Breast pathology 3

Carcinoma of Breast
Dr.CSBR.Prasad, M.D.

Classification of Breast Cancer
• Breast cancers can be classifed histologically based
upon the types and patterns of cells that compose
them.
• Carcinomas can be invasive (extending into the
surrounding stroma) or non-invasive (confined
just to the ducts or lobules).
• The "NOS" categories contain carcinomas not
easily classified into other histologic types or
carcinomas for which minimal tissue was available
for diagnosis.

Source: Sabiston – Text book of Surgery, 15th
Ed, Vol-1
Medullary carcinoma
Mucinous carcinoma
Adenoid cystic carcinoma

Non-invasive Carcinomas of the Breast
Histologic Type
Frequency
(%)
5-year
Survival (%)
Intraductal Carcinoma (DCIS) 3.6 >99
Lobular Carcinoma in situ (LCIS) 1.6 >99
DCIS & LCIS 0.2 >99
Papillary Carcinoma 0.4 >99
Comedocarcinoma 0.3 >99

Invasive Carcinomas of the Breast
Histologic Type
Frequency
(%)
5-year
Survival
(%)
Infiltrating Ductal Carcinoma 63.6 79
Infiltrating Lobular Carcinoma 5.9 84
Infiltrating Ductal & Lobular Carcinoma 1.6 85
Medullary Carcinoma 2.8 82
Mucinous (Colloid) Carcinoma 2.1 95
Comedocarcinoma 1.4 87
Paget's Disease 1.0 79
Papillary Carcinoma 0.8 96
Tubular Carcinoma 0.6 96
Adenocarcinoma, NOS 7.5 65
Carcinoma, NOS 3.5 62

Clinical features
• Mass in the breast
• Retraction of the nipple
• Pain
• Peau d’ orange
• Lymphadenopathy
• Eczema or ulceration of nipple
• Mammographic densities / calcifications
• Nipple discharge

Ed, Vol-
1

Paget’s disease of
the nipple.

Peau d’ orange of
the breast

Schirrhous
carcinoma of
the breast.
Note the
shrinkning
and elevation
of the breast
with nipple
retraction.

Large fungating carcinoma of the right breast with
enlarged axillary lymphnodes.

Carcinoma of the male breast – advanced.

Lymphangiosarcoma developed after 3years after radical
mastectomy.

Source: Sabiston –
Text book of
Surgery, 15th
Ed,
Vol-1

-Phyllode’s
tumor in a
women of
18years.
-Weight 18kgs.
-Ulceration
(arrow) due
to pressure.

Carcinoma in situ
DCIS – malignant population of cells limited to ducts and lobules by the
basement membrane.
• Vaguely palpable mass
• Mammographic calcifications / densities
• Incidental finding in biopsy done for some other reason
Sub types (based on the architecture):
1-comedo ca
2-solid ca
3-cribriform ca
4-papillary ca
5-micropapillary ca

Carcinoma in situ - comedo
• Grossly on the cut surface worm like
extrusions (comedons) occur when pressure
is applied laterally to the involved area.
• Size of the carcinoma vary, some measuring
several centimeters.

The gross appearance of a comedocarcinoma pattern of intraductal carcinoma is seen here, with small,
yellow central necrotic areas in the ducts. This pattern is not common, but the overall prognosis for
patients with this type of breast carcinoma is generally good. Source: webpath

• Microscopy:
solid sheets of pleomorphic cells with
high grade nuclei.
central necrosis.
intact basement membrane.
there may be microcalcifications.
periductal concentric fibrosis.
Carcinoma in situ - comedo

Here is a comedocarcinoma pattern of intraductal carcinoma, which is
characterized by the presence of rapidly proliferating, high-grade malignant
cells. Note the prominent central necrosis in the ducts (arrows). Source: webpath

The cells in the center of the ducts with comedocarcinoma are often necrotic and calcify,
as shown here. This central necrosis leads to the gross characteristic of extrusion of cheesy
material from the ducts with pressure (comedone-like). Source: webpath

Carcinoma-in-situ of the comedo pattern distending an acinus, not a duct.
The lumen contains red cells, necrotic epithelial cells and macrophages
with brown pigment. H&E.
http://www.georgetown.edu/dml/educ/path/cpc/gyn_breast/06.html

