It is a seminar on approach to proliferative diseases of breast according to the latest edition of WHO , with explanation for each topic with histopathology and IHC images. At the end approach to the signs and symptoms of patients leading to the diagnosis is explained.

1. -Dr.Yogeeta Tanty

2. The breast is a
modified sweat gland
located in the
superficial
fascia of the anterior
chest wall.

3. BREAST
Dynamic structural
changes throughout
life
Symbol of femininity-
social, cultural, and
personal .
Nutritional support
to another
individual,the infant.

6. Terminal ductal lobular unit,
consists of a duct
with branching acini embedded in
connective tissue.
Normal adult female breast. The
lactiferous ducts show a branching
shape .

7. Normal duct or acinus with a basally located myoepithelial cell layer (cells with
dark, compact nuclei and scant cytoplasm) and luminal cell layer .

8. NONPROLIFERATIVE
BREAST CHANGES
• Cystic change often with
apocrine metaplasia
• Fibrosis
• Adenosis in pregnancy.
• Others- Lactational
adenomas
• Flat epithelial atypia
PROLIFERATIVE BREAST
DISEASE
• Without atypia
• Epithelial hyperplasia
• Sclerosing adenosis
• Complex sclerosing lesion
• Papilloma
• With atypia
• Atypical ductal hyperplasia
• Atypical lobular hyperplasia
-Robbins

10. Proliferative Breast
Disease - Robbins
Without Atypia
 Epithelial hyperplasia
 Sclerosing adenosis
 Radial scar /complex
sclerosing lesion
 Papilloma
With atypia
 Atypical ductal
hyperplasia
 Atypical lobular
hyperplasia
WHO classification
 Benign proliferations and
precursors
 Usual ductal hyperplasia
 Columnar cell lesions ,FEA
 Atypical ductal hyperplasia
 Adenosis and benign
sclerosing lesions
 Sclerosing adenosis
 Apocrine adenosis
 Microglandular adenosis
 Radial scar/compex sclerosing
lesion
 Papillary neoplasms
 Intraductal papilloma
 Non invasive lobular neoplasia
 Atypical lobular hyperplasia

12.  It is an architecturally ,cytologically and molecularly
heterogeneous benign epithelial proliferation
primarily involving terminal duct lobular unit.
 On mammography ,microcalcifications are seen if
present.

13. UDH- cohesive proliferation of epithelial and myoepithelial cells .
The nuclei are normochromatic, with slight overlap .
Clefts/secondary
lumen are
preferentially
located at the
periphery
The nuclei surrounding the secondary lumina
tend to run parallel to the lumina
The cells have
indistinct
borders
,syncytial or
streaming
pattern

14.  The nuclei are variably sized, often with grooves and
intranuclear cytoplasmic pseudoinclusions.
 Proliferation can also be of solid pattern .
 Micropapillations have a broad base , narrow or pinched
tip with hyperchromatic ,almost pyknotic looking nuclei.
 Apocrine metaplastic epithelial cells can be seen.

15.  IHC-Positive for
 low molecular weight cytokeratins CK 7 ,CK 8, CK 18-
luminal type
 high molecular weight cytokeratins CK 5/6 ,CK 14
,ck903- basal type (heterogenous or mosaic pattern)
 ER staining –positive ( heterogeneous pattern)

16. Triple staining 1)LMW CK (red cytoplasmic staining) 2)HMW CK (brown
cytoplasmic stain) 3)myoepithelial cells at periphery show P63 nuclear staining
(brown) B. ER – nuclear staining of variable intensity

17.  It is defined as a relative increase in the number of acinar
units per lobule (TDLU).
 Non- neoplastic lobulocentric proliferation of tubules and
acini .
 The two cell population and basement membrane are
maintained.
 Benign sclerosing lesions additionally have a central
sclerotic nidus from which the glandular structures radiate.

18.  It is a lobulocentric proliferation of benign glandular
structures distorted by fibrosis .
 Macroscopic appearance
 small, usually grossly inapparent
 gritty to cut .
 Epithelial cells appear more atrophic with preferential
proliferation of myoepithelial cells .
 IHC- p63,calponin,SMMHC for myoepithelial cells.

