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 BREAST PATHOLOGY
BENIGN LESIONS
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https://www.facebook.com/pages/Human-Pathology/169869373198364

Dr. Khurshid Anwar

 Breast- Anatomy
Symmetric double organ
Reaches normal size b/w 16-19 yrs
B/w 2nd and 6th ribs and Sternum and Axilla
Nipple and areola, superficial skin
Breast is divided into 10-20 lobes, each lobe lobules (ducts + acini= TDLU)
Embedded in stroma
Breast- Histology
Milk Line
 Disorders of Breast
• Congenital
Amastia, Athelia, Polymastia, polythelia, Hypertrophy, Congenital inversion of the
nipple, Accessory axillary breast

• Inflammatory
– Infections (acute/chronic mastitis)
– Traumatic Fat necrosis
– Duct ectasia (discharge, sinus),
– Galactocele

• Benign epithelial changes (Fibrocystic Disease)

• Neoplastic
– Benign – Fibroadenoma, Intraductal papilloma etc.
– Malignant – Breast cancer
CLINICAL PRESENTATION OF BREAST
PATHOLOGY

Palpable lump
Inflammatory mass
Nipple discharge
Non-palpable abnormality
 Diagnostic Modalities
• BSE
• Mammogram
• US
• Technetium (99mTc) sestamibi Scans (Scintimammogram)
• MRI and CT
• Blood Tests
• CXR and Bone Scans
• PET Scans
• Ductal Lavage
• FNA
• Biopsy (Incisional biopsy, Excisional biopsy, Image-guided biopsy)
• Immunohistochemistry
• Molecular techniques (Microarray studies)

Sentinel Lymph Nodes: The first lymph node that receives breast
drainage/metastasis. Usually central group (level 1).
 Breast Imaging Techniques

Mammogram MRI Breast

PET Scan Technetium (99mTc) sestamibi

 Fine Needle Aspiration (FNA)

FNAC: 90% sensitive and 95% specific. Fibrotic areas difficult to aspirate.
False (–) small tumors, tubular CA, cribriform CA.
False (+) with florid ductal hyperplasia.
Negative FNA with lingering suspicion
Breast Biopsy Procedures
Immunohistochemistry

ER

Her-2neu

PR
 Current assay of HER2/neu

 Immunohistochemistry

‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)

 Fluorescence in situ hybridization (FISH)

HER2 gene no amplification HER2 gene amplification

FISH negative FISH positive
Non-Neoplastic- Congenital lesions
Accessory Breast Tissue
Found in the axillary fossa, can be misdiagnosed as axillary LN metastasis

Ectopic Breast Tissue

May develop along mammary line
(failure of any portion of mammary ridge to involute)

Macromastia
Excessive breast tissue

Nipple inversion
Associated with large pendulous breasts- May be confused with CA

Supernumerary Breasts/Nipples
Persistent epidermal thickenings along milk line from axilla to perineum
 Accessory Breast Tissue

Ectopic Breast Tissue

Nipple inversion
Non-Neoplastic- Acquired Breast Lesions
Acute Mastitis/Abscess
Tender, associated with lactation- cracks in nipple. Staph and Strep

Periductal Mastitis
Mammary Duct Ectasia
Fat Necrosis
Glactocele
Lymphocytic Mastitis

Silicone Implants
Form a fibrous capsule (synovial metaplasia).
Gel may seep through intact implant shells.

Benign Epithelial Changes (Fibrocystic Disease)

 Acute Mastitis
Clinically most important form of mastitis
Breast-feeding  cracks/fissures in the nipples
 Bacterial infection (esp. Staph. aureus & Strep) involving breast parenchyma (puerperal mastitis)
Usually unilateral—acute inflammation in the breast can lead to abscess formation
Rapid onset of red, hot, swollen, tender breast with high fever
Keep breast-feeding

Treatment: antibiotics/continued expression of milk & rarely surgical drainage

 PERIDUCTAL MASTITIS
(Recurrent subareolar abscess, Squamous metaplasia of lactiferous ducts, Zuska disease)

Painful erythematous subareolar mass, clinically appears to be an infectious process.

More than 90% of the afflicted are smokers.
Inverted nipple, most likely as a secondary effect of the underlying inflammation.
Strong association with cigarette smoking
Keratinizing squamous metaplasia of the nipple ducts (Vitamin A deficiency).
Keratin plugs the ductal system, causing dilation and eventually rupture of the duct. An intense
chronic and granulomatous inflammatory response develops once keratin spills into the
surrounding periductal tissue. Sometimes a secondary bacterial infection supervenes and causes
acute inflammation.
In most cases en bloc surgical removal of the involved duct and contiguous fistula tract is
curative. When bacterial infection is present, antibiotics also have a therapeutic role
 Mammary Duct Ectasia
Occurs predominantly in fifth and sixth decades & affects mainly large ducts
Underlying cause is unknown (non-bacterial inflammation)
Present as a thick, cheesy nipple discharge +/- palpable periareolar mass, skin retraction
inspissated secretions plug ducts and “spill” into the surrounding stromal tissue eliciting a marked
plasmacytic and/or granulomatous inflammatory response, periductal fibrosis  skin retraction
Fibrosis may lead to nipple retraction or mass mimicing carcinoma clinically and on mammogram