In-situ and invasive ductal carcinoma with microcalcification.
H&E.
http://www.hopkinsbreastcenter.org/pathology/malignant/

Ductal carcinoma in-situ (comedo-type). FNAC. PAP.
http://www.hopkinsbreastcenter.org/pathology/malignant/33

Ductal carcinoma in-situ (comedo-type) with central
microcalcification. H&E

Permanent section of the breast lump showing Ductal carcinoma in situ (DCIS -
Comedo pattern with central necrosis) along with invasive glands. (H/E, 10x)

DCIS ("comedo type), low magnification. (Actual field size 1.5 X 1 mm) This duct has a central plug of
necrotic cellular debris (outlined by the arrow heads). The distance from the edge of this necrotic zone
to the basal lamina is constant throughout this duct and pathologists assume that the necrosis is due to a
lack of a crucial nutrient such as oxygen in cells that have a high metabolic demand. The box shows the
area for next Figure. <http://www.georgetown.edu/dml/educ/path/cpc/gyn_breast/06.html>

DCIS ("comedo type"), high magnification.
When the cells die, the nuclei undergo pyknosis, or collapse of the nuclear
membrane and collapse of the chromatin into dense masses. Over several days, the
pyknotic nuclei lose all staining, presumably as the DNA is autolyzed.

• Monomorphic population of cells
• Low to high nuclear grades
• Intraepithelial spaces are evenly distributed
and regular in shape – cookie cutter-like
Carcinoma in situ - Cribriform

The classic cribriform pattern of intraductal carcinoma of the breast is shown
here. The neoplastic epithelial cells within the duct show minimal
hyperchromatism and pleomorphism, but they surround holes with sharp
margins, as though punched out by a cookie cutter.

The rigid bars (A) and the round, punched-out open spaces
(B) characteristic of this, the most common in situ carcinoma,
are apparent under low magnification.
www.wisc.edu/wolberg/comedb_s.html

Both intraductal and infiltrating ductal carcinoma are seen here. Note the intraductal component in the
center with cribriform pattern and prominent microcalcifications. Surrounding this are infiltrating
carcinoma cells. Source: webpath

Carcinoma in situ – Solid type
• Cells completely fill the involved spaces

Ductal carcinoma in-situ (solid-type). H&E..

This high power microscopic view demonstrates intraductal carcinoma. Neoplastic cells
are still within the ductules and have not broken through into the stroma. Note that the
two large lobules in the center contain microcalcifications. Such microcalcifications can
appear on mammography. Source: webpath

Carcinoma in situ –
Papillary/mcoropapillary types
• Papillary DCIS grows in to spaces and lines the
fibrovascular spaces
• No myoepithelial lining
• Micropapillary DCIS shows bulbous protrusions
without a fibrovascular core
• May form complex intraductal patterns

Figure 23-18 Noncomedo DCIS. A, Papillary DCIS. Delicate fibrovascular
cores extend into a duct and are lined by a monomorphic population of tall
columnar cells. Myoepithelial cells are absent. B, Micropapillary DCIS. The
papillae are connected to the duct wall by a narrow base and often have bulbous
or complex outgrowths. The papillae are solid and do not have fibrovascular
cores.

Ductal carcinoma in-situ,
micropapillary type. H&E.
Source: jhu week-91case-4

Ductal carcinoma in-situ, micropapillary type. H&E.

Ductal carcinoma in-situ, micropapillary type. FNAC, PAP.

Carcinoma in situ – Paget’s disease
• It’s a rare manifestation of breast ca (1-2%)
• Palpable mass is present in 50-60% of cases
• Unilateral erythematous eruption with a scale crust
• Pruritus is common
• May be mistaken for eczema
• Malignant cells extend from DCIS into the nipple without crossing the
BM.
• Carcinomas are usually poorly differentiated and over express
HER2/Neu
• Prognosis depends on the extent of underlying carcinoma

Figure 23-19 Paget disease of the nipple. DCIS arising within the ductal system of
the breast can extend up the lactiferous ducts into nipple skin without crossing the
basement membrane. The malignant cells disrupt the normally tight squamous
epithelial cell barrier, allowing extracellular fluid to seep out and form an oozing
scaly crust over the nipple skin.

