Breast pathology

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 Contents
• Introduction
• Developmental anomalies
• Inflammation (mastitis)
• Stromal lesions (fibroadenoma and phyllodes tumor)
• Benign Epithelial Lesions (non proliferative,
proliferative ± atypia)
• Carcinoma of the Breast

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 Introduction
• 2 breasts with the following sets of characteristics
• 2 mammary ridges; Right and left(highly modified,
evolved apocrine sweat glands)
• 2 structures; TDLU (functional unit) + large ducts
(transport)
• 2 cell lining; Epithelial and myoepithelial
• 2 stroma; Interlobular and intralobular
• 2 ovarian hormone; Progesterone and estrogen
• 2 pituitary hormone; Prolactin and oxytocin

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15 to 20

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 Anatomic origin of common breast lesions

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 Symptoms
• Mastalgia or mastodynia is the most common
• Discrete palpable masses are the second most
common
• Nipple discharge is a less common but is a concern
when it is spontaneous and unilateral; Bloody or
serous discharges are most commonly associated with
benign lesions like solitary large duct papilloma, cysts,
etc… or rarely carcinoma.

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 Polymastia
Amastia Macromastia

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Galactorrhea
• Milk production outside of
lactation
• Abnormal if it persists for longer
than 6 months after childbirth
or discontinuation of
breastfeeding
• Nipple stimulation (common
physiologic cause),
prolactinoma of the anterior
pituitary (common pathologic
cause), Hypothyroidism and
drugs

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 Acute Mastitis

• S aureus is most
common pathogen
followed by
streptococci.
• Staphylococci - single or
multiple abscesses
• Streptococci - cellulitis
• Treatment with
antibiotics and continue
breastfeeding.

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 Squamous metaplasia of lactiferous ducts
(SMOLD)
• = recurrent subareolar abscess, periductal mastitis,
and Zuska disease
• > 90% are smokers
• Relative deficiency of vitamin A associated with
smoking or toxic substances in tobacco smoke alters
the differentiation of the ductal epithelium
• Painful erythematous subareolar mass with nipple
retraction
• Rarely develop in to squamous cell carcinoma
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Duct ectasia
• Dilation of the subareolar ducts
• Palpable periareolar mass that is
often associated with thick, white
(green-brown) nipple secretions
and occasionally with skin
retraction
• In the fifth or sixth decade of life,
usually in multiparous women
• Not associated with cigarette
smoking

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Fat necrosis

• Necrosis of breast fat

• Usually related to
trauma (like biopsy,
surgery etc….). Up to
50% of patients may
not report trauma.
• Presents as a mass on
physical exam or
abnormal calcification
on mammography (due
to saponification).
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 Fibroadenoma(FA)
• Commonest type of benign tumor of female breast
• Easily movable spherical masses in the breasts of
young women in the 20- to 35-year- age group
• Hormonally responsive (grows during pregnancy and
late luteal phase, regresses after menopause) may be
painful during the menstrual cycle.
• By it self benign with no increased risk of carcinoma

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 Phyllodes tumor

• FA like tumor with

overgrowth of the fibrous
component
• Most over 40 years of age
(postmenopausal women)
• Arises de novo (not from FA)
• The stroma of is hypercellular,
and in 10% of cases it may be
overtly malignant
(overexpression of HOXB13).
• Gain in ch1q

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Non proliferative Breast Changes (Fibrocystic
Changes/FCC)
• Most common change in the
premenopausal breast
• 20 and 40 years; peaks at or just
before menopause
• Presents as vague irregularity of
the breast tissue ('lumpy bumpy
breast') usually multiple and
bilateral, mammographic
densities/calcification or nipple
discharge
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Non proliferative Breast Changes (Fibrocystic
Changes)
• Termed nonproliferative to indicate that they are not
associated with an increased risk of breast cancer
but some of these changes do involve increased
proliferation (adenosis with “flat epithelial atypia”)
and may even be associated with clonal genetic
aberrations (deletions of ch16q)

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 Hormonal imbalance: ↑estrogen and ↓
progesterone

Three principal patterns of morphologic change:

1. Cyst formation, often with apocrine metaplasia;
2. Fibrosis; and
3. Adenosis Apocrine
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metaplasia
 Proliferative Breast Disease Without Atypia
• Commonly detected as mammographic densities,
calcifications, or incidental findings in biopsies
• Considered predictors of risk, rather than direct
precursors of carcinoma.

