SYSTEMIC 3MLab & 4MLab BREAST PATHOLOGY

PATHOLOGY
Midterm PRACS 2 Dr. Jimmy Rosales | March 2016

Slides/textbook | histopath findings | audio

NORMAL BREAST
o Special modified skin appendage in both males and females
o Paired mammary glands of specialized epithelium and stroma on the
pectoralis muscle with 6-10 major ductal systems that originate from the
nipple
o Major ductal systems branch  extralobular terminal ducts 
intralobular terminal ducts in each lobule
o For each terminal duct  grape-like cluster of small acini
o Acini will form lobules (“collection of acini”)
o Stroma
o Depend on patient’s age: elderly  more adipose
2 types:
 Intralobular: around acini composed of hormone-responsive
breast-specific fibroblast-like cells.
 Interlobular: intermixed adipose and dense fibrous connective
tissue
 Stroma and Ductal Epithelial System (or Acini) are responsive to hormones
 Ducts and Lobules: lined by 2 Cell Types
a) Myoepithelial cells: lie close or beneath to luminal cell ejection of milk
b) Luminal cells: cuboidal; for production of milk
 Nipple
o Stratified squamous epithelium
o Ducts are lined by single layer of cuboidal epithelium
 CLINICAL PRESENTATIONS OF BREAST DISEASE  As you age, palpable mass is less likely and malignancy is more common
 Discharge is not common
 Myoepithelial cells are important in the assessment of breast pathology  Mammographic lesions: most common is calcifications (directly related with
especially if considering malignant lesions age)
 Palpable mass or lumpiness: most common complaint
 Careful when interpreting or assessing patients with palpable mass  ask for BREAST PATHOLOGY
the menstrual cycle Inflammatory
 Advise patient to palpate breast 7 days after her period o Near the nipple
 If it persists  true mass; regress  associated with menstrual cycle o Rare, present as erythematous painful breast
 Discharge o Not all inflammatory lesions are benign
o DDx: inflammatory breast carcinoma

Acute Mastitis
- Most common; usually occurs during lactation, esp. in 1st months of nursing
- How? Periareolar fissures or
ulcerations  entry of
microorganisms  inflammatory
reaction
- Staphylococcus aureus: localized
lesion
- Streptococcus: diffuse lesion
- Mx: Neutrophils and abscess
formation lining the ducts or acini, or
within the ducts or acini
- Usually only one duct is involved
Periductal Mastitis/Zuska’s Disease - Mx: Epithelioid macrophages, multinucleated giant cells, lymphocytes,
- Squamous metaplasia of lactiferous ducts results in keratin shedding and neutrophils and plasma cells
subsequent ductal plugging; duct dilation and rupture then leads to intense
chronic and granulomatous inflammation that presents as a painful subareolar
mass in both sexes
- Keratinizing squamous epithelium extending to an abnormal depth (in orifices of
ducts)
- Ductal epithelium is replaced by Keratinized stratified squamous epithelium
- 90%: smokers
o Decrease vitamin A, which is important in the differentiation of the
epithelial lining
- Mx: SSE and keratin + neutrophils and abscess
- Tx: Remove involved duct and fistula

Mammary Duct Ectasia

- 5th or 6th decade of life and multiparous women
- Defined as a palpable periareolar mass Benign Epithelial (Non-proliferative) Lesions
- Not associated with smoking o MC in the TDLU
- Mx: Dilation of ducts and inspissation of breast secretions with chronic o 3% or negligible risk of malignancy
inflammatory cells lining the ducts (lymphocytes + plasma cells)
- Marked periductal and interstitial chronic inflammatory infiltrate Fibrocystic Changes
- Clinicians will feel lumpy, bumpy breasts on palpation
- Radiologists see dense breast with cysts
- Three morphological changes:
o Cyst Formation
 Formed by the dilation and unfolding of lobules
 Lined by flattened epithelium or cells altered by apocrine
metaplasia
o Apocrine Metaplasia
 Abundant eosinophilic, granular cytoplasm
o Adenosis
 Increase in the number of acini