Periductal inflammation

Dilated ducts containing

amorphous debris &
macrophages.
 Fat Necrosis
Trauma- patient may not give history
Generally related to lactation, pregnancy or sports activity, surgery
May present as ill-defined painless mass
Focus of necrotic parenchyma with marked acute and chronic inflammation which includes
foreign body giant cells and lipid-laden macrophages
May show calcification (mamographically)
May cause retraction of skin
DD- Carcinoma
 Galactocoele
Cystic dilatation of duct during lactation, may become infected (acute mastitis) with abscess
formation

LYMPHOCYTIC MASTOPATHY
(SCLEROSING LYMPHOCYTIC LOBULITIS)

Presents with single or multiple hard palpable masses (may be bilateral)

Needle biopsy may be difficult.
Microscopically, they show collagenized stroma surrounding atrophic ducts and lobules. The
epithelial basement membrane is often thickened. A prominent lymphocytic infiltrate surrounds
the epithelium and small blood vessels.
Most common in women with type 1 (insulin-dependent) diabetes or autoimmune thyroid disease.
its only clinical significance is that it must be distinguished from breast cancer
Silicone Implant and Associated Changes

Granulomatous mastitis
Breast prostheses or nipple piercings
systemic granulomatous diseases (sarcoidosis, WG)
Granulomatous infections (tuberculosis, fungal infection)
 Benign Epithelial Changes
(Fibrocystic Disease/Change)
Common hyperplastic disorder and accounts for the majority of surgical procedures
performed on the female breast
Usually occurs at 20-40 years of age
Morphologic changes affect glandular and stromal elements of the breast parenchyma
Morphologic changes are due to estrogen excess & estrogen-progesterone imbalance &
Decreased risk with OCT
Produces breast mass that must be differentiated from carcinoma
Atypical hyperplasia of the ductal epithelium (present in 5% of fibrocystic lesions) is
associated with increased risk of carcinoma
May hamper adequate/optimal mammography

Grouped into
Non-proliferative breast changes,
Proliferative breast changes
(WITHOUT ATYPIA & WITH ATYPIA)
NON-PROLIFERATIVE (“FIBROCYSTIC”) CHANGES

No associated risk of progression or cancer

? Due to hormonal imbalances

Morphological features
Cystic change often with apocrine metaplasia
Fibrosis with Stromal lymphocytic infiltrate

The acini are often enlarged, but are not distorted. The acini are lined by columnar cells which may
appear benign or show atypical features ("flat epithelial atypia"). These lesions may be the earliest
recognizable precursor of epithelial neoplasia.
NON-PROLIFERATIVE FIBROCYSTIC CHANGES NON-PROLIFERATIVE FIBROCYSTIC CHANGES-
WITH APOCRINE METAPLASIA

GROSS
PROLIFERATIVE DISEASE WITHOUT ATYPIA
Characterized by slight increase (1.5-2 fold) in risk of breast cancer

Epithelial Hyperplasia (incidental finding)

 number of layers of cells lining ducts and acini (> 2 cell layers)
Involved ducts and acini are filled with overlapping, proliferating cells

Sclerosing Adenosis (palpable mass or calcification)

Characterized by  number of acini + stromal fibrosis within lobules
Can be associated with calcifications which may be detected on mammography

Complex Sclerosing lesion

Sclerosing adenosis, papilloma & epithelial hyperplasia (radial scar)

Papillomas
Occur in dilated duct & Epithelial hyperplasia & apocrine metaplasia frequently +
EPITHELIAL HYPERPLASIA WITHOUT ATYPIA
 Sclerosing Adenosis
Grossly hard, rubbery consistency, similar to that of breast cancer

Histologic examination shows proliferation of luminal spaces (adenosis)

lined by epithelial cells and myoepithelial cells, yielding
masses of small glands within a fibrous stroma Aggregated glands may be virtually back to
back. Marked stromal fibrosis, which may compress and distort the proliferating epithelium.
(This overgrowth of fibrous tissue may completely compress the lumina of the acini and ducts, so that they appear as solid
cords of cells—a pattern that is difficult to distinguish histologically from carcinoma)

Risk of CA 1.5 to 2x normal

Associated with clustered microcalcification

• from invasive ductal carcinoma.

Sclerosing Adenosis
PROLIFERATIVE DISEASE WITH ATYPIA
Characterized by moderate increase (5 fold) in risk of breast cancer

Epithelial hyperplasia characterized atypical architectural & or cytologic features

Can affect; ducts atypical ductal hyperplasia, or

lobules atypical lobular hyperplasia.
Atypical features resemble but fall short of in-situ cancer

No special diagnostic clinical or radiologic features

 Incidence with use of screening mammography and  number of breast biopsies

 Atypical Ductal Hyperplasia
Features suggestive but not diagnostic of DCIS
Risk equal in both breasts- maybe multifocal & usually bilateral

Consists of a relatively monomorphic proliferation of regularly spaced cells, sometimes with

cribriform spaces, multilayering of cells with progressive loss of nuclear polarity, enlarged
nuclei, and nucleoli
Loss of heterozygosity at 16q. 40% clonal.