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Several morphologically distinct patterns
• Epithelial hyperplasia- >2 luminal cells, usually an
incidental finding.
• Sclerosing adenosis – acini ≥2x of normal + distorting
fibrosis , come to attention as a palpable mass, a
radiologic density, or calcifications.
• Complex sclerosing lesion (radial scar) = sclerosing
adenosis + papilloma + epithelial hyperplasia.
• Papilloma

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 Radial Scar

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Intraductal papilloma
• Papillary growth, usually into a
large duct typically beneath areola.

• Classically presents as Unilateral

serous or bloody nipple
discharge in a premenopausal
woman.

• Benign, but associated with 1.5 to

2.0 x risk of carcinoma, higher risk
if multiple papilloma.

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 Characterized by fibrovascular projections lined by
epithelial (luminal) and myoepithelial cells

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 Morphologic DDX

Papilloma Papillary carcinoma

Epithelial cell Present Present
Myoepithelial Present Absent
cell
Mainly in Premenopausal Postmenopausal

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 Gynecomastia
• Gr; gyne, woman, and mastós, “breast”
• Breast enlargement in males is usually the result of an
increased estrogen/ androgen ratio.
• Physiologic in newborn, pubertal(2/3 of them), and
elderly males.
• Pathologic causes include cirrhosis, Klinefelter syndrome
(40% of them), testicular tumors, and drugs
(Spironolactone, Cimetidine, Finasteride, Ketoconazole).
• The relative risk of breast cancer is increased in men with
gynecomastia, although the absolute risk is relatively
small.
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Lobule formation is almost never observed
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 Proliferative Breast Disease With Atypia
• Atypical hyperplasia is a clonal proliferation having
some, but not all, of the histologic features of
carcinoma in situ.
• Two forms, atypical ductal hyperplasia (ADH) and
atypical lobular hyperplasia (ALH).

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 Carcinoma in situ
• Latin phrase that means "on-site".
• Neoplastic cells (malignant) limited to ducts and
lobules by the basement membrane, doesn’t invade
into lymphatics and blood vessels and cannot
metastasize.
• Two types DCIS and LCIS.
• Both may display a variant called Paget's disease of
the nipple

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 Ductal carcinoma insitu (DCIS)
• Malignant proliferation of cells in ducts with
no invasion of the basement membrane.
• 10-20% bilateral.
• Does not usually produce a mass and often
detected as calcification on mammography.
• Grade: low, intermediate, and high
• Progression varies by grade: for low grade, 0-
10% progress to invasive disease vs. 40% for
high grade.

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 Mammography
Microcalcifications

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Linear and branching calcifications
 Morphologic types of ductal carcinoma in situ
(DCIS)

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 Lobular carcinoma in situ (LCIS)
• Malignant proliferation of cells in lobules with no invasion
of the basement membrane.

• Does not produce a mass or calcifications and is usually

discovered incidentally on biopsy.

• Characterized by discohesive cells lacking E-cadherin

• Often multifocal (75%) and bilateral (40%)

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 E-cadherin–positive normal Proliferation of small , uniform
luminal cells and E-cadherin– cells with in the ducts and lobules
negative LCIS cells spreading that fill , distend or distort at least
along the basement 50 % of acinar units of a single
membrane. lobule

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 Paget disease of the
nipple
• DCIS and rarely LCIS can
spread from lactiferous ducts
in to the contagious skin of
nipple with out violating the
basement membrane barrier.
• Appears eczematous or
ulcerated
• Paget disease of the breast is
almost always associated with
an underlying in situ lesion or
carcinoma (50% to 60% have
underlying lump or mass).

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 Paget cells are
PAS+, mucin+,
keratin+, and
S100-/+.