Granulomatous Mastitis
- 20 - 40 years old
- Non-caseating granulomas (periductal and interductal) or even caseating
granulomas
- Associated with systemic granulomatous disease such as sarcoidosis or Wegener’s
Granulomatosis
- Caused by Mycobacterium (MC in Philippines) and fungal infections
- Grossly: Irregularly ovoid mass, yellow white surfaces and cysts
- Sometimes it will have brown to blue secretions  “Blue-Domed Cyst”
Sclerosing Adenosis
- Number of acini per terminal duct: increase to at least twice the normal number
- Intralobular stroma will proliferate and compress the acini
- Acini are compressed and distorted in the center but dilated at the periphery
- Sometimes mistaken for invasive carcinoma

- Other changes can be noted:

o Fibroadenomatous change
o Chronic Inflammation
o Fibrosis – extrusion of secretions brought about by cyst rupture
o Calcification

Lactational Adenoma/ Galactocele Complex Sclerosing Lesion (Radial Scar)

- Palpable masses in pregnant women
- Normal appearing breast tissue with adenosis and lactational changes - Stellate lesions characterized by a
- Cells become vacuolated and nuclei is sometimes apical central area of entrapped glands in
- Not true neoplasms hyalinized stroma
- Due to exaggerated focal response to hormonal influences - Resemble malignancy
mammographically or on gross
Benign Proliferative Lesions examination
(Proliferative Breast Disease without Atypia) - Not associated with injury or surgery
o Also in the TDLU
o Higher risk of malignancy
o Rarely form palpable masses
o Group of disorders characterized by proliferation of ductal
epithelium and/or stroma

Epithelial Hyperplasia
- Presence of more than 2 cell layers (N= 2)
- Moderate to florid: more than four cell layers
Papilloma (Intraductal)
- Papilloma = Papillon = Butterfly-like
- Occur in the lactiferous sinuses (large) or anywhere (small)
- Multiple branching fibrovascular cores, having a connective tissue axis
- Arborization of papillae
- Growth occurs within a dilated duct
- Epithelial hyperplasia and apocrine Malignant Proliferative Lesions
metaplasia are frequent (Proliferative Breast Disease with Atypia)
- Large duct: solitary, in lactiferous o TDLU
sinuses, can twist and congest  o Carcinoma in situ
bloody discharge o Invasive carcinoma
- Small duct: multiple, deeper within
ductal system
Atypical Ductal Hyperplasia
- Monomorphic proliferation of regularly spaced cells filling up to the lumen
- Histologic resemblance to DCIS: difficult to sign out
- Harbour the same genetic loss or gain present in carcinoma

Stromal Lesions
o Fibroadenoma and phyllodes arise in intralobular stroma

Fibroadenoma
- MC benign tumor of the breast; Common in the intralobular stroma
- Before age 30, multiple and bilateral
- Regression after menopause
- Spherical nodules that are usually well defined
- Whorling pattern
- Mx: stroma is delicate, cellular and often mixed enclosing glandular component
CARCINOMA OF THE BREAST
 Most common non-skin malignancy in women
 Risk Factors: AGE
 Age at menarche
 First live birth
 First degree relatives with breast cancer
 Breast biopsies with atypical hyperplasia
 Race
And according to your book, the most important factor would be GENDER.

