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PATHOLOGY

BOOBIES
Dr. Soccorro Cruz-Yanez

January 3, 2012

NORMAL ANATOMY OF THE BREAST

Histology

In humans, paired mammary glands rest on the pectoralis


muscle on the upper chest wall
The breasts are composed of specialized epithelium and
stroma that may give rise to both benign and malignant
lesions.
Histologically, the following are present:
o Lobe 10 in one whole breast
o Lobule Many per lobe
o Acinus/Alveolus Many (5-10) per lobule
Functional secretory unit of the breast
The pathology of the breast is related to the origin of
the functional anatomy of the particular area.
o Ducts Intra or interlobular leading to the lactiferous ducts
in the nipple and is the non-secretory that just conducts
milk
6 10 major ductal system, subdivided into lobules
Successive branching of the large ducts eventually leads to
the terminal duct lobular unit
In adult women, the terminal duct branches into a grapelike
cluster of small acini to form a lobule
Each ductal system typically occupies more than one
quadrant of the breast, and the systems extensively overlap
one another
Drains to lactiferous sinuses

Mammary Lobules
- The secretory units of the breast
- Each lobule consists of a variable number of acini, or glands,
embedded within loose connective tissue and connecting to
the intralobular duct
- Each acinus is lined by two types of cells,
1. Epithelial
2. Myoepithelial
1. Epithelial or ductal cells (columnar, luminal location)
- Luminal epithelial cells overlay the myoepithelial cells.
- Only the lobular luminal cells are capable of producing
milk.
- Responsible for secretion
2. Myoepithelial (investing, basal location)
- Also known as Sentinel Cells
- When these cells are present, it indicates the presence of
a benign Lesion
- Contractile myoepithelial cells containing myofilaments lie
in a meshlike pattern on the basement membrane.
- These cells assist in milk ejection during lactation and
provide structural support to the lobules

Fig. 3. Normal histology of breast acinus

Fig. 1. Normal breast histology

Notes:
Functional unit of secretion of milk for nourishment of baby
Made up of several lobules of mammary breast draining
into the nipple
Drainage of lymphatic channels Disease of breast,
st
particularly malignancy, breast carcinoma: 1 line of
metastasis is regional lymph node, particular axillary node
(80-90%), internal mammary group of chain of lymph node,
particularly the inner quadrant of the breast, and
supraclavicular group of lymph node.

Lymphatic Drainage
Axillary Most common site because tumor cells in the outer
quadrant travels this drainage
Internal Mammary Where tumor cells in the Inner Quadrant
enter and travel to the intrathoracic artery
Supraclavicular If this is affected, it indicates a more
advanced stage of a disease

Fig. 2. Lymphatic drainage of the breast

SECTION B

There are also 2 types of breast stroma:


1. Interlobular stroma Consists of dense fibrous
connective tissue admixed with adipose tissue.
2. Intralobular stroma Envelopes the acini of the lobules
and consists of breast-specific hormonally responsive
fibroblast-like cells admixed with scattered lymphocytes.
There is important cross-talk between breast epithelium
and stroma that promotes the normal structure and
function of the breast.
3 Normal phases of breast development:
1. Active Gland and Stroma ratio are equal (50:50)
2. Lactating
- Mostly glands
- There are more glands than stroma due to an increase
in the secretion and proliferation of glands
- This can be observed in pregnancy
- This enlargement isnt purely fatty but because theres
an increase in the number of lobules. (>>>50/50)
- Active production of milk, after pregnancy
3. Atrophic
- Mostly stroma
- More strome than glands (<<<50/50)
- Seen in post menopausal female and pre-pubertal age
group

Fig. 4. Left: Active phase. Middle: Lactating phase. Right: Atrophic phase

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ANATOMIC SITES OF BREAST LESIONS

Laboratory Diagnosis of Breast Cancer

Majority of diseases of the breast are in the female because


of the active physiologic function of the organ.
Some Anatomic Sites of Breast Lesions
o Lobule Fibroadenoma, cyst, lobular carcinoma
o Terminal duct Hyperplasia, breast carcinoma
o Lactiferous duct Intraductal papilloma
o Nipple Pagets disease
o Nipple, Lactiferous duct Nipple adenoma

A. Imaging
- Mammography (age 40 screening mammography)
i. Densities
Most neoplasms are radiologically denser than
the intermingled normal breast tissue.
The average size of an invasive carcinoma
detected by mammography (1.1cm) is less than
half that of carcinomas detected by palpation
(2.4cm)
ii. Calcification (Malignant Heavy speckled type of
whitish calcification that are group around)
They form on secretions, necrotic debris, or
hyalinized stroma.
Ductal carcinoma in situ (DCIS) is most
commonly
detected
as
mammographic
calcifications, which are deposited in a linear,
branching pattern as the carcinoma fills the
ductal system.
- Ultrasound, MRI
B. Biopsy
- Fine Needle Aspiration
- Tissue biopsy
- Immunohistochemistry