Paget's disease of the breast is shown here. Note the overlying hyperkeratosis of the skin, which helps to
produce the rough, red, scaling appearance seen grossly, and there is often ulceration. The large cells
infiltrating into the epidermis represent intraepithelial extension of an underlying ductal carcinoma in situ or
invasive ductal carcinoma. Source: webpath

At high magnification, the large Paget's cells of Paget's disease of breast have abundant
clear cytoplasm and appear in the epidermis either singly or in clusters. The nuclei of the
Paget's cells are atypical and, though not seen here, often have prominent nucleoli. webpath

A PAS stain demonstrates mucin within the Paget's cells of Paget's disease of the breast. This is
evidence for their origin from an underlying ductal carcinoma. By immunoperoxidase staining, they
will also be keratin positive and epithelial membrane antigen positive. Source: webpath

Dr.James Paget.
Famous man of St.
Barts. Described
diseases of breast and
bone

DCIS with microinvsion
• Def: foci of tumor cells <0.1cm in diameter
invading the stroma.
• Microinvasion is most commonly seen in
association with comedocarcinoma.

Lobular Carcinoma in situ - LCIS
• Always an incidental finding in biopsies
• Not associated with calcifications / densities
• Bilateral in 20-40% of women (cf. 10-20% in DCIS)
• More common in younger women (80-90% occur before
menopause)
• Small cells that have oval or round nuclei with small
nucleoli that do not adhere to one another.
• Signet ring cells containing mucin are present commonly.
• LCIS rarely distorts the architecture, and the involved
acini remain recognizable as lobules.
• LCIS always express ER/PR and may be negative for
HER2/Neu.

Lobular carcinoma in-situ. H&E

Lobular carcinoma in-situ. FNAC, PAP

Infiltrating lobular carcinoma. FNAC, PAP.

Invasive carcinomas
• Almost always present as palpable masses
• 50% will have LN mets
• Clinical features of malignancy is present
• Inflammatory carcinoma is a clinical entity
and is not a specific histological type

Detailed views of the
microcalcifications in the CC of
the left breast.
[79 year old asymptomatic
woman with screening
mammogram.]
http://www.rad.washington.edu/quickcases/cases/Case11/answers.html

Detailed views of the
microcalcifications in the CC of the left
breast.
This pattern of microcalcifications is
classic for ductal carcinoma of the
breast. There is not really any
differential diagnosis here. This patient
needs surgery.
79 year old asymptomatic woman79 year old asymptomatic woman
with screening mammogram.with screening mammogram.

Detailed views of the microcalcifications in the CC of the left breast.
http://www.rad.washington.edu/quickcases/cases/Case11/answers.html

Source: webpath
This mammogram
demonstrates a lesion
consistent with a neoplasm
in the upper portion above
and just to the left of the
white dot marking the point
the patient felt some pain on
palpation. On biopsy, this
was an infiltrating ductal
carcinoma.

Invasive carcinoma - NST
• Most common type (70-80%)
• Firm to hard and have irregular border
• Center of the lesion shows streaks of chaky white
elastotic stroma
• Gives a grating sensation while cutting
• They are well differentiated with tubules lined by
minimally atypical cells
• Typically ER/PR+ when they are WD
• And ER/PR- when they are PD

The irregular mass lesion seen here is an infiltrating ductal carcinoma of breast. The
center is very firm (scirrhous) and white because of the desmoplasia. There are areas of
yellowish necrosis in the portions of neoplasm infiltrating into the surrounding breast.
Such tumors appear very firm and non-mobile on physical exam. Source: webpath

This breast biopsy demonstrates a carcinoma. Note the irregular margins and varied cut surface. This
small cancer was found by mammography. The margins of the specimen have been inked with green
dye following removal to assist in determining whether cancer extends to the margins once histologic
sections are made. Source: webpath

Infiltrating ductal carcinoma.Hematoxylin and Eosin stain

This is infiltrating ductal carcinoma of breast. Note the infiltration of ill-defined glands into the
surrounding collagenous stroma. There is also a small microcalcification at the lower right of center,
a finding that could be seen by mammography. About 65 to 80% of breast cancers are of this type.
Source: webpath