It is distinguished from DCIS by being limited in extent and only partially filling ducts

Atypical Lobular Hyperplasia (ALH)

Resembles LCIS but does not fill or distend 50% or more acini within a lobule
Has focal preservation of luminal spaces.
If extends to ducts through pagetoid spread, associated with increased risk of invasive carcinoma
Atypical Epithelial Hyperplasias

ADH ALH
 Benign Neoplasms
Fibroadenoma
Duct Papilloma
Adenoma
Connective tissue tumors (Phyllodes tumor)
 Fibroadenoma
Most common benign tumor
Typically younger woman 20-35
Classic presentation is that of a firm, mobile lump (“breast mouse”)
Giant forms can occur, especially in younger patients
Fibroadenomatosis- mutifocal disease in post renal transplant and with EBV in
immunosuppressed
May have neoplastic stromal component with polyclonal epithelial component
Hormonally responsive- may grow in pregnancy & regress after menopause
Malignant transformation <0.1%
Gross- sharply circumscribed and freely mobile

Histologically it is circumscribed lesion composed of both proliferating glandular and stromal

elements. Glandular epithelium without atypia. Myoepithelial cells are present.
Stroma generally not very cellular (d/d Phyllodes)
May have coexisting features of fibrocystic change, sclerosing adenosis
Juvenile/Giant cell variant
adolescent, often bilateral, often very large and may have very cellular stroma and glands (d/d
phyllodes tumor)

FNA very helpful in regular variant

Fibroadenoma
 Large Duct Papilloma
Mean age 48 (premenopausal)
Solitary
Close to nipple, lactiferous ducts and sinuses.
1.5-2.0x risk of Cancer. Clonal

Serous/bloody nipple discharge (80%)- nipple retraction may be present.

Gross: <3cm, soft, hemorrhagic

Papillae are fibrovascular stalks lined by layers of proliferating epithelial and myoepithelial cells
Multiple papillae in complex arborizing pattern. Calcification possible. Myoepithelium present
(S100+)

Benign but can recur (especially if inadequately excised)

Malignant if severe atypia, abnormal mitoses, single cell layered, pseudostratification, no

vascular core or cribriform morphology

Treatment is surgical excision

Large Duct Papilloma
 Phyllodes tumour
(Cystosarcoma phyllodes)

<1% of breast tumours

Present as breast lump
Range in size from a few cm to massive lesions
Neoplastic overgrowth of stroma
Classically have a “leaf-like” configuration
Ranges from benign to malignant (increased stromal cellularity, anaplasia, high mitotic
activity, rapid increase in size, and infiltrative margins)

Most are low-grade lesions that can recur locally but do not metastasize
Others are of high-grade and exhibit aggressive clinical behaviour -spread to distant sites
(cystosarcoma phyllodes)

Recur if incompletely excised

Complete excision for benign phyllodes; mastectomy for malignant
Phyllodes Tumor

Benign
Most tumors. Resemble Fibroadenoma with cellular stroma. Rx- Wide local excision

Borderline
More mitotic figures than benign. Tend to recur. Rx- Wide excision.

Malignant
Rare; >5 mitoses/10HPF AND stromal>ductal growth, tumor necrosis, heterologous stromal
elements, marked nuclear atypia. Stroma may be sarcomatous. Local recurrence. 3-12% mets
(stromal). Simple mastectomy
Phyllodes Tumor
Breast Cancer
 Cancer Statistics Abu Dhabi, 2011
Cancer is the second leading cause of death among national and third among non-
nationals. it account for 15% of total deaths
The 5 most common types of cancer that kill men are (in order of frequency): lung,
colorectal and liver, leukemia and pancreas.

The 5 most common types of cancer that kill women are (in the order of
frequency): breast, colorectal, leukemia, liver and pancreas.

Breast cancer is the most common cancer among all, account for 25% of all
cancers, 45% of females’ cancer.

Colorectal cancer is the second most common cancer, account for 9% of all cancers. In Males, it
is the most common cancer 14% of all cancer in men and third in females 7% of all cancers.
Most (60%) of the colorectal cancer cases were men and 40 % were women, 85% of cases are
40 years and above.

Cervical cancer is the second most common cancer in women 7.2%, after breast cancer. About
half of all cases of cervical cancer occur in women between 35-55 years of age.
 Breast Cancer Statistics

• 178,480 women were diagnosed with invasive breast cancer & 62,030 cases of in-situ
carcinoma of breast (85% ductal) in 2007

• A woman’s chance of getting CA increases with age to about 1:10 by age 80. In a lifetime, the
chance is 1:8

• ER-positive and ER-negative carcinomas show differences in regard to patient characteristics,

pathologic features, treatment response, and outcome

• Mortality of breast cancer has decreased from 30% to 20%. However, it is less impressive for
African American women, women in other ethnic groups, and women with ER-negative
cancers, even though the incidence of cancer is < in white women.