19. small acinar or tubular structures
seen compressed or distorted by
stromal collagen,resulting in
solid or cord like growth pattern.
Microcalcifications can
be present in either
fibrotic stroma or
glandular lumina .

20. Sclerosing adenosis extending
into fat.
B: A calponin stain highlights the
myoepithelial cells .

21. Sclerosing adenosis glands are seen in the perineurium
without invading the nerve.

22.  Apocrine change is the most common metaplastic
change ,
 in association with sclerosing adenosis the lesion is
called apocrine adenosis.
 Macroscopic appearance- grossly inapparent,
some cases- rubbery grey mass
gritty to cut

23.  Cytoplasm may contain supranuclear golden brown
granules that are PAS and prussian blue(iron) positive
IHC-
 AR,EMA ,CK 8/ 18 -positive
 ER and PR- negative .

24. Apocrine metaplasia in sclerosing adenosis.
The apocrine cells cells show abundant granular eosinophilic cytoplasm
,nuclear enlargement and prominent nucleoli.
Plump apocrine epithelial cells seen.

25.  It is a haphazard proliferation of small round glands
consisting of a single layer of epithelial cells .
 Macroscopic appearance-can look like normal breast or a
poorly defined nodularity or mass.
 Luminal spaces are open and contain colloid like
eosinophilic PAS positive diastase resistant secretions .

26.  IHC-
 S 100 ,cathepsinD, EGFR (HER1)- positive
 EMA,ER,PR,ERBB2(HER2)- negative

27. Microglandular adenosis. A: Regular ,small ,round glands lined by cuboidal cells with
small nuclei and amphophilic cytoplasm , diffusely distributed in fibrofatty stroma.
Myoepithelial cells are absent.
clear cell
variant.

28. Microglandular adenosis. A: Prominent basement membrane B: The basement
membrane is highlighted by the silver reticulin stain in this clear cell MGA. C:
Laminin reactivity outlines each gland in MGA. D: Laminin immunoreactivity in
sclerosing adenosis is shown for comparison.

29.  It is a benign lesion with fibroelastosis and entrapped
glandular structures with or without proliferative epithelial
lesions.
 Radial scars are small lesions typically with stellate
configuration,
 Complex sclerosing lesions are larger and more
disorganized.
 On imaging, the irregular stellate configuration are
radiolucent centre which is indicative of radial scar as
opposed to carcinoma.

30.  Multiple and are frequently bilateral.
 Macroscopic appearance-irregular area of firmness
that can exhibit yellow streaks reflecting the
elastotic stroma.
 Can be associated with benign changes like cysts,
usual ductal hyperplasia ,sclerosing adenosis etc.

31.  Two cell layer is retained but the myoepithelial
cells are occasionally attenuated.
 In complex sclerosing lesions- sclerosing
micropapillomas and various patterns of epithelial
proliferation is seen.
 IHC -p63 ,calponin, SMMHC for myoepithelial
cells.

33. Radial sclerosing lesion. (A)
Irregular
central mass . (B) Grossly the
mass appears fibrotic ,
irregular borders, but it is not
as firm as an
invasive carcinoma. (C) The
mass consists of a central
nidus of small
tubules entrapped in a
densely fibrotic stroma with
numerous projections.
Around the periphery
,various degree of ductal
dilatation noted.

34.  It is a benign breast lesion arising within a duct
composed of papillary projections with fibrovascular
core.
 Central (solitary ) –
 unilateral, circumscribed retroareolar mass , dilated
duct , associated with serosanguineous nipple discharge
,rarely microcalcifications .
 Peripheral (multiple) –
 microcalcifications, nodular prominence of ducts on
mammography.

35.  Well circumscribed round tumors of papillary fronds
attached by one or more pedicles to the wall of the dilated
duct.
 The size varies from few mm to > 5cm.
 Focal necrosis or hemorrhage may be present.
 Apocrine change ,squamous metaplasia can be seen.
 IHC –SMMHC ,calponin, CK 5 ,CK14 ,p63 for myoepithelial
cells
 UDH if present - non uniform ER staining.

36.  Sclerosis is commonly seen and can obscure the
underlying papillary architecture
-sclerosing papilloma .
 Foci of ADH or DCIS are seen more commonly in
peripheral papillomas.
 Myoepithelial cells may be scant/absent from this
foci.