This infiltrating ductal carcinoma of breast at low magnification appears to radiate from a central area
of desmoplasia. This collagenous component gives the neoplasm a hard "scirrhous" consistency that is
palpable. Such an invasive carcinoma may be fixed to underlying chest wall, making it non-mobile.
Source: webpath

Note the small nests and infiltrating strands of neoplastic cells with prominent bands of collagen between them in
this ductal carcinoma of the breast. It is this marked increase in the dense fibrous tissue stroma that produces the
characteristic hard "scirrhous" appearance of the typical infiltrating ductal carcinoma. Note the nerve surrounded by
the neoplasm at the lower left. Source: webpath

At high magnification, the pleomorphism of the carcinoma cells within the duct in
the center (in a cribriform pattern), as well as the neoplastic cells infiltrating
through the stroma and fat, can be seen with this infiltrating ductal carcinoma.

• Clinical presentation is similar to NST
• 25% will have diffuse growth pattern without desmoplasia
• High incidence of bilaterality
• Most tumors are firm to hard with irregular margins
• Minimal desmoplasia
• Indian file pattern (typical of LC)
• Tumor cells may be seen around the normal duct in
concentric pattern
Invasive Lobular carcinoma

Infiltrating lobular carcinoma. H&E – Indian file pattern

Lobular carcinomas:Lobular carcinomas: They exhibit different
pattern of metastasis
They prefer:They prefer:
Peritoneum
Retroperitoneum
Meninges
GIT
&
Ovaries

Mucinous carcinoma
•1-6% of all breast cancers
•Well circumscribed
•Extremely soft
•Majority express hormone receptors
•BRCA1 mutations
•Gray blue gelatinous appearance
•Tumor cell float in a see of mucin

Colloid (mucinous) carcinoma. FNAC, Diff-Quik stain.

Colloid (mucinous) carcinoma. FNAC, PAP.

Colloid (mucinous) carcinoma. H&E.

This variant of breast cancer is known as colloid, or mucinous, carcinoma.
Note the abundant bluish mucin. The carcinoma cells appear to be floating in
the mucin. This variant tends to occur in older women and is slower growing,
and if it is the predominant histologic pattern present, then the prognosis is
better than for non-mucinous, invasive carcinomas.

Tubular carcinoma
•2% breast cancers
•Multifocal with in one breast 10-55% of cases
•Bilateral in 10-38% of cases
•Well formed tubules
•No myoepithelial layer
•Apocrine snouts in the epithelial cells

Tubular carcinoma. H&E.

Ductal carcinoma of the breast showing lymphovascular invasion.
H&E http://www.hopkinsbreastcenter.org/pathology/malignant/33

Tumor embolus from ductal carcinoma in a lymphatic channel. H&E

Medulalry carcinoma
• Well circumscribed carcinoma of the breast
• May be mistaken for fibroadenoma
• Rapidly growing with pushing margins
• BRCA1 positive
• Solid syncytium of cells (75% of the tumor)
• High nuclear grade
• Lymphocytic infiltration
• No lymphatic or vascular invasion

Medullary carcinomas account for less than 5% of breast cancers. They can sometimes be large,
fleshy masses up to 5 cm in size. At low power, sheets and nests of cells are surrounded by a
lymphoid stroma with little desmoplasia. The prognosis with medullary carcinoma is better than
for infiltrating ductal or lobular carcinoma. Source: webpath

At high magnification, medullary carcinoma is composed of cells with
pleomorphic nuclei that have prominent nucleoli. Though not seen here, foci of
necrosis and hemorrhage can be found. Source: webpath

Metaplastic carcinoma
Source: jhu week-113 case-2
St. John's Medical College, Bangalore

This metaplastic breast carcinoma has elements of squamous metaplasia as shown
here at high magnification. Such tumors are rare in humans (though common in
canines). The metaplastic patterns can include cartilagenous, bony, and myxoid
areas as well. Source: webpath

Ductal carcinoma. FNAC. Diff-Quik stain.