• Utilization of mammogram within past two years is significantly lower in women below poverty
level
Breast Cancer Statistics

• The lifetime probability of being diagnosed with breast cancer for

American women is 1 in 8 (NCI, SEER, 1997)

AGE IS the MOST

IMPORTANT RISK FACTOR

Median Age of Diagnosis is

Between 60-65 (NIH, 2000)
 EPIDEMIOLOGY

Incidence rates are highest in North America, Australia & Western Europe;
intermediate in South America, the Caribbean and Eastern Europe and
lowest in Asia (China, Japan and India) & Africa
ETIOLOGY AND PATHOGENESIS
 Breast Cancer Risk Factors
• Age
• Prior breast cancer
• High risk pre-malignant lesion LCIS, ADH
• Excess endogenous or exogenous hormones
– Early menarche
– Late menopause
– HRT
• Nulliparity or age >35 at birth of first child
• History of breast biopsies
• Family History, e.g. BRCA 1/2
• Radiation exposure before age 40
• Mammographic density
• Energy balance, lifestyle factors (alcohol)
70% of breast cancers occur in women who
have no identifiable risk factors.

This is why you are supposed to examine

yourself and have yearly Breast check up
 Hereditary Breast Cancer
(Genetics)
• The inheritance of a susceptibility gene or genes is the primary cause of
approximately 12% of breast cancer
• First degree relatives at increased risk.
• Risk even higher if the affected relative has bilateral disease, early incidence in
relative or >1 relative affected

• Li-Fraumeni syndrome (germline p53 mutations)- 25% patients affected

• BRCA1 (17q21) and BRCA2 (13q12) (tumor suppressor genes) involved in familial
cancer (5-10% of breast cancer cases and 1% of general population)

• Cowden disease (multiple hemartoma syndrome) (10q mutation)- much increased

risk
• Heterozygous carriers for ataxia-telangiectasia

The known high-risk breast cancer genes account for only about one quarter of
familial breast cancers
 Breast Cancer- Genetics
GENE % HGC BC-RISK COMMENTS
BRCA1 (17q21) 52% 40% to 90% Breast carcinomas are commonly
Familial breast (2% of all breast poorly differentiated and
and ovarian cancers) triple negative (basal-like),
cancer (1 in and have P53 mutations.
860)
BRCA2 (13q12-13) 32% 30% to 90% Biallelic germline mutations
Familial breast (1% of all breast cause a rare form of Fanconi
and ovarian cancers) anemia )
cancer (1 in
740)
p53 (17p13.1) 3% >90% p53 is the most commonly
Li-Fraumeni (1 (<1% of all breast mutated gene in sporadic
in 5,000) cancers) breast cancers
CHEK2 (22q12.1) 5% 10% to 20% May increase risk for breast
Li-Fraumeni (1% of all breast cancer after radiation
variant (1 in cancers) exposure
100)

First degree relatives at increased risk. Risk even higher if the affected relative has bilateral
disease, early incidence in relative or >1 relative affected
 Sporadic Breast Cancer
(Hormonal & other factors)
• The major risk factors for sporadic breast cancer are related to hormone exposure: gender,
age at menarche and menopause, reproductive history, breastfeeding, and exogenous
estrogens along with estrogen secreting ovarian tumors.

• The majority of sporadic cancers occur in postmenopausal women and are ER + ive.

• Hormonal exposure increases the number of potential target cells by stimulating breast
growth during puberty, menstrual cycles, and pregnancy.

• Estrogen may also play a more direct role in carcinogenesis. Metabolites of estrogen can
cause mutations or generate DNA-damaging free radicals in cell and animal model systems.

• Variants of genes involved in estrogen synthesis and metabolism could increase the risk of
breast cancer. Such variants would be analogous to cytochrome P-450 alleles that alter the
metabolism of tamoxifen in some women)
 cancer stem cell hypothesis

Cancer stem cell

Luminal cells
Myoepithelial cells
 Race

Breast Density

Radiation

Geographic influence

Breast feading

Environmental toxins

Excercise
 Relative Risk
Pathologic Lesion (Absolute Lifetime Risk)*
Nonproliferative breast changes (Fibrocystic changes) 1.0 (3%)
Duct ectasia
Cysts
Apocrine change
Mild hyperplasia
Adenosis
Fibroadenoma w/o complex features
Proliferative disease without atypia 1.5 to 2.0 (5% to 7%)
Moderate or florid hyperplasia
Sclerosing adenosis
Papilloma
Complex sclerosing lesion (radial scar)
Fibroadenoma with complex features
Proliferative disease with atypia 4.0 to 5.0 (13% to 17%)
Atypical ductal hyperplasia (ADH)
Atypical lobular hyperplasia (ALH)
Carcinoma in situ 8.0 to 10.0 (25% to 30%)
Lobular carcinoma in situ (LCIS)
 Malignant Tumours of Breast
Primary Secondary

Epithelial (Carcinoma) Non-epithelial Renal carcinoma

Melanoma etc.

