women breastfeed, the greater the reduction in risk.
Lactation suppresses ovulation and may trigger terminal differentiation of luminal
cells. The lower incidence of breast cancer in developing countries can largely be
explained by the more frequent and longer nursing of infants
Familial Breast Cancer: Approximately 12% of breast cancers occur due to
inheritance of an identifiable susceptibility gene or genes.
Mutations in BRCA1 (on chromosome 17q21) and BRCA2 (on chromosome 13q12.3)
are responsible for 80% to 90% of “single gene” familial breast cancers and about 3%
of all breast cancers. Penetrance (the percentage of carriers who develop breast
cancer) varies from 30% to 90% depending on the specific mutation present.
Mutations in BRCA1 also markedly increase the risk of developing ovarian carcinoma
and male breast cancer.

Types of Breast Carcinoma:

Almost all (>95%) of breast malignancies are adenocarcinomas that first arise in the
duct/lobular system as carcinomain situ; at the time of clinical detection the majority
(at least 70%) will have breached the basement membrane and invaded the stroma
Carcinoma in Situ:
 Ductal Carcinoma in Situ (DCIS):
is a malignant clonal proliferation of epithelial cells limited to ducts and lobules by
the basement membrane DCIS comprises 15% to 30% of carcinomas in screened
populations. DCIS can be divided into two major subtypoes
o Comedo DCIS: defined by two features: (1) tumor cells with pleomorphic,
highgrade nuclei and (2) areas of central necrosis
o Noncomedo DCIS lacks either high-grade nuclei or central necrosis. Several
patterns may be seen. Cribriform DCIS may have rounded spaces within the
ducts, or a solid DCIS pattern. Micropapillary DCIS produce bulbous
protrusions without a fibrovascular core, often arranged in complex intraductal
patterns

comido non comido cribriform

If untreated, women with small, low-grade DCIS develop invasive cancer at a rate of
about 1% per year. Tumors with high-grade or extensive DCIS are believed to have a
higher risk for progression to invasive carcinoma.

Lobular Carcinoma in Situ

LCIS is a clonal proliferation of cells within ducts and lobules that grow in a
discohesive fashion, usually due to an acquired loss of the tumor suppressive adhesion
protein E-cadherin

Invasive (Infiltrating) Carcinoma

Breast carcinomas have a wide variety of morphologic appearances. One third can be
classified morphologically into special histologic types ( including lobular
carcinoma), some of which are strongly associated with clinically relevant biologic
characteristics
The remainder are grouped together and called “ductal” or no special type
(NST).

ER-positive, HER- negative (also termed “luminal,” 50% to 65% of cancers):

Most common subtype. Rate of proliferation of cells determine the outcome of cancer
in this group.
HER2-positive (approximately 20% of cancers) is the second most common
molecular subtype of invasive breast cancer. About half of these cancers are ER-
positive. Can metastasize when small in size and early in the course, often to viscera
and brain.
ER-negative, HER2-negative tumors ( triple negative carcinoma), approximately
15% of cancers) are the third major molecular subtype. These cancers are more
common in young premenopausal women The majority of carcinomas arising in
women with BRCA1 mutations are of this type.

MORPHOLOGY:
GROSSLY:
They most commonly present as a hard, irregular radiodense mass When cut or
scraped, such tumors typically produce a characteristic grating sound (gritty) foci or
streaks of chalky-white desmoplastic stroma and occasional foci of calcification

Larger carcinomas may invade the pectoralis muscle and be fixed to the chest wall or
invade into the dermis and cause dimpling of the skin.

MICROSCOPICALLY:
Almost all (>95%) of breast malignancies are adenocarcinomas.
All types of invasive carcinoma are graded using the Nottingham Histologic Score.
Carcinomas are scored for tubule formation, nuclear pleomorphism, and mitotic rate
and the points added to divide carcinomas into grade I (well differentiated), grade II
(moderately differentiated), and grade III (poorly differentiated) types.

ER-positive, HER2-negative carcinoma. Many morphologic patterns are possible,

with grades ranging from well to poorly differentiated. Essentially all well
differentiated carcinomas are in this group.
HER2-positive carcinoma. The majority of these carcinomas are poorly
differentiated with only a few classified as moderately differentiated
ER-negative, HER2-negative carcinomas. Almost all of these tumors are poorly
differentiated and several typical histologic patterns are recognized

well differentiated moderately differentiated poorly differentiated

Special Histologic Types of Invasive Carcinoma:

 Lobular carcinoma most commonly forms hard irregular masses similar to

other breast cancers, but (as already mentioned) may also have a diffuse
infiltrative pattern with minimal desmoplasia This is the most common type of
breast carcinoma to present as an occult primary
 Mucinous (colloid) carcinoma
 Tubular carcinoma
 Papillary carcinoma,
 medullary carcinoma.
 Secretory carcinoma
 inflammatory carcinoma. these tumors show extensive invasion and
proliferation within lymphatic channels, causing swelling that mimics non-
neoplastic inflammatory lesions. These tumors are usually of high grade, but
do not belong to any particular molecular subtype

Pathological diagnosis of breast cancer:

1) Fine needle aspiration cytology: minimally invasive, rapid, cheap, less painful
and can test wide area with one skin brick. Accurate with expert examiner.
Disadvantages include many false negative cases, cannot differentiate between
insitu and invasive carcinoma and further evaluation on the aspirated material
is very difficult.

