BENIGN EPITHELIAL BREAST

LESIONS

GUIDE –DR CHHAYA RANI SHERVRA MAAM

SPEAKER –Dr Akanksha Srivastava
 Outline
•Anatomy
•Approach to diagnosis of breast lesions
•Non proliferative breast diseases
•Proliferative breast diseases without
atypia
•Proliferative breast diseases with atypia
•Carcinoma in situ
•Microinvasive carcinoma
ANATOMY
•STROMA
• INTERLOBULAR

less cellular, dense fibrous tissue, adipose tissue.

• INTRALOBULAR

more specialized, hormonally responsive,

delicate, myxomatous stroma, scattered lymphocytes
Normal breast, H + E stain.
Each of the lobules is surrounded by myoepithelial cells which stain for high molecular weight
cytokeratin, p63, calponin, etc. On this H and E, these cells are seen as spindled cells surrounding
the lobules.
Ducts & Lobules are lined by two cell types -

Epithelial cells (luminal) Outer Myoepithelial cells

(Secretory & absorptive) (abluminal)
CK 8, 18, 19 CK 14
EMA S-100
Mammaglobin P- cadherin
Milk fat globular membrane Smooth muscle actin
antigen
GCDFP-15 Smooth muscle myosin heavy
chain
Alpha-Lactalbumin Calponin
Maspin
Caldesmon (ductal portion)
p63
p75NTR
CD109
Immunohistochemistry of normal lobules with antibody against
smooth muscle actin decorating a continuous layer of myoepithelial
cells.
Normal breast, p63 stain.
Normal breast, calponin stain.
Staining of the myoepithelial layer is a key diagnostic criteria for identifying a process
as noninvasive.
Normal breast, ER stain.
Estrogen receptors are normally expressed in breast epithelium. Staining for estrogen and
progesterone receptors are routinely done on cases of ductal carcinoma in situ and invasive
carcinoma.
PR stain.
Typical progesterone receptor staining in breast epithelium. ER and PR are typically performed
on ductal carcinoma in situ and invasive carcinoma in order to guide chemotherapy.
Figure 23-1 Anatomic origins of common breast lesions.
 Outline
•Anatomy
•Approach to diagnosis of breast lesions
•Non proliferative breast diseases
•Proliferative breast diseases without
atypia
•Proliferative breast diseases with atypia
•Carcinoma in situ
•Microinvasive carcinoma
 Epithelial breast lesions and the risk of
developing invasive carcinoma
Pathologic lesion Relative risk (Absolute life time risk)
Non proliferative breast changes 1.0 (3%)
• Duct ectasia
• Cysts
•Apocrine change
•Mild hyperplasia
•Adenosis
•Fibroadenoma without complex features

Proliferative disease without atypia 1.5-2.0 (5% - 7%)

•Moderate to florid hyperplasia
•Sclerosing adenosis
•Papilloma
•Complex sclerosing lesions
•Fibroadenoma with complex features
Pathologic lesion RR (absolute life time risk)
Proliferative disease with atypia 4.0-5.0 (13%-17%)
•Atypical ductal hyperplasia
•Atypical lobular hyperplasia
Carcinoma in situ 8-10 (25%-30%)
•Lobular carcinoma in situ
•Ductal carcinoma in situ
Term Definition

Adenosis An increased number, or enlargement,

of glandular components

Epithelial hyperplasia An increased number of epithelial

(papillomatosis/epitheliosis) cells within preexisting glandular
components

Cysts Pathologically dilated sacs lined by

epithelium and containing fluid

Epithelial metaplasia Change from one fully differentiated

type of epithelium to another, not
normally found at that
site-squamous,apocrine
Papilloma A structure composed of fibrovascular
cores covered by epithelium
❖ NON PROLIFERATIVE BREAST DISEASES
Duct ectasia (Periductal mastitis)

• aka Plasma cell mastitis, mastitis obliterans,

granulomatous mastitis and comedo mastitis

• Premenopausal parous women

• Disorder of extralobular ducts

• Clinical findings mimic those of carcinoma

 Key histologic features
• Inspissation of lipid-rich secretions within duct lumen