Ductal carcinoma, FNAC, Papanicolaou stain

Inflammatory carcinoma
• The definition of inflammatory carcinoma is
currently a matter of debate.
• Many feel that the diagnosis should be based on
clinical exam with the classic symptoms being
increased warmth, erythema, peau d'orange, and
skin thickening.
• Others feel that the diagnosis should be made
solely on the basis of dermal biopsy.
• The histological appearance is one of diffuse
carcinomatous involvement of the dermal
lymphatics.
References:
Cardenosa, G Breast Imaging Companion. Philadelhia: Lippincott-Raven, 1997 Kopans, D Breast imaging . second
edition.Philadelphia: Lippincott Williams & Wilkins 1998

This mastectomy specimen demonstrates the gross findings of "inflammatory" carcinoma of breast. This is not a
specific histologic type of breast cancer, but rather it implies dermal lymphatic invasion by some type of
underlying breast carcinoma. Such involvement of dermal lymphatics gives the grossly thickened, erythematous,
and rough skin surface with the appearance of an orange peel ("peau d'orange"). Source: webpath

The skin overlying the breast has prominent lymphatic spaces filled with small
metastases from breast carcinoma. Carcinomas often metastasize to lymphatics. Breast
cancers most often metastasize to the axillary lymph nodes, and these nodes are often
removed at the time of surgery for breast cancer. Source: webpath

The microscopic appearance of a dermal lymphatic distended by ductal
carcinoma of the breast is shown here. This is the hallmark of so-called
inflammatory carcinoma of the breast. Source: webpath

Metastatic small cell carcinoma from the lung. FNAC. PAP

Squamous cell carcinoma. FNAC. PAP

Metastatic malignant melanoma. FNAC. PAP.

Prognostic & predictive factors
• Prognosis is determined by pathological
examination of:
1-Primary carcinoma
2-Axillary LNs
• This is essential to assess
1-The possible outcome of the disease
2-To choose the appropriate Tx.

• They are divided into:
1-Major PF ((strongest predictor of death from breast cancerstrongest predictor of death from breast cancer))
2-Minor PF
The predictive factors are used to determine the
likelihood of response to a particular Tx.

MAJOR PF MINOR PF
Invasive Vs in situ Small tumor w or w/o node
positivity
Distant mets ER/PR status
LN mets Her-2/Neu
Tumor size Tumor grade
Locally advanced disease Histological type
Inflammatory carcinoma Proliferation rate
DNA content
LVI

Predictive factors - Major
• Invasive Vs in situ
- Majority with DCIS when adequate Tx is
given they will be cured of the disease
- 50% of invasive Ca show local distant
mets at the time of diagnosis.

• Distant mets:
---with distant mets cure is unlikely
---Long term remission is possible with
hormonally responsive tumors.
Favoured sites for distant mets:
Lungs, Bone, Liver, Adrenals and Brain.

• LN mets:
--most important factors in the absence of distnat
mets.
--LN biopsy is necessary for accurate assessment
--Clinical assessment of nodal involvement is very
inaccurate
10yr disease free survival
LN negative 70-80%
One LN positive 35-40%
10 or more LN positive 10-15%

• Sentinel LN biopsy
--Radiotracer / colour dye
--Identifies the draining LN with high
probability of mets
--The question of axillary dissection
--Macromets (>0.2cm) – is of proven importance
--Micromets (IHC / RT-PCR) – is of unclear
significance

• Tumor size:
Risk of axillary LN mets increases with
increasing size of cancer
1-Tumor <1cm LN-negative
survival is similar to women witout br.ca
10yr survival is 90%
2-Tumor >2cms
50% will have LN mets
Many will die of their disease

• Locally advanced disease:
Tumors with skin or skeletal muscle
involvement are frequently associated with
concurrent or subsequent distant mets.