37. According to some authorities
 Papilloma with ADH -atypical epithelial population is
less than 3 mm.
 Papilloma with DCIS- atypical epithelial population is
more than 3 mm.

38. Intraductal papilloma.
A central fibrovascular
core extends
from the wall of a duct.
The papillae arborize
within the lumen and
are
lined by myoepithelial
and luminal cells.

39. Intraductal papilloma B. p63 demonstrates myoepithelial cells lining the fibrovascular
cores. C. cytoplasmic SMMHC staining demonstrates a continuous layer of
myoepithelium.

41.  Columnar cell lesions(CCL) are clonal alterations of
the TDLU characterized by
 enlarged, variably dilated acini lined by columnar
epithelial cells.
 Involved acini usually have irregular contours.
 Lesions with 1-2 cell layer thickness - Columnar cell
change
 Cellular stratification >2 cell layer thickness -
Columnar cell hyperplasia

42. Columnar cell change. At low magnification, several ductules within the
enlarged lobule are slightly dilated

43. The long axes of the nuclei is oriented perpendicularly to the basement
membrane..
Nucleus-ovoid with
even chromatin
and inconspicuous
nucleoli.
The apical snouts
represented by
cytoplasmic
blebs seen.

44. Columnar cell change. Oestrogen receptor (ER) staining shows relatively
diffuse nuclear positivity of columnar cells

45. It is characterized by low grade (monomorphic) cytological
atypia .
 Replacement of the native epithelial cells of the TDLU by
one to several layers of mildly atypical cuboidal to columnar
cells often with apical snouts.
 Involved acini - smooth contours , may contain secretory
material.
 IHC-
 ER -strong and diffuse nuclear staining
 High molecular weight cytokeratin CK 5/6-negative

47. Flat epithelial atypia There is a “dark” appearance of the epithelial cells due
to increased nuclear–cytoplasmic ratio.
Psammomatous calcifications are observed.

48. Columnar cell change and flat epithelial atypia are often associated with calcifications
that are detected on mammography as clustered and resemble crushed stones.

49.  Atypical ductal hyperplasia(ADH)
 Atypical lobular hyperplasia(ALH)

50.  It is an epithelial proliferative lesion with
cytological and architectural features similar to
those of low grade DCIS but less developed in
architecture ,degree of TDLU involvement and
contiguous extent.
 It is a estrogen driven process.
 Mammography –microcalcifications .

51.  Monotonous cells containing round nucleus with
dense chromatin and well defined cell borders.
 The architectural features-
 rigid bridges , bars, arcades of uniform thickness,
bulbous micropapillations and a cribriform pattern.
 IHC
 ER – strong and diffusely positive
 High molecular weight cytokeratins CK 5/6- negative.

52.  When duct spaces are uniformly involved , the
distinction is based on size /extent criteria.
 Page at al proposed-with less than 2 involved
spaces -classified as ADH.
 Tavassoli and Norris proposed that lesions less
than equal to 2 mm in contiguous extent can be
classified as ADH.

53. Atypical ductal hyperplasia. Monomorphic cells and cribriform
pattern seen.

54. Atypical ductal hyperplasia. (a) Several small
ducts show an atypical epithelial proliferation .
Calcifications and some mucinous material are
seen within the lumens. (b) Nuclear overlapping,
with some nuclei oriented perpendicularly to the
directions of the bridges. (C)(arrow)

58. Atypical ductal hyperplasia. IHC for p63 shows positive nuclear staining of
myoepithelial cells around the duct wall.
As with CK14, no staining of cells is seen around secondary lumens.

60. CK 7 positive P63 Positive

61. CK 5/6 positive

62.  It is a non invasive neoplastic proliferation of small,
dyscohesive cells originating in the TDLU with or
without pagetoid involvement of terminal ducts.
 It is often multicentric and bilateral .
 Usually an incidental microscopic finding in breast
biopsies
.

63.  Some authorities have applied approaches for practical
diagnostic purpose
 1) Comparing the caliber of the involved acini to that of
acini of adjacent uninvolved lobules
 if the involved acini are larger , they are considered
distended.
 2) Estimating the number of cells in the involved acini
 if more than 8 cells present across the diameter of an
acinus, they are considered distended.