In situ (15-30%) Invasive (70-85%) Lymphoma

DCIS Sarcoma
IDC
LCIS Malignant Phyllodes
ILC
Others
Paget’s disease (medullary, colloid,
mucinous, tubular,
papillary,
metaplastic)

Paget’s disease
 Classification according to origin

Mammary ducts Mammary lobules

- Intraductal carcinoma (IDC)- 80% (15-30%) - LCIS -20% (15-30%)
- Infiltrating duct carcinoma 90% (70-85%) - Invasive lobular carcinoma 10%
- No special typecarcinoma ("ductal") 79% (70-85%)

- Medullary carcinoma 2%
- Mucinous (colloid) carcinoma 2%
-Tubular 6%
-Papillary carcinomas 1%
-Metaplastic carcinoma <1%
-Adenoid cystic

-Paget’s disease 78
Recently developed techniques that examine the DNA, RNA, and proteins of carcinomas
globally have provided a framework for new molecular classifications of NST invasive
ductal carcinoma
"Luminal A" (40% to 55% of NST cancers):
ER positive and HER2/neu negative, majority are well- or moderately differentiated, and
most occur in postmenopausal women. Slow growing and respond well to hormonal
treatments. Conversely, only a small number will respond to standard chemotherapy.
"Luminal B" (15% to 20% of NST cancers):
ER & HER2/neu positive, higher grade, triple-positive cancers. They compose a major
group of ER-positive cancers that are more likely to have lymph node metastases & may
respond to chemotherapy.
"Normal breast-like" (6% to 10% of NST cancers):
Usually well-differentiated ER-positive, HER2/neu-negative cancers characterized by the
similarity of their gene expression pattern to normal tissue. It is not yet clear whether or
not this is a specific tumor expression pattern.

"Basal-like" (13% to 25% of NST cancers):

Negative for ER, PR, and HER2/neu (triple negative) and the expression of markers typical
of myoepithelial cells and progenitor cells, or putative stem cells & high grade (medullary
carcinomas, metaplastic carcinomas). Many carcinomas arising in women with BRCA1
mutations are of this type. They are associated with an aggressive course, frequent
metastasis to viscera and the brain, and a poor prognosis. However, approximately 15% to
20% will have a pathologic complete response to chemotherapy.

"HER2 positive" (7% to 12% of NST cancers):

ER-negative carcinomas that overexpress HER2/neu protein (> 90% amplification), usually
poorly differentiated, have a high proliferation rate, and are associated with a high
frequency of brain metastasis.
 Molecular Portrait of Breast Cancers

HER-2 “Normal” Luminal B

Basal-like Luminal A
This is seminal working from
Torres Sorlie, Chuck Perou, and
the Brown bostein lab to look at
molecular profiles in breast
cancer. As with all the
expression arrays I will show,
genes that are upregulated are
expressed in red, those down
regulated are expressed as green.
When Sorlie and Perou looked at
the gene expression profiles of
breast cancers, they found that
the cancers segegated into 5
clusters. Two luminal clusters,
luminal A and B, that most
closely resembled luminal
epithelium. A Normal group
who’s profile most closely
resembled normal breast tissue,
the basal like group I’ll discuss
here, and the her-2 group, which
had previously been identified
immunohistochemically.
The use of the these molecular
portraits has not made it into the
clinic yet, but this is a
technology which we hope will
prvide us predictive and
prognostic information
 Possible clinical presentations of all invasive
cancers

Hard, fixed mass

Ulceration of overlying skin
Bloody nipple discharge
Inverted or retracted nipple
Paget's disease of the nipple
"peau d' orange" (orange peel) change of overlying skin

Mammographic abnormality
With the increased use of screening mammography, advanced clinical presentations are less
common than in previous years. Patients are now frequently diagnosed with small tumors
detected as abnormal densities or microcalcifications on mammogram.
Ductal Carcinoma in situ (intraductal carcinoma)
• Tumor confined to glandular component- no stromal invasion
• Often multi-focal and can spread along ducts

• Comedocarcinoma (cells with high grade nuclei with extensive central necrosis);
Non-Comedo DCIS cribriform (cells arranged around “punched-out” spaces); papillary,
micropapillary & solid (cells fill spaces)

• 4x more common than LCIS

• 15-30% of all CA- mammography
• Calcifications; mammographic density, vaguely palpable mass or rarely discharge
• Assoc with development of invasive CA at or near the site
• Rx: Surgery + Radiation
• Cytologic features help in grading- low vs. high grade. Low (0-10%) vs. High (40%) progress
• Recurrence & increased relative risk (8-10 X) for IDC
• Mostly express ER, less often PR. Excellent prognosis –
• Mastectomy is curative in 95%
Ductal Carcinoma In Situ (DCIS)
 Lobular Carcinoma in situ
• Generally incidental- no distinguishing features at gross exam, no palpable mass and no
microcalcification.
• 1-6% of all carcinomas
• Cells of LCIS and invasive lobular carcinoma are identical in appearance and share genetic
abnormalities, such as loss of expression of E-cadherin, a transmembrane cell adhesion protein
that contributes to the cohesion of normal breast epithelial cell
• 20-40% bilateral (vs. 10-20% for DCIS) & 75% multicentric
• 30% risk of invasive disease in either breast (relative risk 9x normal). Invasive dz may be of
ductal or lobular type
• 5% have coexistent invasive CA
• Lobular cancerization of ducts
• Small, uniform epithelial cells with bland round nuclei arranged in discohesive clusters in ducts
and within the lobules. Intracellular mucin vacoules (signet ring cells) are common.
• Always expresses ER & PR. Overexpression of HER2/neu is -ive
• Minimal risk of dying from cancer if periodically examined
• Rx: Watchful waiting vs. ip/bil mastectomy & tamoxifen
Lobular Carcinoma-in-situ
 In situ carcinoma Breast