Fig. 5. Sites of breast lesions

Clinical Presentation of Breast Disease


1. Pain (mastalgia/ mastodynia)
- Diffuse cyclic pain No pathologic correlate; more on
hormonal changes
- Noncyclie pain Usually localized to one area of the
breast (Causes: ruptured cysts, physical injury, infections,
but most often no specific lesion is identified
- 95% of painful masses are benign
- Usually associated with hormonal cyclic changes
Menstruation
- Associated with inflammatory condition to the breast,
particularly with sign of tenderness
- 10% of breast cancers are painful
2. Mass (palpable or detected through mammography)
- Discrete palpable masses are common and must be
distinguished from the normal nodularity or lumpiness of
the breast.
- Non-palpable lesions called densities (lumpiness on
breast) can be detected through mammography
- Invasive carcinomas, fibroadenomas, cysts
- At least 2 cm size breast mass to become palpable
- Most common in premenopausal women but the likelihood
of a palpable mass being malignant increases with age
(age directly proportional to malignancy)
3. Nipple Discharge/ Retraction
- Less common finding
- Most worrisome when it is spontaneous and unilateral
since it might be from an underlying carcinoma
- The risk of malignancy with discharge increases with age.
1. Milky discharge (galactorrhea)
- Not associated with malignancy
- Associated with elevated prolactin levels (eg. Pituitary
adenoma), hypothyroidism, or endocrine anovulatory
syndromes, oral contraceptives, TCA drugs,
methyldopa, phenothiazines
2. Bloody or serous discharge
- Most commonly associated with benign conditions
- The most common etiologies are solitary large duct
papillomas and cysts.

PATHOLOGY OF THE BREAST


1.
2.
3.
4.
5.
6.

Disorders of development (congenital maldevelopment)


Inflammatory conditions (mastitis)
Pathology of breast implants
Fibrocystic changes (hormonally related, not a real tumor)
Proliferative breast diseases
Tumors, either benign or malignant which originate from
- Epithelial cells
- Stromal cells
- Epithelial/stromal

Disorders of Development
Supernumerary Nipples Disease (Milkline remnants)
Due to persistence of epidermal thickening along the milk line,
which extends from the axilla to the perineum
2 or more nipples
can occur in both males and females
Heterotopic, hormone-responsive foci, which most commonly
come to attention as a result of painful premenstrual
enlargements
Developmental anomaly

Fig. 6. Nipple lines from the axilla to the pubic region. Also known as milk lines

Accessory Axillary Breast Tissue


Breast epithelium outside of the breast proper (axillary area)
might undergo lactational changes or give rise to tumors that
appear to be outside the breast
Nodular growth pattern at the axillary line
Rudimentary protrusion of the lactiferous side
Breast tissue in the axillary area Clinically in apparent
Fibroadenoma arising from accessory breast
Carcinoma of the breast arising from the axillary area

Fig. 7. The most common location of an accessory breast is the axilla.

SECTION B

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Note:
Breast tissue always extends to the axilla, and when it does
form an actual protuberance, it can be called an accessory
breast. Breasts are modified apocrine sweat glands
embryologically.

Nipple Inversion

Particularly occurs in women with large or pendulous breasts


Congenital or acquired
Failure of the nipple to evert during development
It is common and may be unilateral
Congenitally inverted nipples usually correct spontaneously
during pregnancy, or can sometimes be everted by simple
traction
One of the cardinal signs of breast CA
Majority caused by inflammation (fat necrosis, ductal ectasia,
piercings-acquired)

Fig. 8. Inverted nipple

Macromastia

Abnormal enlarged breast


May be unilateral or bilateral
Symmetrical enlargement
May be due to variations in body habitus or to an unusual
tissue response to hormones

Fig. 9. Macromastia

Inflammatory Conditions
Inflammatory diseases of the breast are uncommon.
Women usually present with an erythematous, swollen painful
breast
Inflammatory Disorder:
1. Acute Mastitis
2. Periductal Mastitis
3. Mammary Duct Ectasia
4. Fat Necrosis
5. Granulomatous mastitis
6. Lymphocytic Mastitis
7. Silicone Breast Implants
Note:
Periductal mastitis, mammary duct ectasia and fat
necrosis may be mistakenly clinically seen as malignancy
due to same clinical presentation like scarring and nipple
inversion.
Be sure to know the difference among the inflammatory
disorders, like how acute mastitis morphologically differ
from lymphocytic mastitis.

Acute Mastitis
Almost all cases of acute mastitis occur during the first month
of breastfeeding.
Difficulty during lactation
Associated with breaks, cracking in the skin, lactation
(mechanical trauma due to sucking of the baby) Breast is
vulnerable to bacterial infection
Big, swollen, erythematous painful breasts with pus, fever
Predominant inflammatory cells: Neutrophils inside the ducts
and stroma

SECTION B

S. aureus (more common) from skin & strep: Usual etiologic


agents
Staph infection
o Localized area of suppurative inflammation
o Redness, tenderness, pain and fever
o Single/multiple abscesses
Strep infection
o Seat of inflammation is diffuse throughout the parenchyma

Fig. 10. Left: Gross There is erythema and edema. Right: Histological Hallmark
Presence of many pigmented neutrophilic infiltration(yellow arrow) inside the ducts.