DUCTAL CARCINOMA-IN-SITU
 Proliferation of neoplastic cells limited to ducts by the basement membrane
 Frequently presents as mammographic calcification
 Myoepithelial cells are preserved. Myoeptithelial cells are important when
discussing invasive carcinoma kasi pag wala to ang tawag sakanya ay
INVASIVE CARCINOMA.
 Five architectural subtypes: comedocarcinoma, cribriform, solid, papillary and
micropapillary
 Comedo
 Solid sheets of pleomorphic cells
 High grade nuclei
 Central necrosis and sometimes the necrotic part can
calcify so makikita yan ng radiologist that there are multiple
calcifications or on sonomammogram they will say that
there are calcifications.
 Usually associated with microinvasion. Microinvasion is
defined as foci of tumor cells less than 0.1 cm in diameter
that is invading the stroma. Pag greater than, that is
already your invasive carcinoma.

Non-comedo carcinoma type:

 Cribriform type
 Aka “cookie-cutter” appearance
 Proliferation of neoplastic cells with intraluminal spaces
that are usually regular in shape. Unlike for your atypical
ductal hyperplasia where you see slit-like spaces and
irregular siya diba and although may makikita kang regular
spaces, mas maraming irregular or slit-like spaces.
 Solid - No intraluminal space
  Papillary
 Protrusion of the luminal cells with central or with
fibrovascular core
 Micropapillary
 Papillae or bulbous projections but you do not see
fibrovascular core. Sometimes meron silang fibrovascular
core but not that much.

LOBULAR CARCINOMA IN SITU

 Always an incidental finding on biopsy
 More common in young women
 Frequently multi centric and bilateral
 Consists of small cells that have oval or round nuclei with small nucleoli
 Signet ring cells may be seen
 Well-differentiated
 Prominent tubules with small round nuclei
 Rare or occasional mitotic figures
 Moderately-differentiated
 Tubules but in solid clusters or single tumor cells infiltrating
the stroma
 Poorly-differentiated
 Nest or sheets of a large irregular nuclei with mitotic figures
associated with tumor necrosis

GRADING of INVASIVE DUCTAL CA: NOTTINGHAM’S HISTOLOGIC GRADING

INVASIVE CARCINOMA OF THE BREAST
 Types include: ductal type (most special type), lobular, tubular and
metaplastic type.
INVASIVE DUCTAL CARCINOMA
 Firm to hard with irregular borders
 Benign counterpart is your radial scar (gross)
 If you cut or scrape the specimen (grating sound) parang singkamas
 Due to elastopic stroma with an occasional foci of calcifications
 Histologic appearance: Well-differentiated, moderately differentiated and
poorly differentiated.
 Tubular differentiation
 Score of 1: 75% of tumor cells forming glandular or tubular structures
 Depends on the glandular or tubular structures that you see
 Nuclear Pleomorphism
 Score of 1: nuclei that is small with little increase in size compared to
normal cells
 Score of 2: Larger than normal epithelial cells
 Score of 3: Vesicular nuclei with prominent nucleoli
 Presence of Mitotic Figures
 Score of 1: <3 MF
 Score of 2: 4-7 MF
 Score of 3: >8 MF
 Overall grade
 After each of the three components of the histologic grade have been
assesses, the scores for tubule formation, nuclear pleomorphism, and
mitoses are then added together and assigned to grades.
 Grade 1 = scores of 3-5 (well-differentiated)
 Grade 2 = scores of 6-7 (moderately differentiated)
  Grade 3 = scores of 8-10 (poorly differentiated)

After your routine H&E, most doctors now would request for
IMMUNOHISTOCHEMISTRY (it will tell you if the patient can be given specific
hormones to treat the carcinoma)