• Periductal inflammation mainly of plasma cells

• Foamy histiocytes within luminal secretions

• Evidence of duct rupture

• Periductal fibrosis; obliteration

of duct lumen

• Dilatation of ducts
Fibrocystic changes

• Combination of breast changes

cyst formation

apocrine metaplasia

columnar cell change (blunt duct adenosis)

various other adenosis

Cysts

• Arises from process of lobular involution

• May be single or multiple

• Two main forms of cysts

❖ Lined by single layer of cuboidal or flattened
attenuated epithelium
❖ Lined by apocrine- type epithelium
Cysts: the one on the left is lined by cuboidal epithelium. The one on the right is lined by
apocrine epithelium
 Apocrine-type epithelium Cuboidal lining epithelium

pH high low

sodium:potassium ratio low high

Cyst fluid Similar to intracellular fluid Similar to plasma

Rate of recurrence high low

Differential diagnosis of cysts
Cystic hypersecretory DCIS

Apocrine metaplastic cells

ER: –ve
bcl-2: –ve
androgen receptor: +ve
GCDFP: +ve
Cystic hypersecretory DCIS
The variably sized cysts can contain eosinophilic homogenous secretions
similar to colloid seen in the thyroid gland.
Cystic hypersecretory DCIS
The tufted epithelial lining with nuclear atypia warrants a diagnosis of DCIS.
Apocrine metaplasia

• Frequent finding and a/w cyst formation, sclerosing

adenosis, papillomas and fibroadenomas.

• May present in single layer or may have papillary

configuration.

• Apocrine adenosis- apocrine metaplasia along with

adenosis.
Key histologic features

• Enlarged epithelial cells with abundant granular eosinophilic

cytoplasm

• May show apical luminal blebbing or snouting

• Supranuclear vacuoles or eosinophilic granules may be

present

• Variable size nuclei, may be hyperchromatic or vesicular

• Generally prominent nucleoli

Differential diagnosis of apocrine adenosis

• Invasive adenocarcinoma
Columnar cell change (blunt duct
adenosis)
Columnar cell change resulting in expansion of TDLU
Columnar cell change (columnar alteration of lobules).
Collumnar cells lining the expanded TDLU are oriented to basement
membrane,having apical cytoplasmic snouts and relatively regular ovoid
nuclei
Columnar cell change with hyperplasia.
 Flat epithelial atypia. Columnar cell change with prominent apocrine snouts and secretions.
There is a hyperplasia of the epithelial cells with more than one layer of cells evident. In some of
the ducts, the nuclei are atypical.
 Columnar Cell Columnar Cell Flat Epithelial
Change Hyperplasia Atypia

Topography Enlarged TDLUs Enlarged TDLUs Enlarged TDLUswith

with variably with variably variably dilated
dilated acini;acini dilated acini;acini acini;acini tend to
tend to be irregular tend to be irregular have round
in contour contours;involved
TDLUs often more
basophilic than
normal TDLUs

Architecture One to two layers of Cellular One to several

columnar cells stratification with layers of cuboidal to
more than two cell columnar epithelial
layers of columnar cells;complex
cells,sometimes architectural
forming tufts or patterns not
mounds;complex present
architecture
patterns not
present
Cytology Columnar cells with Columnar cells with Cuboidal to
uniform ovoid to uniform ovoid to columnar cells with
elongated elongated monomorphic-type
nuclei;nucleoli nuclei;nucleoli cytologic atypia;
absent or absent or cells may resemble
inconspicous inconspicous;hobn those of tubular
ail cells may be carcinoma
present
Atypical snouts Often present; Often present; may Often present; may
usually not be exaggerated be exaggerated
prominent or
exaggerated