DCIS LCIS
 Paget’s Disease of Nipple

• Rare manifestation of breast cancer (1% to 4% of cases)

• Presents as a unilateral erythematous eruption with a scale crust.
• Pruritus is common, and the lesion may be mistaken for eczema.
• Malignant cells (Paget cells) extend from DCIS within the ductal system, via the lactiferous
sinuses, into nipple skin without crossing the basement membrane
• Paget cells are readily detected by nipple biopsy or cytologic preparations of the exudate.

• Palpable mass is present in 50% to 60% of women with Paget disease, and almost all of
these women have an underlying invasive carcinoma.

• Majority of women without a palpable mass have only DCIS.

• Carcinomas are usually poorly differentiated, large cells with clear cytoplasm, nucleoli &
abundant mucin, ER negative, and overexpress HER2/neu.

• Prognosis of Paget disease depends on the features of the underlying carcinoma and is not
affected by the presence or absence of DCIS involving the skin when matched for other
prognostic factors
 Paget’s Disease (Epidermal invasion)

On histologic examination, there are malignant cells lying singly or in groups within the epidermis
of the nipple. These cells often contain intracytoplasmic mucin, and stain positively for
carcinoembryonic antigen, features that identify them as malignant duct cells.
Invasive/infiltrative Ductal Carcinoma-NST/NOS

• Most common type (80%)- scirrhous

• Usually associated with DCIS but rarely with LCIS
• Penetrative (crab-like- cancer)
• Calcification-
• Tumor may be fixed to the chest wall
• Microscopically; infiltrating clusters of malignant epithelial cells surrounded by dense,
fibrous stroma (scirrhous carcinoma),, Nuclear pleomorphism and number of mitoses
• 2/3 express ER or PR &about 1/3 over-express HER-2 (ERBB2)
•
Term is used for all carcinomas that can not be classified into any of specialized subtypes
and does not indicate that this tumor specifically arise from ductal system. Synonyms to
carcinoma of “no special type” or “not otherwise specified’ (NOS)
 Infiltrating Ductal Carcinoma

Invasive Ductal Carcinoma with focal

Intraductal Carcinoma Invasive Ductal Carcinoma with focal Intraductal Carcinoma, Comedo-type
 Lobular Carcinoma
• 10% of all breast carcinomas & 2/3 of cases
are associated with adjacent LCIS
• 20% bilateral, often multicentric

• Mets to CSF, BM, GIT, Serosal surfaces, ovary,

uterus
• Mass lesion may not be present

• Single (Indian) file/targetoid, usually low grade

appearance, signet ring cells small, uniform
cells arranged as strands within a fibrous
stroma (“Indian-file”); can also infiltrate
around uninvolved ducts in “bull’s-eye” pattern

• Most express hormone receptors, but ERBB2

expression is very rare or absent

• loss of expression of CDH1 (encodes E-

cadherin)
 Inflammatory Carcinoma
• It is defined by the clinical presentation of an
enlarged, swollen, erythematous breast usually
without a palpable mass. True inflammation is
minimal or absent, the clinical appearance is due to
blockage of dermal lymphatic spaces by carcinoma
accompanied with thickened skin (Peau d’orange).

• The underlying carcinoma is generally of no special

type and diffusely invades the breast parenchyma
ER/PR negative, Her2/neu positive

• Most of these tumors have distant metastasis and the

prognosis is extremely poor
• Needs aggressive treatment
 Special Types Breast Carcinoma
Mucinous (colloid) Carcinoma
• Rare, Circumscribed
• Older women- slow growth
• Soft , gelatinous on gross
• The tumor cells are arranged in clusters
and small islands of cells within large
lakes of mucin
• Well to moderately differentiated, and ER
positive
• Better survival than ductal (12+ years
after therapy)
Tubular carcinoma
• 2-10% of all malignant tumors
• Rarely presents as palpable (multifocal) masses
• Well differentiated- very favorable prognosis
• Avg age 50 yrs (younger than ductal)
• Lymph node metastases are rare and prognosis
is good even with lymph node +
• 75% tubules (angulated)
• More than 95% of all tubular carcinomas are
diploid, ER positive, and HER2/neu negative
• Tubular carcinomas are frequently associated
with atypical lobular hyperplasia, LCIS, or low-
grade DCIS.
• Excellent prognosis
Medullary carcinoma
Comprise about 2% of cases, most common in 6th decade
Clinically well-circumscribed masses, Soft fleshy
Increased frequency in women with BRCA1 mutations
Microscopically: sheets of syncytium like large anaplastic cells (poorly differentiated) with
pushing well circumscribed borders with pronounced lymphoplasmacytic infiltrate,
overexpression of adhesion molecules and lacking hormone receptors and do not overexpress
ERBB2