IMMUNOHISTOCHEMISTRY
 Immunostains: ER (estrogen receptor) , PR (progesterone receptor) , and
HER2Neu (human epidermal receptor 2)
 ER (+), PR (+): Tamoxifen (anti-estrogen)
 HER2Neu (+): Trastuzumab (Herceptin)
 ER AND PR SCORING SYSTEM: ALLRED SCORING (how much of the cells stain
for ER and the intensity of staining)
 ER and PR are antigens found in the nucleus. Remember these are
steroid receptors.
For example you have a tumor na nagstain ng 33% or one third of the
tumor so score ng 3 plus intensity staining of 2, 3+2 is 5. To call it ER
(+) the score should be >2. Same for PR, you can also use Allred
scoring.
 HER2/neu antigen are found in the cell membrane.
 0-+1 is negative
GENE EXPRESSION PORTRAITS OF BREAST CARCINOMA
 2+  confirmation using FISH
 Gene expression profiling
 (+) is 3+
 Measure the quantities of mRNA
 4 patterns
a) Luminal A
 MC: 40-55% of all invasive ductal carcinoma
 ER: positive, HER2/neu: negative
 Well to moderately differentiated
 Nottingham’s grading of 1 and 2
 Postmenopausal women
 Respond well to hormonal therapy
b) Luminal B
 15-20% of invasive ductal carcinoma
 Triple positive
 ER:positive, PR:positive and HER2/neu:positive
 Higher tumor grade; grade 3
 Positive lymph node metastasis
 Respond to chemotherapy
c) Basal-like
 13-35% of NST
 ER, PR, HER2/neu: Negative
 Triple negative carcinoma
  Medullary carcinoma, Metaplastic carcinoma  Histologic features: small islands of cells within large lakes and mucin
 BRCA1 mutation  Well-differentiated kasi may tubule formation
 High tumor grade  Separated by fibrous stroma/tissue
 Platinum-based chemotherapy  Best prognosis
d) HER2 positive
 7-12% TUBULAR CARCINOMA
 ER and PR: negative, HER2/neu: positive  Small, irregular
 High tumor grade  On mammography: small densities
 High frequency of metastasis  Microscopy: Well-formed tubules kaya well-differentiated
 Mistaken for benign sclerosing lesions
 Absent myoepithelial cell layer, pag wala to tubular kana
INVASIVE LOBULAR CARCINOMA  Apocrine sprouts na parang protrusion into the lumen
 Palpable mass, mammographic density
 Greater incidence or bilaterally STROMAL TUMORS
 Histology: presence of discohesive infiltrating tumor cells arranged in a file:  PHYLLODES TUMOR
“INDIAN FILE” pattern  Proliferation of intralobular stroma
 No tubule formation because the genetic basis of invasive lobular carcinoma  6th decade: palpable masses
is that there is loss of e-cadherin which serves as adhesion gene or it will tell  Bulbous protrusions (leaf-like)
the normal cells that they should bind to each other, pag wala yun,
 Vs fibroadenoma, eto kasi may:
maghihiwa-hiwalay sila
 Metastasize to peritoneum, retroperitoneum, meninges, GI, ovaries and  Increased cellularity
lymph nodes not in the axillary LN  Increased MF
 Small mass or involves the whole breast
MEDULLARY CARCINOMA  Can rupture and produce secondary bacterial infection
 Patients in 60’s
 Well-circumscribed mass; Soft, fleshy
 Poorly differentiated carcinoma
 Better prognosis than high grade ductal carcinoma in situ
 Histologic features:
 Solid syncytium-like sheets of large cells with
vesicular nuclei and prominent nucleoli
 Frequent mitotic figures
 Moderate to marked lymphoplasmacytic infiltrate
surrounding the tumor
 Pushing borders di siya infiltrating
 No DCIS component

MUCINOUS (COLLOID) CARCINOMA

 Older women
 Grossly: Soft or rubbery
 Pale gray-blue gelatin
 If you cut it, you will see gelatinous cut surface
GYNECOMASTIA
 Enlargement of the male breast (unilateral or bilateral)
 Button-like subareolar enlargement
 Histology:
 increase in dense collagenous CT
 marked papillary epithelial hyperplasia of duct lining
 lobule formation is rare
 periductal hyalinization and fibrosis (mukhang may halo)
 on LPO: mistaken as fibroadenoma
 Associated with use of marijuana, alcohol intake, anabolic steroids or
sometimes liver cirrhosis