Intraluminal May be May be present and May be present and

secretions present;usually not prominent prominent
prominent

Calcifications May be present Often present; may Often present; may

be psammomatous be psammomatous
Immunohistochemistry

• CK – 8, 18, 19 +ve

• ER, PR – intense & diffuse nuclear expression

• bcl-2 – strong cytoplasmic expression

• HMW-CK – ve
• Differential diagnosis
• Benign apocrine lesions

• UDH, ADH, DCIS

FIBROEPITHELIAL LESIONS
Fibroadenoma

• Most often occur between 20-35 years

• Most common cause of benign breast lump

• Most measure b/w 1 – 2 cm

• Grossly- sharply demarcated firm mass

• cut surface lobulated with slit-like spaces

 Contrasting gross features

Infiltrating Carcinoma Fibroadenoma

Outline Irregular Smooth;may be rounded

or lobulated

Relationship to Fixed;concave cut surface Mobile;protruding,

surrounding tissue convex surface

Texture/consistency Hard,gritty(unripe pear) Rubbery,uniform,;may

have a clefted cut surface

Color Variable;often streaked Variable but uniform in

with yellow(elastic tissue) any one lesion;often
glistening
Fibroadenoma: gross has lobulated cut surface
Key features
• Composed of stromal and epithelial elements

• Intracanalicular and/or pericanalicular patterns

• Epithelium-
usual ductal hyperplasia
apocrine metaplasia
atypical hyperplasias
carcinoma in situ rarely
• Stroma -

myxoid change

hyalinization with or without calcifications

Fibroadenoma: Intracanicular pattern ( nodular structure is evident)
Fibroadenoma: combination of epithelial clefts and cellular intralobular stroma
Fibroadenoma : pericanalicular pattern
Fibroadenoma variants

Complex Fibroadenoma

▪ Present in 20% of cases

▪ Cysts larger than 3 mm

▪ Sclerosing adenosis

▪ Epithelial calcifications

▪ Papillary apocrine change

Juvenile fibroadenoma

▪ Present in young girls and adolescents

▪ More stromal cellularity

▪ Greater degree of epithelial hyperplasia

▪ Rapidly growing

▪ No recurrence after complete excision

• Differential diagnosis
Phyllodes tumors

Mammary hamartoma

Fibromatosis
Hamartoma of breast: Ill-defined lobular structure and ducts are situated within hyalinized
connective stroma
 •Tubular adenoma

✔ Young women
✔ Gross findings and clinical features-same as
fibroadenoma
✔ Hallmark-
:closely packed round to oval glands or tubules
:little intervening fibrous stroma
:double cell lined tubules
:no nuclear atypia
:infrequent mitosis
Tubular adenoma: Numerous small tubular structure composed mainly of secretory epithelial
cells but with less obvious myoepithelial cells, are set in a fine cellular stroma
• Differential diagnosis

Fibroadenoma

Tubular carcinoma
Tubular carcinoma: tubular structures with central lumina infiltrating within a desmoplastic
stroma
Tubular carcinoma: tubules are lined by single layer of small regular nuclei and little nuclear
pleomorphism
 • Lactating adenoma

✔ Aka- nodular lactational hyperplasia

✔ Present only in pregnancy and postpartum period

✔ Large dilated acini showing typical alveolar pattern

✔ Presence of luminal secretion

Lactating adenoma, low power.
The orderly arrangement of glands is evident at low power.
Lactating adenoma, high power.
The secretory nature is illustrated by the clear vacuolization and central
luminal contents.
Phyllodes tumor

• Predominantly-middle age and elderly women

• Gross:-

▪ well circumscribed

▪ bosselated contour

▪ firm lobulated mass

▪ cut surface-whorled pattern, resembling compressed leaf

bud

▪ foci of hemorrhage and necrosis

Benign Phyllodes tumor. Gross image.
These tumors are well circumscribed with a firm bulging cut surface. Larger lesions may have the
characteristic whorled pattern and curving clefts from which the tumor derives its name.
• Microscopic finding:-

▪ Cleft like spaces and ducts lined by inner epithelial and

outer myoepithelial cells

▪ Hypercellular stroma

▪ Focal epithelial hyperplasia may be seen

Phyllodes tumor: large leaf like structure form cleft lined by epithelial cells associated with
cellular stroma
▪ Specific patterns such as:-

Rhabdomyosarcoma

Chondrosarcoma

Osteosarcoma

▪ Squamous metaplasia more often than fibroadenoma

▪ Apocrine metaplasia-less frequent

• Differential diagnosis:-

Fibroadenoma

Fibromatosis

Primary sarcoma

Metaplastic carcinoma
 Outline
•Anatomy
•Approach to diagnosis of breast lesions
•Non proliferative breast diseases
•Proliferative breast diseases without
atypia
•Proliferative breast diseases with atypia
•Carcinoma in situ
•Microinvasive carcinoma
Sclerosing adenosis