Slightly better prognosis than do NST carcinomas & infrequent mitotic figures
 Other Breast Malignancies

Angiosarcoma

• Usually younger women or older

women exposed to radiation Carcinoma In Males
• Poor prognosis
• Anastomosing vascular channels
lined by atypical cells
• Low and high grade

• Rare
• Similar risk factors as women
• Usually painless subareolar mass
• Advanced stage presentation
• Early spread
• Prognosis same as women when stage-
matched
Spread of Breast
Carcinoma:
Major prognostic factors
Invasive carcinoma or in situ disease
Distant metastases
Lymph node metastases
Tumor size
Locally advanced disease
Inflammatory carcinoma

Minor Prognostic Factors

Histologic subtypes
Histologic grade
Estrogen and progesterone receptors
HER2/neu
Lymphovascular invasion (LVI).
Proliferative rate
DNA content
Response to neoadjuvant therapy
Gene expression profiling
 BREAST CANCER
Spread to lymph nodes

Supraclavicular

Subclavicular
Mediastinal
Distal (upper)
axillary Internal mammary

Central (middle)
axillary
Interpectoral
(Rotter’s)
Proximal (lower)
axillary
 Scarff Bloom Richardson System of Grading

Score

1 2 3
A. Tubule formation >75% 10-75% <10%

<7 7-12 >12

B. Mitotic count per high-power field
Near normal Slightly Markedly
Little enlarged enlarged
C. Nuclear size and pleomorphism variation Moderate Marked
variation variation

Cancer is considered grade I if the total score (A + B + C) is 3-5.

Cancer is considered grade II if the total score (A + B + C) is 6 or 7.
Cancer is considered grade III if the total score (A + B + C) is 8 or 9.
The major prognostic factors are used by the American Joint Committee
on Cancer to divide breast carcinomas into clinical stages as follows:

5-Year
M: Distant Survival
Stage T: Primary Cancer Lymph Nodes (LNs) Metastasis (%)

0 DCIS or LCIS No metastases Absent 92

I Invasive carcinoma ≤2 cm No metastases Absent 87

II Invasive carcinoma >2 cm No metastases Absent 75

Invasive carcinoma <5 cm 1 to 3 positive LNs Absent

III Invasive carcinoma >5 cm 1 to 3 positive LNs Absent 46

Any size invasive carcinoma ≥4 positive LNs Absent

Invasive carcinoma with skin or 0 to >10 positive LNs Absent

chest wall involvement or
inflammatory carcinoma
IV Any size invasive carcinoma Negative or positive Present 13
lymph nodes
 Treatment

• Local and regional control, using combinations of surgery

(mastectomy or breast conservation) and postoperative radiation,
and systemic control, using hormonal treatment (tamoxifen) or
chemotherapy or both.

• Axillary node dissection or sentinel node sampling is performed for

prognostic purposes, but the axilla can also be treated with radiation
alone.

• Newer therapeutic strategies include inhibition (by pharmacologic

agents or specific antibodies) of membrane-bound growth factor
receptors (e.g., HER2/neu), stromal proteases, and angiogenesis.
 Gynecomastia

• Enlargement of male breast- hypertrophy

and hyperplasia

• Increased estrogen to androgen ratio

• Puberty- alcohol, cirrhosis, drugs,

Klinefelter's syndrome (testicular
feminization), testicular tumors

• Button or disc-like stromal enlargement

• Ductal epithelial hyperplasia, periductal

stromal edema, and loose fibrosis around
ducts.
 Targeting the
Estrogen Pathway
Block receptor
SERM (selective estrogen
receptor modulators)
Tamoxifen treatment
Raloxifene prevention

Decrease ligand
Aromatase inhibitors
Oopherectomy
GnRH analogs
 HER-2: Trastuzumab
Bench to Bedside
Targets HER2 protein
HER2 epitopes recognized by
hypervariable murine
High affinity (Kd = 0.1 nM) and
antibody fragment specificity
95% human, 5% murine
Decreases potential
for immunogenicity
Increases potential for recruiting
immune effector mechanisms
Human
IgG-1 Early-stage breast ca: 2005
- Herceptin + Chemo
↑OS ↑DFS
 Overview: Molecular Targets
Immune System Activation
(Vaccines, Monoclonal
Antireceptor antibodies)
Antibodies Metalloproteinase
± Toxins Inhibitors
Tumor Cell
Antimetabolites
Growth
Microtubule inhibitors
Factor
Tyrosine Kinase Matrix Degradation
Receptors
Inhibitors Nucleus (Collagenases,
Gelatinases &
Farnesyl
Stromelysins)
Transferase Intracellular
Inhibitors Signaling
Molecules