Periductal Mastitis
Also known as Recurrent Subareolar Abscess, Squamous
Metaplasia of lactiferous ducts, Zuska Disease
Subareolar location
Seat of inflammation is around the duct
Presents with a painful, erythematous, subareolar mass that
clinically appears to be an infectious process.
Recurrences are common
More than 90% of the afflicted are smokers
o Vitamin A deficiency associated with smoking or toxic
substances in tobacco smoke alter the differentiation of
the ductal epithelium
This condition is not associated with lactation, a specific
reproductive history, or age.
May be mistaken clinically for carcinoma due to fibrosis,
scarring, induration and nipple inversion.
Can present clinically as a malignant lesion because of
presentation
Many women with this condition have an inverted nipple, most
likely as a secondary effect of the underlying inflammation
Location is very important: Centrally beneath the nipple
Histology
- Squamous metaplasia of lactiferous duct (normally cuboidal
lining)
- Keratin trapping and duct dilatation Rupture of duct
- Chronic and granulomatous inflammation Develops once
keratin spills into the surrounding preductal tissue
- The inflammation is PERI-ductal, not Intraductal that is why
you would see the inflammatory cells surround the ducts.

Fig. 11. The key histologic feature is keratinizing squamous metaplasia of the nipple
ducts; it also shows lymphocytic infiltration around the dilated ducts(upper left).

Note:
Remember! DILATED, LYMPHOCYTE around the ducts and
METAPLASIA.

Mammary Duct Ectasia

Plasma cell Mastitis


Ductesia: Dilated ducts
Presents with a history of difficulty of lactation
Usually occur in 5th or 6th decade of life, multiparous women
Not associated with cigarette smoking (vs. Periductal
mastitis)
Malignant clinical presentation: Irregular firm induration
periareolar mass ,thick white nipple discharge, nipple/ skin
retraction (due to fibrosis that is why nipple retracted)
Principal significance of this disorder is that it produces an
irregular palpable mass that mimics the mammographic
appearance of carcinoma

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Histology:
- Dilated ducts filled with granular, necrotic debris
- Necrotic, atrophic lining
- Periductal & interductal chronic granulomatous inflammation:
(+) Lymphocytes, macrophages
- Squamous metaplasia of nipple ducts is absent.

Fig. 12. Mammary Duct Ectasia, dilated ducts can be seen and atrophic lining.
Some fibrosis is appreciated.

Fat Necrosis
History of trauma, prior surgery or radiation therapy or those
with big pendulous breasts
Can present as a painless palpable mass, skin thickening or
retraction, a mammographic density, or mammographic
calcifications
Clinically simulate malignancy due to firm fibrosis occurring at
late stages of fat necrosis
The major clinical significance of this condition is its possible
confusion with breast cancer.
Histology:
- Early: Central focus of fat, necrosis, surrounded by lipid,
macrophages, inflammatory cells
- Late: Fibrosis, calcification

Lymphocytic Mastitis
Also known as Lymphocytic Mastitis/Lymphocytic
Mastopathy/ Sclerosing Lymphocytic Lobulitis
Diabetic Mastopathy
Most common in women with Type 1 DM or autoimmune
thyroid disease
Non-Bacterial etiology
Related to Inflammation
A prominent lymphocytic infiltrate surrounds the epithelium
and small blood vessels
Destruction of mammary alveolus
Single or multiple hard irregular palpable masses (The lesions
are so hard that it can be difficult to obtain tissue with needle
biopsy) Malignant clinical presentation
The major clinical significance of this condition is its possible
confusion with breast cancer.
Microscopic findings:
o Collagenized stroma
o Atrophic ducts and lobules
o Thickened BM
o Prominent lymphocytic inflammatory infiltrates

Fig. 15. Lymphocytic Mastitis, plasma cell and lymphocyte can be seen.

Pathology of Implants
Silicone Breast Implants

Fig. 13. Fat necrosis, some calcification are seen and necrosis of fat cells which
looks like ghost cell.

Histologic response to implants is chronic granulomatous


inflammation, giant cell reaction and fibrosis
Silicone gel seeps bleeds through intact silicone shells
Silicone breast implant: Refractile, glassy, crystalline matter
found in the connective tissue stroma, surrounded by chronic
inflammatory process
Leak and puncture get into the tissue, inside form a foreign
body granulomatous inflammation

Granulomatous Mastitis

Non-bacterial etiology
Idiopathic
Non-caseous type of TB
Associated with systemic granulomatous
disease,
mycobacteria, fungal infection, immunocompromized, foreign
body, hypersensitivity reaction associated with lactation
Causes include systemic granulomatous diseases that
occasionally involve the breast, and granulomatous infections
caused by mycobacteria or fungi
Most common in immunocompromised patients or adjacent to
foreign objects such as breast prostheses or nipple piercings
Granulomatous Lobular Mastitis is an uncommon breastlimited disease that only occurs in parous women
The granulomatous inflammation is confined to the lobules,
suggesting that it is caused by a hypersensitivity reaction to
antigens expressed by lobular epithelium during lactation.

Fig. 14. Granulomatous mastitis, giantcells are seen and can be mistaken for
TB therefore differentiated with an AFB stain.

SECTION B

Fig. 16. Silicone Breast Implant, the white parts are silicone that has leaked.