• Pre- or peri-menopausal age

• Presentation:-

✔ Ill-defined mass

✔ Pain and tenderness

✔ mass lesion – nodular sclerosing adenosis

• Microcalcification
• Key features:-

▪ Lobulocentric proliferation of small glands and tubules

▪ Variable compression by fibrotic stroma

▪ Two layered structure is usually visible

▪ Obliteration of acinar lumina

▪ Associated calcification common

▪ Epithelium typically cuboidal or flattened

▪ May show apocrine metaplasia or atypical apocrine

changes

▪ May be involved by DCIS or LCIS

Sclerosing adenosis: nodular disorganized proliferation of epithelial glands and intralobular
Microglandular adenosis

• Benign lesion

• Age: 45-60 yrs

• Palpable mass with relatively sharp margin

• Cut surface: Ill-defined area of fibro-fatty tissue

• Microscopy:

▪ Proliferation of haphazardly arranged small round acinar

structures

▪ Stromal and adipose tissue infiltration

▪ Single layer of lining epithelium

▪ Epithelial cells-cuboidal,clear or eosinophilic cytoplasm,

lack apical snouts
▪ Mitosis absent or rare

▪ No associated stromal reaction

▪ Intraluminal eosinophilic, PAS +ve & diastase resistant

secretion
 • Immunohistochemistry:-

✔ S-100 protein : +ve

✔ Cathepsin D : +ve

✔ EMA, ER, PR, HER2/neu: -ve

Radial scar/ complex sclerosing lesion

• Pre- and peri-menopausal age

• Multiple and frequently bilateral

• Stellate lesions having fibro-elastotic centre

• Lesions measuring

1-9 mm: radial scar

>/= 10mm : complex sclerosing lesion

• May mimic invasive carcinoma mammographicaly and

upon gross and microscopy
❖ Key features:- RADIAL SCAR

• Central fibroelastotic core with entrapped glands

• Glands surrounded by myoepithelial layer

• Peripheral ducts or lobules radiates circumferentially from

central core

• Varying degree of adenosis, hyperplasia, papilloma, and

cysts
❖ Key features: COMPLEX SCLEROSING LESIONS

• Fibrotic or fibroelastotic stroma containing entrapped

glands

• Glands surrounded by myoepithelial layer

• Associated ducts or lobules show varying degree of

adenosis, hyperplasia, papillomas and cysts

• Generally larger and with a less organized appearance

than radial scars
 Sclerosing Radial Scar Tubular Microglandu-la
Adenosis Carcinoma r Adenosis

Glandular Lobular outline, Flower head Haphazard Haphazard,

distribution rounded stellate usually no
and overall lobular outline
pattern
Glandular Variable, with Centrally small, Angulated with Rounded with
shape small, with variably open lumina open lumina
compressed shaped
lumina lumina;periphe
rally dilated

Intraluminar Rare Centrally rare Uncommon Striking,

secretion colloid-like

Lining Two cell types Two cell types One cell type One cell type
epithelium
 Sclerosing Radial scar Tubular Microglandul-ar
adenosis carcinoma adenosis

Cytologic atypia Nil Nil Usually mild Nil

Cytoplasmic Uncommon Centrally Present Absent

protrusions uncommon
(apical snouts)

Luminal bridging Absent Centrally absent Frequently Absent

present

Basement Present Present Absent Present

membrane

Stroma Fibrous or Centrally hyaline Desmoplastic Collagenous or

hyaline with elastosis (reactive and fatty;
cellular) hypocellular
Intraductal papilloma

Key histologic features:-

• Variable fibrotic fibrovascular cores attached by a stalk

• Outer cuboidal or columnar secretory cell layer

• Inner myoepithelial layer

• May exibit foci of UDH, ADH,or DCIS

• Apocrine metaplasia and/or squamous metaplasia

Duct papilloma: A large duct papilloma distends and fills a duct space
Duct papilloma: The papillary fronds have a fibrovascular core and are covered by a bilayer of
myoepithelium and epithelium
 Central papilloma Peripheral papilloma