Angiogenesis Inhibitors
Apoptosis (Angiostatin, Endostatin
Agonists & Anti-VEGF)
Hormone Agonists/ Antisense
Antagonists
 Challenges for the future
• Identify women more specific risk profiles and tailor
preventive interventions
• Identify subsets of patients for whom systemic
therapy can be avoided
• Tailor systemic therapy to individual tumor/host
characteristics
– Targeted therapy: ER, HER2, EGF-R, PARP Inhib
– Novel targets and pathways
CURRENTLY USED CLASSIFICATION

COMBINATION OF TISSUE OF ORIGIN AND BEHAVIOUR

PATTERN

Supplemented by histological description

Suffix “oma” is used to denote neoplasm
TUMOR NOMENCLATURE

Benign tumor of surface epithelia are:

PAPILLOMA

Benign tumors of solid or glandular epithelia are:

ADENOMA
(when tumor has dilated glandular spaces Cystadenoma)

Malignant tumors of surface epithelial are:

CARCINOMA

Malignant tumors of glandular epithelia are:

ADENOCARCINOMA
TUMOR NOMENCLATURE (continued--)

Benign tumors of connective tissue are named after the tissue of origin by
adding suffix “oma”
like- chondroma fibroma etc.

Malignant tumors of connective tissue named after the tissue of origin by

adding suffix “sarcoma”
Like- chondrosarcoma, fibrosarcoma etc.
EXCEPTION TO THE ABOVE RULES

Tumor arising from specialized connective tissue

(neuroglia, ependyma, lymphoid & hematopoietic tissue, melanocytes & chromaffin
tissues)

Tumors arising from fetal trophoblasts

Tumors arising from Germ cells

Tumors arising from Embryonic tissues

Tumor arising from Embryonic vestiges

Hemartomas
POD-MCQ-28

A 50-year-old man has had increasing fatigue for the past 3 months. On physical
examination he has a palpable spleen tip. Laboratory studies show a WBC count
of 129,000/uL. The peripheral blood smear shows many mature and immature
myeloid cells present. Cytogenetic analysis of cells obtained via bone marrow
aspiration reveals a t(9:22) translocation. Which of the following genes is most
likely translocated to cause these findings?

A. HER-2
B. RB
C. FAP
D. ABL
E. RAS
POD-MCQ-29

A 56-year-old man has had a chronic cough for the past year. He is a non-smoker.
He had an episode of hemoptysis 3 days ago. No abnormal findings are noted on
physical examination. A chest x-ray demonstrates a 6 cm perihilar mass. A
sputum sample is collected, and the sputum cytology report reads 'Atypical cells
present suggestive of squamous cell carcinoma.' Which of the following
environmental exposures is most likely to be associated with these findings?

A. Asbestos
B. HPV
C. Vinyl chloride
D. Nitrosamine
E. Radon

Khurshid
POD-MCQ-30

A 64-year-old woman presented with an 8 cm firm mass with irregular borders in

her left breast. Biopsy of the mass confirmed the diagnosis of invasive ductal
carcinoma. Four weeks after surgical resection of the mass she is given radiation
therapy to destroy undetectable cancer cell. Which of the following cellular
mechanisms is most likely to account for this type of treatment?

A. Point mutations in DNA

B. Generation of free radicals
C. Loss of the blood supply
D. Secondary inflammation
E. Adenosine triphosphate depletion

Khurshid
POD-MCQ-31

A 38-year-old male has felt lumps in his right neck for the past 4 months. On
physical examination there is painless lymphadenopathy in the right cervical
region. One of the lymph nodes is biopsied and on microscopic examination
shows effacement of the nodal architecture by many lymphocytes that are large,
with clumped chromatin and occasional mitoses. The characterization of this
population of lymphocytes as a neoplasm is best accomplished by which of the
following methods?

A. Flow cytometry indicating high S-phase

B. Immunohistochemical stain for leukocyte common antigen
C. Gene rearrangement studies demonstrating clonality
D. Differential white blood count showing a lymphocytosis
E. Light microscopy demonstrating nodal fibrosis

Khurshid
AU-NS-PATH-MCQ-01

A 45-year-old woman was hospitalized with a severe respiratory infection. Two

weeks later, she presented to her primary care doctor's office with pain and
weakness of the lower limbs. Physical exam revealed facial-muscle weakness,
flaccidity, and loss of deep tendon reflexes. Which of the following findings is
most likely on cerebrospinal fluid analysis?

A. Increased neutrophils and protein, decreased glucose

B. Increased lymphocytes and protein, normal glucose
C. Normal white blood cells, increased protein, and normal glucose
D. Oligoclonal bands
E. Increased lymphocytes and protein, decreased glucose

Khurshid
AU-NS-PATH-MCQ-01

A 45-year-old woman was hospitalized with a severe respiratory infection. Two

weeks later, she presented to her primary care doctor's office with pain and
weakness of the lower limbs. Physical exam revealed facial-muscle weakness,
flaccidity, and loss of deep tendon reflexes. Which of the following findings is
most likely on cerebrospinal fluid analysis?

A. Increased neutrophils and protein, decreased glucose

B. Increased lymphocytes and protein, normal glucose
C. Normal white blood cells, increased protein, and normal glucose
D. Oligoclonal bands
E. Increased lymphocytes and protein, decreased glucose

Khurshid