BENIGN EPITHELIAL LESIONS


Fibrocystic Changes
rd

th

Most common breast disorder, 3 -4 decade of life


Non proliferative breast changes
Not a tumor, not neoplasm, underlying pathology is hormonal
(lumpy bumpy)
Pathogenesis: Hyperestrenism
o Ask patient is she had a history of estrogen therapy
Increase proliferative activity
Target cells are mammary lactiferous breast cell Induce
proliferative activity
Produces hypernodularity
Principal morphologic changes:
o Cyst
Formation with apocrine metaplasia: From dilation
and unfolding of lobules, change of columnar ductal
cell Columnar apocrine cell
Cysts are alarming when they are solitary and firm to
palpation
The diagnosis is confirmed by the disappearance of
the cyst after fine needle aspiration of its contents.

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o Fibrosis
As cysts rupture, chronic inflammation and scarring
fibrosis result Palpable firm breast
o Adenosis
Increase in the number of acini per lobule
The acini are line by columnar cells, which may
appear benign or show atypical features (flat epithelial
atypia)
These atypical features may be the earliest
recognizable precursor of epithelial neoplasia
o Ductal epithelial hyperplasia (ducts affected have
increased proliferative activity.
This is more worrisome due to the increased risk of
malignancy.

Sclerosing Adenosis
Increased number (to at least double the number) of distorted
and compressed acini within the lobule, CT sclerosis within
the mammary lobule
The normal lobular arrangement is maintained
Myoepithelial cells are usually prominent
Firm with induration
May be confused with Breast CA because of the CNT
proliferation
1-2 times increased risk of malignancy

Fig. 20 Sclerosing adenosis. There is connective tissue that grows inside the
adenotic lobule

Ductal Papilloma

Fig. 17. Fibrocystic Disease. There is adenosis beside the cysts. Without
hyperplasia = no risk of malignancy. With hyperplasia, high incidence of malignancy

Fig. 18. Left: Blue dome cyst which appears to be like dome, brown to blue cyst
due to leak with contamination of blood. Right: The encircled is the fibrocysts
surrounding the connective tissue and nodular upon palpation.

Are clinically silent


Composed of multiple branching fibrovascular cores, each
having a connective tissue axis lined by luminal and
myoepithelial cells
Growth occurs within a dilated duct
(+) Epithelial hyperplasia and apocrine metaplasia
Large duct papillomas are usually solitary and situated in the
lactiferous sinuses beneath the nipple
Small duct papillomas are commonly multiple and located
deeper within the ductal system
Note:
Number 1 commandment in pathology: NEVER diagnosis a
malignant papilloma on a frozen section!! NEVER. Dr. Yanez

Fibrocystic Change: Clinical Significance


No risk of carcinoma in the absence of proliferative breast
disease
No ductal hyperplasia, the risk of carcinomas zero
Carcinoma increased 25 times if with ductal epithelial
hyperplasia.

Fig. 21. Hyperplastic proliferation of duct which is confined in the ductal lumen

Proliferative Disease Without Atypia


Typically more than one lesion is present, frequently in
association with proliferative breast changes
Characterized by proliferation of ductal epithelium and/or
stroma without cytologic or architectural features suggestive
of carcinoma in situ.
2 cell layer rule is broken
Solid cribiform proliferation

Ductal Epithelial Hyperplasia

Increased proliferation of the lining cells (>2 layers)


2 cell rule is broken
The lumen is practically non-existent
The additional cells consist of both luminal and myoepithelial
cell types that fill and distend ducts and lobules.
Benign since myoepithelial cell is appreciated (since
malignancy is associated with monoclonal proliferation which
means, once it is already malignany; myoepithelial cell is not
appreciated.)
Usually an incidental finding

Fig. 19. Left: Normal ductal epithelium. Right: Ductal hyperplasia (more than 2
layers of cells)

SECTION B

Proliferative Disease With Atypia


Associated with increased risk of malignancy
Increase mitosis, pleomorphic, increase nucleus, irregular
chromatin pattern
Atypical hyperplasia is a cellular proliferation resembling
carcinoma in situ but lacking sufficient qualitative or
quantitative features for diagnosis as carcinoma.
Atypia: Increase cells showing mitoses; pleomorphism,
nucleoli is seen, irregular chromatin pattern.

Atypical Ductal Hyperplasia (ADH)


Histologic resemblance to ductal carcinoma in situ (DCIS)
Shows hyperchromaticity, more rounded cells, N:C ratio
disturbed, and loss of cellular polarity
2 cell rule is broken
It is distinguished from DCIS by being limited in extent and
only partially filling ducts.

Fig. 22. Atypical Ductal Hyperplasia. No invasion of the stroma is seen. Atypical
cells are appreciated.

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Atypical Lobular Hyperplasia (ALH)


It is defined as a proliferation of cells identical to those of
lobular carcinoma in situ (LCIS), but the cells do not fill or
distend more than 50% of the acini within a lobule.