(pleomorphic cells with increased nucleocytoplasmic ratio and prominent

nucleoli)

2) Core needle biopsy: more accurate than FNA, less invasive than excisional
biopsy, but it examined relatively small area, immunohistochemistry can be
performed on the speciemen
 3) excisional biopsy of the mass: more tissue for sampling with safe margin.
4) conservative breast surgery: part of the breast excision with safe margin and
lymph node resection applicable for cosmetic reason and social acceptance
5) radical mastectomy :resection of the whole breast and axillary lymph nodes
more applicable for tumor staging.

PROGNOSIS:
in situ carcinoma understandably have an excellent prognosis
Once distant metastases are present, cure is unlikely,
 Axillary lymph node status is the most important prognostic factor for
invasive carcinoma in the absence of distant metastases
 Tumor size.
 Locally advanced disease.
 Inflammatory carcinoma
 Molecular subtype. The molecular subtype, determined by expression of ER
and HER2 and proliferation, is an important prognostic factor
 Special histologic types (tubular, mucinous, lobular, papillary, adenoid cystic)
is better than that of women with cancers of no special type.
Guidelines OF EARLY DETECTION BREAST:
 Age 20+
- Self-breast examination(optional) monthly
- Breast clinical examination every 3 yrs
-
 Age 40+
- Mammography annually(or biannually)
 High Risk m a m m ography annually + 30 + MRI
Breast Self-Examination (BSE)
Potential Benefits
o Simple and non-invasive test
o Women gain a sense of control over their health
o Become comfortable with their own breasts
o Some breast cancer has been detected with BSE
o Increased awareness of breast changes
o Lumps can be palpated with a BSE
But it may increase the number of benign breast biopsies and increases levels of
cancer-related anxiety
Mammography
Special type of low-dose x-ray imaging used to create detailed images of the breast.
Currently it is the best available population-based method to detect breast cancer at an
early stage, when treatment is most effective It can demonstrate microcalcifications
smaller than 100 μm. Often reveals a lesion before it is palpable by clinical
examination and, on average, 1-2 years before noted by self-examination can be
diagnostic or screening test.
Ultrasonography:
It is useful in detecting occult breast cancer in dense breasts. Highly operator-
dependent

Stromal Tumors:

Fibroadenoma:
Fibroadenoma is by far the most common benign neoplasm of the female breast. It is
a biphasic tumor composed of fibroblastic stroma and epithelium-lined glands;
They usually manifest as solitary, discrete, mobile mass 1 cm to 10 cm in diameter
and of firm consistency Histologic examination shows a loose fibroblastic stroma
containing ductlike, epithelium-lined spaces of various shapes and sizes

Phyllodes Tumor:
biphasic, being composed of neoplastic stromal cells and epithelium-lined glands.
However, the stromal element of these tumors is more cellular and abundant, often
forming epitheliumlined leaflike projections (phyllodes is Greek for “leaflike”).
these tumors usually are benign. Ominous changes suggesting malignancy include
increased stromal cellularity, anaplasia, high mitotic activity, rapid increase in size,
and infiltrative margins. Fortunately, most phyllodes tumors remain localized and are
cured by excision; malignant lesions may recur, but they also tend to remain
localized. Only 15% of all cases are fully malignant, metastasizing to distant sites.

LESIONS OF THE MALE BREAST:

Gynecomastia:
enlargement of the male breast, or gynecomastia, may occur in response to absolute or
relative estrogen excesses. The most important cause of hyperestrinism in the male is
cirrhosis and the consequent inability of the liver to metabolize estrogens. Other
causes include Klinefelter syndrome, anabolic steroids, and some pharmacologic
agents. Physiologic gynecomastia often occurs in puberty and in extreme old age.
Carcinoma :
less than 1% of that reported for women. It typically is diagnosed in advanced age.
Because of the scant amount of breast tissue in men, the tumor rapidly infiltrates the
overlying skin and underlying thoracic wall. Both morphologically and biologically,
these tumors resemble the invasive carcinomas seen in women. Unfortunately, almost
half have spread to regional nodes or more distant sites by the time they are
discovered.

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