• Inflammatory carcinoma:
1-Breast swelling
2-Skin thickening
Very poor prognosis with 3yr survival rate of only
3-10%

• Women with node + and / or Ca >1cm
will benefit from systemic Tx
• Women with node – and small carcinoma
minor prognostic assessment will tell
who needs additional Tx and who can be
left alone.
Among them ER/PR/Her2 are most useful
predictors of response to specific Tx.
Predictive factors - Minor

• Histological subtypes:
10yr survival >60% 10yr survival <20%
1-Tubular ca
2-Mucinous ca
3-Medullary ca
4-Lobular ca
5-Papillary ca
6-Adenoid cystic ca
Carcinoma -NST

• Tumor grade: (Scarff-Bloom-Richardson)
1-Nuclear pleomorphism (Small uniform, Moderate
variation, marked variation)
2-Tubule formation (>75%, 10-75%, <10%)
3-Mitotic activity (7, 8-14, >15/10hpf)
10yr survival:
Grade-I 80%
Grade-II 60%
Grade-III 15%

• ER / PR status:
Receptor Response to hormone Tx
Both ER+ & PR+ 80%
Either ER+ or PR+ 40%
ER negative
PR negative
10%

Mechanism of
estrogen action
on cancer cells
having estrogen
receptor.
Source: Sabiston – Text
book of Surgery, 15th
Ed,
Vol-1

The cells of this breast carcinoma are highly positive for estrogen
receptor with this immunoperoxidase stain. Source: webpath

This is progesterone receptor (PR) positivity in a breast carcinoma. Carcinomas that are
PR positive, but not ER positive, may have a worse prognosis. Source: webpath

This is positive immunoperoxidase staining for C-erb B-2 (HER-2/neu) in a breast carcinoma. Note
the membranous staining of the neoplastic cells with the antibody directed against the HER-2 gene
product. The drug trastuzumab is a monoclonal antibody directed against HER-2 positive breast
cancer cells. Source: webpath

Marker studies
• The hormone receptor status of the breast
cancer cells can be useful information for
treatment and prognosis.
• The neoplastic cells can express a variety of
receptors.
• The presence of these receptors can provide
a means for controlling cell growth through
chemotherapeutic agents.

Marker studies
• Estrogen receptor (ER)
• Progesterone receptor (PR)
Other markers:
• Cathepsin D
• C-erb B-2 (HER-2/neu)

• In general, cancers in which the cells express
estrogen receptor (ER) in their nuclei will have a
better prognosis. They can respond to hormonal
manipulation.
• The drug tamoxifen is often utilized for this
purpose.
• Almost three-fourths of breast cancers expressing
ER will respond to this therapy, whereas less than
5% not expressing ER will respond.
Marker studies

• The significance of progesterone receptor
(PR) positivity in a breast carcinoma is less
well understood.
• In general, cancers that are ER positive will
also be PR positive.
• However, carcinomas that are PR positive,
but not ER positive, may have a worse
prognosis.
Marker studies

• C-erb B-2 (HER-2/neu) is another marker in breast
carcinomas, and it is identified around the cytoplasmic
membrane of the cells with immunohistochemical
methods.
• HER-2 oncogene overexpression is typically the result of
gene amplification (more gene copies) and is detected by
the fluorescence in situ hybridization (FISH) assay, but in
a few cases may be due to transcription activation.
• This gene encodes for an epithelial growth factor receptor
on the cell membrane that stimulates cellular proliferation.
There is a correlation between HER-2 positivity and high
nuclear grade and aneuploidy.
Marker studies

• LVI (lymphovascular invasion)
Tumor cells with in either lymphatic or
vascular spaces is associated with poor
prognosis as many have LN mets.

Ed, Vol-
1
Significance of negative surgical
margins in Invasive (A)
compared with intraductal (B)
carcinoma.

• Proliferative rate
flow cytometry
thymidine labelling
mitotic count
Ki 67
cyclin E count
Tumors with high proliferative index are associated
with much worse prognosis.

• Tumror DNA content:
tumor aneuploidy is asociated with worse
prognosis.

This mammogram
demonstrates a large
10 cm mass lesion
consistent with a
phyllodes tumor.
Source: webpath

Cystosarcoma phyllodes. H&E

A phyllodes tumor of the breast is shown here. They arise from interlobular stroma, but unlike
fibroadenomas are not common and are much larger. They are low-grade neoplasms that rarely
metastasize. They are more cellular than fibroadenomas. Projections of stroma into the ducts create the
leaf-like pattern for which these tumors are named
(from the Greek word phyllodes meaning leaf-like).

Breast pathology 3

More Related Content

What's hot

Viewers also liked

Similar to Breast pathology 3

More from Prasad CSBR

Recently uploaded

Breast pathology 3

Editor's Notes