Phyllodes Tumor

Fig. 23. Atypical Lobular Hyperplasia

Clinical Significance
Increase risk of carcinoma is proportional to the type of PBD
(Proliferative Breast Diseases) and presence of atypia
No risk: Adenosis, cysts, apocrine metaplasia and mild
epithelial hyperplasia
No atypia = No risk of malignancy
Type of Atypia: Mild, Moderate, Severe
Slight increase: 1.5-2 times Sclerosing adenosis, moderate
to florid epithelial hyperplasia, papillomas
Moderate increase risk: 4-5 times ADH, ALH

Benign Breast Tumors


Stromal Tumors
Recall: There are 2 types of stroma in the breast- intralobular
and interlobular
o Intralobular stroma:
Fibroadenoma
Phyllodes tumor
o Interlobular stroma:
Lipomas
Angiosarcomas
Pseudoangiomatous stromal hyperplasia
Myofibroblastomas
Fibrous tumors

Fibroadenoma
Most common benign tumor of female breast
A new growth composed of fibrous and glandular tissue
More common before 30 yrs of age [previous trans says
before 20-30 yrs of age]
Morphology
o Spherical nodule, sharply circumscribed, freely movable,
palpable, soft, rubbery mass, small, demarcated, no
fixation
o VS Malignant
Irregular, thick, poorly demarcated border, firm gritty
to stony hard
o Frequently occur in the upper outer quadrant
o Size varies from 1cm to 10-15cm (giant!)
o Fibrous stromal and ductal epithelial proliferation

Also known as Cystosarcoma phylloides


Epithelial stromal tumor, resembles fibroadenoma
Large bulky tumor with bulbous protrusions
Older population (mean age 45)
High incidence of recurrence
Benign(majority), Intermediate malignancy and Malignant
categories
Malignant counterpart with stromal atypia due to overgrowth
and pleomorphism of the tumor
closely resembles Fibroadenoma
Phylloides Tumor is characterized by having MORE CELLS in
the stroma and is a bulkier lesion than Fibroadenoma
When the stroma becomes atypical, and the glands
proliferate, then it becomes a Malignant Phylloides Tumor

Gross
- Large , bulky , well circumscribed, cleft like spaces
- Hemorrhage, necrosis , cysts
Histology
- Stromal hypercellularity
- Not true sarcoma
- More fibroblastic cells within the connective tissue
- Benign glandular elements, often in canalicular slits with or
without hyperplasia

Fig. 26. Left: Gross Notice the well circumscribed, cleft-like spaces. Right:
Histology There is increased stromal cellularity, cytologic atypia, and stromal
overgrowth giving rise to the typical leaflike structure.

Criteria of Malignancy:
o Stromal cell atypia
Mitosis
Pleomorphism
Nuclear atypia
o Cellular stroma overrunning epithelial component
o Infiltrative borders vs pushing borders
Clinical Behavior
o Tendency for local recurrence
o Malignant PT, metastasis by hematogenous route

Breast Carcinoma
Carcinoma of the breast is the most common non-skin
malignancy in women
The majority of carcinomas are estrogen-positive (ER)
positive.

Incidence and Epidemiology


Most common malignant tumor of female
Affects 1 of 9 women in the U.S., especially those who live in
urban populations
Increases with increasing age
More frequent in women of low parity with first child after 30

Fig. 24. Left: Gross White circumscribed tumor in the middle. Right:
Mammography showing calcification

Risk Factors

In obesity because fat can be metabolized to estrogen


With prior breast biopsies showing atypical hyperplasia
With history of breast carcinoma
In women with mother or sibling with breast cancer
With mutations in BRCA1 or BRCA2 genes in hereditary
breast Ca, mutation in the tumor suppressor gene, p53
Gender: Rare (1%) in male
Age: 61 yrs Average age of diagnosis

Fig. 25. Proliferation of intralobular stroma: ducts are compressed.

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Age at Menarche
o Those <11 years of age have a 20% increased risk
compared to women who reach menarche when >14
years of age
o Late menopause also increases risk.
Age at First Live Birth
o Women with a first full-term pregnancy at <20 years old.
Race / ethnicity: Highest among white americans
Estrogen exposure Hormonal Replacement Therapy 1.2 to
1.7 increase risk
Oral Contraceptive use
High breast radio density
Radiation exposure
Carcinoma of contra lateral breast Ca ( 1 % ) and ovarian
Ca
Diet:
o Increase risk: Alcohol, fat
o Decrease risk: Caffeine
o Post menopausal Obesity
Exercise: Protective factor
Breast feeding --. Lower risk
Environmental Toxins (pesticides)
Tobacco

Etiopathogenesis
The major risk factors for the development of breast cancer
are hormonal, radiation and genetic
Breast cancers can therefore be divided into sporadic cases,
probably related to hormonal exposure, and hereditary cases,
associated with germline mutations.
Hormonal factors
o Hyperestrenism, endogenous and exogenous
Environmental factors
o Radiation
o Diet: Fat, moderate alcohol consumption
Increasing age
Proliferative breast disease
CA in contralateral breast
Parity
o Decreased parity Higher risk
o When the woman is pregnant, theres an interruption in
estrogen production there less risk for breast CA
Obesity
Genetic factors
o Gene line mutations in BRCA1 and BRCA2, p53,
Autosomal inherited
o sSngle gene mutation of breast susceptible cancer
gene: BRCA1 and BRCA2, p53
o BRCA1 : 17q21
Increase risk of developing ovarian CA
Poorly differentiated , triple negative IHC
(-) ER, Estrogen, Progesterone, HER2
Poor prognosis, alternative hormonal treatment is not
an option
o BRCA2: 13q12-13
Associated carcinoma
Ovarian(lesser extent), prostate, pancreatic stomach
CA
Poorly differentiated, more often ER positive.
Amenable for hormonal treatment
o Germline mutation of p53 (17p13.1)
Associated with Li-Fraumeni syndrome with sarcoma,
lymphoma, leukemia, brain tumors
Sporadic breast cancer
o Major risk factors related to hormone exposure
o Usually post-menopausal and are ER +
o Well-differentiated