64.  The proliferation may exhibit two cell types either
singly or mixed type
 Type A cells –
 scant cytoplasm , round, small to slightly enlarged
hyperchromatic nuclei (1 to 1.5 times the size of a
lymphocyte nucleus ) and inconspicuous nucleoli.
 Type B cells –
 abundant cytoplasm , larger vesicular nuclei (2 times the
size of a lymphocyte nucleus )with more variability in
size and prominent nucleoli.

65. Atypical Lobular Hyperplasia. A, solid proliferation of dyscohesive monomorphic
epithelial cells filling and expanding less than 50% of the acini.
B, The cells often have intracytoplasmic lumina.

67.  Loss of membranous E Cadherin is a hallmark of
lobular lesions
 Beta catenin , alpha catenin and p120 catenin
(proteins known to complex with E Cadherin)
 also demonstrate loss of membranous expression.
 However ,15% of lobular lesions retain E Cadherin with
an aberrant staining pattern,
which should not exclude lobular phenotype.

68. nipple
discharge
• Milky (galactorrhea) -elevated prolactin levels ,hypothyroidism, oral contraceptives
• Bloody or serous discharges -duct papillomas,DCIS,carcinoma (in 7% )
Pain/mastal
gia
• Diffuse cyclic - premenstrual edema.
• Noncyclic pain –localized - ruptured cysts, physical injury, infections, 5% of cancer.
lumpiness
• diffuse nodularity, usually is normal glandular tissue.
palpable mass
• 2 to 3 cm
• round / oval/ mobile/circumscribed borders- mostly benign i.e fibroadenomas and cysts.
• hard, scirrhous in consistency, irregular borders- malignant tumors.
Redness /warmth
(Inflammation)
• Breast abscess during breastfeeding time period
• inflammatory breast carcinoma

69. Proliferation
Lobulocentric
proliferation
Sclerosing
adenosis
Myoepithelial
cells present
P63,SMMHC,
calponin
positive
Basement
membrane
present
Haphazard
proliferation
Microglandul
ar adenosis
No
myoepithelial
cell
Basement
membrane
Laminin ,type
IV collagen
reactivity
(S100-pos;
ER,PR,Her2/n
eu- neg;
EMA-neg)
Tubular
carcinoma
Basement
membrane
absent
(S100-neg;ER
,PR,Her2/neu-
pos;EMA-pos)

70. Epithelial hyperplasia
Usual ductal hyperplasia Heterogenous cell
population
Epithelial bridges –thin
and stretched
HMW cytokeratin CK 5/6
,CK14-Heterogenous and
mosaic pattern.
Estrogen receptor- Patchy
and heterogenous
nuclear positivity.
Atypical ductal
hyperplasia/low grade
DCIS
Monomorphic cell
population
Rigid bridges, arcades,
micropapillary,cribriform
pattern etc
HMW cytokeratin CK 5/6
,CK14-Dimished or
absent reactivity
Estrogen receptor- diffuse
nuclear positivity

71. Usual ductal hyperplasia. IHC for CK14 shows mosaic-like positivity of epithelial
cells in UDH. CK5/6 and CK14 staining patterns are usually similar.

72. ADH –ER diffuse and
intense nuclear staining of
epithelial cells.
UDH shows non diffuse patchy
ER staining.

73. Epithelial
hyperplasia
E Cadherin
positive
ADH
monomorphic
cell population
<2 involved
spaces
≤2mm
contiguous
extent
Low grade
DCIS
monomorphic
cell population
>2 involved
spaces
≥2mm
contiguous
extent
E Cadherin
negative
ALH
2 types of cell-
type A,type B

74.  Kumar V , Abbas A.K and Aster J.C Robbins and Cotran
Pathologic Basis of Disease 10etd ,Elsevier2021.
 Goldblum J R,Lamps L W,McKenny J K,Myers J L;Rosai and
Ackerman’s Surgical Pathology. 11th edition, Elsevier2018
 Rosen PP, Hoda S.A, Brogi E, Koerner F C;Rosen’s Breast
Pathology, 4th edition,Lippincott William and Wilkins,2014
 Tan PH ,Sahin A A ,Atlas of Differential Diagnosis in Breast
Pathology;Springer;2017
 WHO classification of breast tumors,5th edition;International
Agency for research on Cancer;2019

75. THANK YOU