Biopsy better
than cytology
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Breast cancer
• Most common and second deadly
cancer in women
• 1 in 8 (9) women will develop
breast cancer during her life span.
• Breast cancer is rare in women
younger than age 25 and
increases in incidence rapidly
after age 30
• Majority occur in
postmenopausal women

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 Left >> right

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 Familial/hereditary breast cancer
• ~ 5%–10% of all breast cancers
• Only 2–4% of families with familial breast cancer have
an identified mutation in either BRCA-1 or BRCA-2
genes (i.e. hereditary)
• Clinical features; multiple first-degree relatives with
breast cancer, tumor at an early age, and multiple
tumors in a single patient.

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 > 1,000 different
mutations identified

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 Prophylactic Surgery

• Bilateral mastectomy reduces breast cancer risk by 97%

• Bilateral salpingo-oophorectomy reduces breast cancer

risk by 50% and papillary serous carcinoma risk by 50-
96%

• There remains a 4-5% risk of papillary serous carcinoma

of peritoneum remains

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Male breast cancer
81% are ER-positive
• Represents < 1% of all breast
cancers(1:100=M:F)
• Subareolar mass in older males
• May produce nipple discharge
• Associated with BRCA2 mutations
and 3–8% associated with Klinefelter
syndrome and decreased testicular
function
• Often presents at high stage since
minimal breast substance
• Share many features of female
carcinoma with regards to risk factor,
histologic type, and prognosis.

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 Morphologic types of invasive carcinoma.
• Invasive ductal carcinoma no special type (70-80%).

• Special types: lobular(10%), Medullary, Mucinous,

Tubular, Papillary, Metaplastic carcinoma, etc…

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 Invasive ductal carcinoma no special type
• Nipple contraction. White • Irregular solid groups of cells in a
tissue represents the fibrous dense fibrous stroma, with an
(scirrhous) reaction associated lymphocytic infiltrate

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 Infiltrating lobular carcinoma:
• Bilateral and multifocal
• Strands of single cells (Indian
file/single file) invade fibrous
stroma without induction of a
desmoplastic response

lack of E-cadherin

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 Tubular carcinoma

Relatively good prognosis

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 Mucinous (colloid) carcinoma
Tumor cells floating in a mucus pool

Tends to occur
in older
women
(average age is
70 years)

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Medullary Carcinoma
• Medulla is Latin for “marrow”;
soft, fleshy consistency
• Overexpression of E-cadherin
and basal like gene expression
• 67% there is hypermethylation
of the BRCA1 promoter
• Slightly better prognosis than
NST and poor than other
special type
 Invasive Paget disease

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 Inflammatory breast cancer(carcinoma
erysipeloides )Lymphatic obstruction by tumor cells
Presents classically as an inflamed, swollen
breast with no discrete mass;

Can be mistaken for acute mastitis

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 Triple test/assesment

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Imaging
 Relative risk of breast cancer increases with increasing
mammographic breast density

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Pathology
 Predictive and prognostic factor
• Prognosis is based on grade and stage (TNM).
• Predictive factors predict response to treatment
(ER,PR,Her2)

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 Molecular Classification
• Based on gene expression profiling, breast cancers cluster
into three main groups:
• Luminal A (40-55%): ER +ve and HER2/neu –ve; generally
slow growing
• Luminal B (15-20%): TPBC; higher grade and more likely
to have LN metastasis.
• Basal-like (13-25%): TNBC; medullary carcinoma,
metaplastic carcinoma, carcinomas with a central fibrotic
focus and cancer BRCA-1 mutations
• HER2 enriched (7-12%): ER -ve but overexpress
HER2/neu
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Because these molecular subtypes correlate reasonably
well with ER and HER2 protein expression

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 Predictive factor
Treatment ER PR Her2 Molecular type
response
Very good + + - Luminal A

Good + + + Luminal B

Poor - - + Her2 enriched

Very poor - - - Basal like

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 Other cancers/malignancy account for < 5%
• Angiosarcoma

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Lumpectomy + Radiotherapy  Angiosarcoma

Secondary angiosarcoma - Superficial Primary angiosarcoma - deep

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Radical mastectomy  Lymphedema  lymphangiosarcoma (Stewart-Treves
syndrome (STS)

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 TIP

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The life time risk for breast cancer in
female is 1:9 = 11.1% which is the absolute
risk. Patient with ADH or ALH has 4.5X
increased risk which is relative risk. The
likelihood of developing breast cancer in in
this patient is 11.1% x4.5 = 50%
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