SECTION B

Histologic Types of Breast CA


A. In situ Ca
- Ductal Ca in situ
- Lobular Ca in situ
B. Invasive ( infiltrating ) Ca
- Ductal ca
- Lobular Ca
- Tubular Ca
- Colloid (Mucinous Ca )
- Medullary Ca
- Papillary Ca

15 30 %
80 %
20 %
70-85 %
79 %
10 %
6%
2%
2%
1%

Features of Atypia

Loss of stroma between acini


Swiss-Cheese hyperplasia *
Cribriforming **
Cellular pleomorphism
Cellular hyperchromasia
Increased abnormal mitosis *
Roman bridges***
Necrosis *** (COMEDO-carcinoma)

Note:
The asterisked items, are more suspicious than the nonasterisked items. Intraductal NECROSIS is the most suspicious
feature of all.

Invasive Breast Carcinoma

Ductal Carcinoma in Situ (DCIS)


Also known as Intraductal Carcinoma
Increase incidence due to mammographic screening
o Among cancers detected mammographically, almost half
are DCIS
Tumors confined within ducts Malignant population of cells
limited to ducts and lobules by the basement membrane
Progression to invasive carcinoma
Myoepithelial cells are preserved, but may be diminished in
number
DCIS is a clonal proliferation and usually involves only a
single ductal system
Tumor confined in the duct
Presence of Roman Bridge
Types:
a. ComedoCa
b. Noncomedo DCIS
c. Pagets disease of the nipple

A. Comedocarcinoma (High-grade DCIS)


Characterized by solid sheets of pleomorphic cells with highgrade nuclei and central necrosis, calcification commonly
detected on mammogram
When the breast is squeezed, a paste like substance oozes
out of the nipple
NECROSIS in a hyperplastic duct is usually DCIS

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Lobular Carcinoma in Situ (LCIS)

B. Non-comedo DCIS
Consists of a monomorphic population of cells with nuclear
grades ranging from low to high
Solid without necrosis
Morphologic variants:
o Cribriform DCIS
o Solid DCIS
o Papillary DCIS
o Micropapillary DCIS

Fig. 27. Left: Roman Bridges. Right: DCIS comedo pattern.

C. Pagets Disease of the Nipple


Rare manifestation of breast carcinoma
Presents as a unilateral erythematous eruption with a scale
crust, nipple appear fissured, ulcerated and oozing
Pruritus is common, might be mistaken for eczema
Ulceration and involvement of the external skin can be
observed
o Form of DCIS that extends from the nipple ducts into
contiguous skin of nipple.
50-60 % associated with underlying invasive ductal CA
Importance: Infiltration of the breast
Presence of Paget cells in the epidermis
o Paget cells Lymphatic, large, round cells with
perinuclear halo. Atypical, look like duct cells.
Progression to invasive carcinoma

Proliferation of terminal ducts, acinar lobules


Bilateral in 50-70 %: Must do a contralateral mammography to
check for malignancy
Due to its bilaterally, do a mirror image biopsy
Presence of signet ring cells containing mucin
Slowly growing , many years before it infiltrates, in contrast to
DCIS
The best management may be judicious neglect, i.e.,
observation
o Dra. Yanez said to disregard this, if detected, treat it
immediately
If it does infiltrate, however, it is at least as bad as DCIS
infiltrating, or probably WORSE, showing Indian files
Always an incidental finding in a biopsy performed for
another reason, as it is not associated with calcifications or a
stromal reaction that would form a density
More common in young women, 80% to 90% of cases
occurring prior to menopause
ALH, LCIS, and Invasive Lobular Carcinoma all consist of
dyscohesive cells with oval or round nuclei and small nucleoli

Fig. 29. LCIS: A whole lobule filled with monotonous cells of the same type can be
called LCIS, or lobular carcinoma in situ.