Duct of origin Large ducts TDLU

number single multiple

age 30-50 yrs Slightly younger age

presentation Bloody nipple discharge Less often

Subareolar mass

gross Circumscribed nodule Not identifiable

within a dilated duct or
cyst
Infarction Frequently undergo infrequent

Risk of carcinoma No increased risk Increased risk

 Intraductal papilloma Papillary DCIS

Cell types Epithelial and Epithelial only

myoepithelial

Cell orientation haphazard Uniform, perpendicular to

fibrovascular stalks;solid,
cribrifom, or
micropapillary pattern

nuclei normochromatic hyperchromatic

Stroma of papillae Prominent; fibrosis with delicate

epithelial entrapment

Apocrine metaplasia present absent

Proliferation in adjacent hyperplasia DCIS

ducts
 Benign papilloma Papillary carcinoma

Firovascular cores Well developed Usually delicate or absent

Luminal epithelium May show features of benign Variable in

hyperplasia with oval nuclei thickness;sometimes tall
perpendicular to central core
Myoepithelium Present, usually prominent Generally absent;
occasionally focally present,
but no continuos layer

Nuclei Benign Malignant features present,

but may be subtle;
sometimes open and clear
Apocrine Frequent Rare
metaplasia
Surrounding tissue Often benign lesions Ductal carcinoma in situ, or
even invasive carcinoma may
be present
Clinical Nipple discharge frequent Nipple discharge less
presentation common; usually presents as
mass
Nipple adenoma

• Most common in 5th- 6th decades

• Relatively circumscribed glandular proliferation involving

nipple stroma

• Diffuse papillary ductal epithelial proliferation, often

intermingled with adenomatous areas

• Double layer cell arrangement

• Stromal fibrosis may entrap glandular epihelium-

pseudoinfiltrative pattern
Nipple adenoma. In this photograph of a nipple specimen, a rounded gray-white nodule
is seen
immediately below the nipple skin.
 Nipple adenoma Syringomatous Tubular carcinoma
adenoma
Site Areolar and Subareolar Breast parenchyma
subareolar
Glandular Circumscribed Haphazard Haphazard
distribution

Glandular shape Variable Comma-shaped Rounded and

angulated
Lining epithelium Two cell types Two cell types One cell type

Cytologic atypia Uncommon Absent Present

and mitosis
Luminal briding Absent Absent Often present

Basement Present Present Absent

membrane
Squamous Sometimes present Present Absent
metaplasia
Changes in Papillary Nil DCIS may be
adjacent ducts proliferation present
Surronding stroma Normal Normal Reactive
Traditional terminology Ductal intraepithelial neoplasia
terminology

Usual ductal hyperplasia Usual ductal hyperplasia

• CLASSIFICATION
Flat epithelial atypia Ductal intraepithelial neoplasia, grade 1A
(DIN 1A)

Atypical ductal hyperplasia DIN 1B

Ductal carcinoma in situ, low grade (DCIS DIN 1C

grade 1)

Ductal carcinoma in situ, intermediate DIN 2

grade (DCIS grade 2)

Ductal carcinoma in situ, high grade (DCIS DIN 3

grade 3)
 Usual ductal hyperplasia
• Hyperplasia is simply defined as presence of more than
two cell layers in ducts and lobules.
• Ductal hyperplasia that is not atypical, is referred to as
‘usual’ type.
Mild Moderate Florid or marked

•3-4 cell layers thick, •>4 epithelial cell layers •Overall proliferation is
exclusive of thick more cellular and
myoepithelium complex than moderate
•Flat or papillary or
•Usually flat or slight micropapillary •Lumen of affected ducts
papillary increase in hyperplasia, bridging, are appreciably
epithelial thickness fenestration distended
(epithelial cells donot Overlapping nuclei, Papillary , bridging
cross the involved streaming, swirling pattern, fenestrations
Architectural features

• Irregular fenestrations
• Peripheral fenestrations around a central bolus of cells
is preserved
• Stretched or twisted epithelial bridges (nuclei parallel
to long axis of bridges)
• Streaming
• Uneven distribution of nuclei and overlapped nuclei
 Cytologic features