Inflitrating Ductal CA
Also known as Invasive carcinoma, No Special Type
(NST/Invasive Ductal Carcinoma)
70 80 % of breast carcinoma
Originates from ducts with invasion into stroma
May have pronounced desmoplasia (Fibrosis) Scirrhous
carcinoma
Most carcinomas induce a marked increase in dense, fibrous
desmoplastic stroma, giving the tumor a hard consistency on
palpation and replace fat, resulting in a mammographic
density (scirrhous carcinoma)

Fig. 28. Paget cells

Classification of DCIS
Based on cyto-nuclear
grade and
architectural growth pattern and necrosis
Grading Classification:
o High grade DCIS Grade 3
o Intermediate grade DCIS Grade 2
o Low grade DCIS Grade 1
o Increase grade Increase necrosis
o Low grade More Solid
High grade DCIS

Intermed
grade DCIS

Nuclei marked variation;


Size > 2.5x; Coarse
chrom, prom nucleoli,
mitosis, atypia

Nuclear
changes in
between

Severe loss of cell


orientaion
Large comedo type of
necrosis

Punctate
necrosis

differentiation

Fig. 30. Infiltrating ductal Carcinoma

Low grade DCIS


Round, uniform,
monotonous,
monomorphic, 1.5 2x
size, few to absent
nucleoli
Polarity, cell orienta-tion
maintained; Cribriform,
papillary
Necrosis absent

DCIS (Low Grade)


- Duct filled by monolayer cells with few rigid round holes
- Little nuclear variation
- No necrosis
- The cells show no orientation to the "holes"
- Tumor cells confined by an intact BM

SECTION B

Graded according to:


o Degree of glandular differentiation
o Degree of nuclear atypia
o Mitotic index (Scarff-Bloom-Richardson System)
Graded according to pleomorphism, tubular production and
mitosis:
o Well differentiated Prominent tubule formation, small
round nuclei, and rare mitotic figures
o Moderately differentiated May have tubules, but solid
clusters or single infiltrating cells are also present with a
greater degree of nuclear pleomorphism and contain
mitotic figures
o Poorly differentiated Often invade as ragged nests or
solid sheets of cells with enlarged irregular nuclei and
high proliferation rate and areas of tumor necrosis are
common
Within the center of the carcinoma, there are small pinpoint
foci or streaks of chalky white elastotic stroma and
occasionally small foci of calcification.
There is a characteristic grating sound (similar to cutting a
water chestnut) when cut or scraped.
Gross: Most are firm to hard with an irregular border

UERMMMC Class 2014

Pathology

8 | 10

Inflitrating Lobular CA

Bilaterality ( 5 10 % )
Multicentric
Diffusely invasive pattern
Frequent metastasis to CSF, serosal surfaces, ovary , uterus
and bone marrow
Greater incidence of bilaterality
Increasing incidence in postmenopausal women
Multicentric: May involve all breast quadrants
Usually present as a palpable mass or mammographic
density
have a diffusely invasive pattern without prominent
desmoplasia
Have a different pattern of metastasis than other breast
cancers
o Metastasis tends to occur to the peritoneum and
retroperitoneum,
the
leptomeninges
(carcinoma
meningitis), GIT, and the ovaries and uterus
In some cases, metastatic lobular carcinoma may be
mistaken for signet ring carcinoma of the GIT, which it closely
resembles
Histologic hallmark: Pattern of single infiltrating tumor cells,
often only one cell in width (in the form of a single file) or in
loose clusters or sheets

Fig. 32. Left: Soft, well circumscribed, pale gray-blue gelatinous consistency. Right:
The tumor cells are seen as clusters and small islands of cells within large lakes of
mucin that push into the adjacent stroma

Tubular Carcinoma
Good carcinoma
Typically detected as irregular mammographic densities
Occur in women in late 40s
All are well-differentiated
Excellent prognosis
Consist exclusively of well-formed tubules and are sometimes
mistaken for benign sclerosing lesions
A myoepithelial cell layer is absent, and tumor cells are in
direct contact with stroma
Frequently associated with ALH, LCIS, or low grade DCIS
Axillary metastases occur in fewer than 100% of cases unless
multiple foci of invasion are present. This subtype is important
to recognize because of its excellent prognosis

Invasive Infiltrating Carcinoma

Fig. 31. Indian File pattern: Like Indians dancing side by side in a single line

Medullary Carcinoma

th

Occurs in older women ( 6 decade)


1% - 5 % of all breast Ca
Large fleshy, well demarcated tumor
Solid, sheets of large, pleomorphic cells with surrounding
lympho-plasmacytic infiltrates
Pushing, non infiltrative border
Better prognosis Good carcinoma
Usually hormone receptor negative

Fig. 32. Medullary Carcinoma. Left: Gross. Right: Histology. Highly pleomorphic
with lymphocytic infiltrates surrounding the tumor cells (important characteristic of
this carcinoma)

Characterized by:
o Solid, syncytium-like sheets of large cells with vesicular,
pleomorphic nuclei, and prominent nucleoli, which
compose more than 75% of the tumor mass
o Frequent mitotic figures
o Moderate to marked lymphoplasmacytic infiltrate
surrounding and within the tumor
o pushing(noninfiltrative) border
All medullary carcinomas are poorly differentiated

Mucinous (Colloid) CA
Tends to occur in older women (Median age is 71 yrs )
Soft, well circumscribed , gelatinous consistency
Better prognosis compared to NOS carcinoma - Good
carcinoma
Usually ER positive
Unusual type of breast CA

SECTION B

Invasive carcinoma almost always presents as a palpable


mass
Palpable tumors are associated with axillary lymph node
metastases in over 50% of patients
Larger carcinomas may be fixed to the chest wall or cause
dimpling of the skin
When the tumor involves the central portion of the breast,
retraction of the nipple may develop.
Lymphatics may become so involved as to block the local
area of skin drainage and cause lymphedema and thickening
of the skin
o In such cases, tethering of the skin to the breast by
Cooper ligaments mimics the appearance of an orange
peel: Peau d orange

Inflammatory Carcinoma
The term inflammatory carcinoma is reserved for tumors that
present with a swollen, erythematous breast
Very aggressive! Youll be dead within months
Involves dermal lymphatics
Usually has a diffuse infiltrative pattern and typically does not
form a discrete palpable mass
Common presentation like mastitis
Ulcerated, red, weeping, eczematoid, skin trophic changes

Fig. 34. Left: Inflammatory carcinoma with its classic Peau dorange appearance.
Right: Lymphatic Invasion in axillary node

Tender, big, no definite mass, dark, red, swollen, mottling


effect, Peau d orange
Tumor embolization in lymphatic channel
Advance axillary node metastatic is a high probability

Invasive Papillary Carcinoma


The clinical presentation is similar to that of carcinomas of
NST, but the overall prognosis is better (in Robbins, poor
prognosis because of lymph node metastases).

UERMMMC Class 2014

Pathology

9 | 10

Clinical Features of Breast Carcinoma

Palpable firm mass


Nipple discharge
Nipple retraction
Skin ulcers/ erosions sign of far advanced cancer
Skin dimpling , peau d orange
Axillary node palpable
Fixation to chest wall

Fig. 35. Left: Palpable firm mass. Right: Nipple retraction

Fig. 36. Left: Skin ulceration. Right: Skin ulcerations with palpable axillary lymph
nodes.

Biological Behavior of Breast Carcinoma


Spread by lymphatic to regional axillary and internal
mammary LN
Hematogenous spread: Bone , liver , lungs ,
SR dependent on stage
o Size
o LN involvement (decrease LN involvement, increase
survival rate)
o Distant Metastasis

PATHOLOGY OF THE MALE BREAST


Gynecomastia
Enlargement of the male breast
May be unilateral or bilateral and presents as a button-like
subareolar enlargement
The lesion must be differentiated only from rare carcinomas of
the male breast.
May occur as a result of an imbalance between estrogen and
androgen
May be found at the time of puberty, in the very aged, or at
any time during adult life when there is cause for
hyperestrinism
Associated with cirrhosis of the liver, since the liver is
responsible for metabolizing estrogen
o If you have a fibrotic or nonfunctioning liver, estrogen
levels increase and stimulates mammary gland to become
proliferative.
In older males, gynecomastia may occur owing to a relative
increase in adrenal estrogens as the androgenic function of
the testis fails
Drugs such as alcohol, marijuana, heroin, antiretroviral
therapy, anabolic steroids used by some athletes and body
builders, and some psychoactive agents have also been
associated with gynecomastia
Marked micropapillary hyperplasia of the ductal linings occurs

Breast Cancer Prognostic Factors

Fig. 37. Gynecomastia

Except in women who present with distant metastasis (<10%)


or with inflammatory carcinoma (<5%) (in whom the prognosis
is poor regardless of other findings), prognosis is determined
by the pathologic examination of the primary carcinoma and
the axillary lymph nodes
Stage
o Size of primary tumor Second most important factor; the
risk of axillary lymph node metastases increases with the
size of the primary tumor
o LN involvement Axillary lymph node status is the most
important prognostic factor for invasive carcinoma in the
absence of distant metastases.
Negative node : 70 80 5 10 yrSR
1 to 3 nodes positive : 35 40 %
10 nodes positive : 10 15 %
o Distant metastasis Once distant metastases are present,
cure is unlikely.
Invasive carcinoma vs. in situ disease
o Breast cancer deaths associated with DCIS are due to the
subsequent development of invasive carcinoma or areas
of invasion that were not detected at the time of diagnosis
Histologic type
Histologic grade
ER/PR: Response to hormonal treatment
Her2/neu over-expression Associated with poorer survival,
predictor for response to trastuzumab treatment
o Well to moderately-differentiated tumors do not
overexpress HER2/neu, while poorly-differentiated tumors
do
Lymphovascular invasion Poor prognosis
Proliferative rate index:
o Mitotic rate
o IHC detection of cellular proteins seen in cell cycle
(cyclins, Ki-67 ,
DNA content
Gene expression profiling

Histology: Proliferation of a dense collagenous connective tissue

SECTION B

Carcinoma of the Male Breast


Rare occurrence (1% of males)
More aggressive than of the females
Risk factors are: First-degree relatives with breast cancer,
decreased testicular function, exposure to exogenous
estrogens, increasing age, infertility, obesity, prior benign
breast disease, exposure to ionizing radiation, and residency
in Western countries
Usually present as a palpable subareolar mass, 2 to 3 cm in
diameter, with nipple discharge as a common symptom.
Ulceration through the skin is more common than in women.
Distant metastases to the lungs, brain, bone, and liver are
common
Most cancers are treated locally with mastectomy and axillary
node dissection.

REFERENCES
1. Dra. Yanezs Lecture and PPT
2. 2013B trans
3. Robbins and Cotrans

UERMMMC Class 2014

Pathology

10 | 10

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