• Heterogenous cell population

• Variation in cell size, shape, and orientation

• Cell borders poorly defined

• Areas of nuclear overlapping

• Oval & normochromatic nuclei with small, single,

indistinct nucleoli; scant/-nt mitosis
• Immunohistochemistry-
• Markers for myoepithelial cells +ve

(myoepithelium markers –ve in an intraductal

proliferation is almost certainly in situ carcinoma)

• HMWCK +ve i.e. CK5/6- mosaic pattern

• E-cadherin +ve

• ER +vity higher than normal breast

 Usual epithelial hyperplasia Well-differential/low grade
Ductal Carcinoma In Situ

Pattern Varied Recognised patterns of ductal

carcinoma in situ

Spaces Irregular, slitlike, mainly Regular, rounded, rigid

peripheral throughout space

Bridges Long axis of nuclei parallel to Long axis of nuclei haphazard or

bridre at right angles(”roman arches”)

Streaming pattern Yes(sometimes subtle) No

Cells Polymorphic; myoepithelial, Monotonous; epithelial cells are

lymphocytes peripheral proliferating layer(except
myoepithelial layer often peripheral myoepithelium, which
obvious, sometimes may be stretched, attenuated,
hyperplastic incomplete, and inconspicous.
Non-proliferative)

Apocrine May be focally present absent

metaplasia
 Usual epithelial hyperplasia Well-differentiated/low-gra
de ductal carcinoma in situ

Cell margins Often indistinct Usually more defined

Nuclear morphology No malignant features Malignant features present

but may be subtle

Nuclear spacing Irregular, often overlapping Evenly spread

Necrosis/hemorrhage Rare May be present, sometimes

marked

Periductal fibrosis and Uncommon May be present, sometimes

inflammation marked

Adjacent changes May merge with other benign May be adjacent to benign
lesions lesions but does not
merge(except for multiple
papillmas)
 Outline
•Anatomy
•Approach to diagnosis of breast lesions
•Non proliferative breast diseases
•Proliferative breast diseases without
atypia
•Proliferative breast diseases with atypia
•Carcinoma in situ
•Microinvasive carcinoma
Atypical ductal hyperplasia (DIN1B)

Architectural features
• Present in a/w atypical cell population

• Bridges and arcades of uniform thickness

• Micropapillations

• Cribriform pattern with polarizations of cells around lumen

• Solid pattern may be seen

• Other areas have patterns of UDH

 Cytologic features-

❑ Cell population similar to low grade DCIS a/w foci of UDH

• Monotonous , uniform rounded cell population
• Ovoid to rounded nuclei, increased N/C ratio, nuclear
hyperchromasia, irregular nuclear chromatin &
enlarged, prominent nucleoli
• Cells may have distinct cell borders
• Cells tend to polarize around microlumens
• Intracytoplasmic lumina +/-
• Intracytoplasmic mucin very rarely present
• Mitosis readily identified
 • Criteria suggested by Page to identify DCIS (and
ADH) are-

1. A uniform population of cells

2. Smooth geometric spaces between cells or

micropapillary formations with even cellular placement

3. Hyperchromatic nuclei
• Architecturally and cytologically, ADH is similar to DCIS
(low grade)- the diagnosis of DCIS is made if :-

❖ 1 or more completely involved duct/ductular cross

sections measuring atleast 2 mm in maximum
diameter
or
❖ Characteristic cytology and architecture present
completely in atleast 2 duct spaces

• Any lesion falling short of this is classified as ADH.

 Atypical lobular hyperplasia Lobular Carcinoma In Situ

Distention of acini Less distended and distorted Distended and distorted

Degree of involvement Often only part of lobular unit Major part of one or more
lobular units

Luminal obliteration Incomplete, If complete, no Complete, except Pagetoid

distention

Cellular composition Less monotonous;may be Round, regular,

variable cell types; less monotonous; one cell type;
regularly spaced evenly spaced
Cellular cohesion More cohesive Non cohesive

Spread Pagetoid spread may occur, Pagetoid spread and other

but less well developed forms