● Interlobular stroma

OUTLINE ○ Stroma in between lobules

I. Review of Anatomy and Histology ● Intralobular stroma
II. Clinical Presentations of Breast Disease ○ Stroma between the glands within the lobules
III. Disorders of Development
DUCTS VS LOBULES
IV. Inflammatory Diseases
V. Benign Epithelial Lesions
VI. Carcinoma of the Breast
VII. Invasive Breast Carcinoma

Legend
Remember Lecturer Book Prev.Trans Presentation

I. REVIEW OF ANATOMY AND HISTOLOGY

A. Normal Anatomy

Figure 3. Normal Histology of the Ducts and Lobules of the Breasts.

Terminal Ducts (TD); External Lobular Ducts (ELD); Lobules (L)

LUMINAL AND MYOEPITHELIAL CELLS

Figure 1. Normal Anatomy of the Breasts. Note the nipple and areola.
Within the areola, you can see the ducts connecting to the lobules. Most of
the contents of your breast is composed your adipose tissues, and
underneath that is your pectoral muscles. Surrounding your breast is your
[axillary] lymph nodes. Dyan bumabagsak ang mga cancer, if meron man.
Kaya usually, pag may mga kulani sa kili-kili, look for pathology in the lymph
nodes. Mayroon din tayong internal mammary lymph nodes, pero more
importantly, gusto ko na mas malaman niyo yung axillary lymph nodes.
B. Normal Histology
INTERLOBULAR STROMA VS INTRALOBULAR STROMA
Figure 2. Normal Histology of the Lobules and Stroma of the Breasts
● Lobules (red circle)
● Stroma (blue arrow)
○ supporting tissue
● Glands (black arrow)
Figure 4. High Power Photos of the Lobules. The glands are lined by
two types of cells in two layers. The lumen is at the center (* and lower
rightmost arrow on right photo) with the purple stained luminal cells
(right photo, curved arrow, lower left) surrounding it. The clear outer
layer of cells are composed of the myoepithelial cells (triangular
arrows). Note that in cancer, nawawala na usually ang myoepithelial cell
layer.
II. CLINICAL PRESENTATIONS OF BREAST DISEASE
● Pain
○ Mastalgia or Mastodynia
○ Cyclic or non-cyclic
■ cyclic means kasabay ng menstruation which is secondary
hormonal problem or noncyclic, walang kinalaman sa
menstruation
○ Diffuse or localized
● Inflammation
○ Erythema or edema
○ Most often caused by infection
○ Must be different with inflammatory breast carcinoma
● Nipple Discharge
○ Normal - small quantities and bilateral
■ usually whitish, parang milk
○ Galactorrhea - not a feature of malignancy

1
 ■ term from galactose, expression of milk in the breast OTHER IMAGING MODALITIES
○ Old age, spontaneous bleeding or discharge, unilateral,
bloody - malignancy ● Digital Breast Tomosynthesis (3D mammography)
● Lumpiness ● Ultrasonography
○ Diffuse nodularity - normal glandular tissue ● Magnetic Resonance Imaging
○ Pronounced - imaging III. DISORDER OF DEVELOPMENT
● Palpable Mass
A. Milk Line Remnant
○ Proliferation of epithelial or stromal cells
● Supernumerary nipples or breasts resulting from the persistence
■ proliferation: lumalaki or dumadami
of epidermal thickening along the milk line
○ Detected - 2-3 cm
● Milk line: axilla to perineum
○ Benign - 95% (round, rubbery, mobile, circumscribed)
● Few cases have persisting ductal system
○ Malignant - hard, irregular, immobile
■ 50% upper outer quadrant
■ metastasize before reaching the palpable size
MAMMOGRAPHIC SCREENING

● detect non-palpable asymptomatic breast carcinomas before

metastatic spread
● currently the most commonly used screening test for breast
cancer
● sensitivity and specificity of mammography increases with age

Detects:

Densities
● Rounded densities - benign
● Irregular - malignant
○ 1cm detected - only 15% have metastasize
Figure 6. Milk line (left) and a case of persisting ductal system (right).
Calcifications
● usually benign lesions [Refer to figure above]
● calcification associated with malignancy: small irregular, - sa milk line (left picture) natin pwede tayong tubuan ng dede or pwede kang
numerous and clustered tubuan ng ductal system (right picture) or pwedeng hindi

B. Accessory Axillary Breast Tissue

● Normal ductal system extends into the subcutaneous tissue of
the chest wall o the axillary fossa (axillary tail of Spence)

Figure 7. Accessory Axillary Breast Tissue

Figure 5. Mammographic screening
C. Congenital Nipple Inversion
● Failure of the nipple to evert during development
○ nakainverted yung nipple, nakapaloob
● Little significance → may correct spontaneously during pregnancy
or to be everted by simple retraction
● Acquired nipple inversion → Malignancy

2
 ● Deficiency of Vit. A associated with smoking alters differentiation of
ductal epithelium
● Keratin shed from these cells is trapped and plugs the ductal
system

Figure 10. Periductal Mastitis

● Histology
○ Outer skin of areola
■ Squamous epithelium
○ Ducts
■ Double layered cuboidal epithelium
Figure 8.Congenital Nipple Inversion
○ Metaplasia
■ Cuboidal epithelium transform to squamous cells
[Refer to figure above] ■ Squamous cells create a plug in the duct, which leads
- Top pic: dati everted tapos nagging inverted, magtaka ka baka to infection and mass (sub areolar abscess) and will
may malignancy or biglaan ka nalang nagkaroon ng inverted form fistula another opening to remove abscess
C. Duct Ectasia
- Bottom pic: kunyari di pantay may lumps & masses usually ● Ectasia = Dilated ducts
malignant ● Palpable periareolar mass with thick white nipple secretions with skin
retractions
IV. INFLAMMATORY DISORDERS ● 5th or 6th decade, multiparous women
A. Acute Mastitis ● Not associated with smoking
● Ectatic ducts are filled with inspissated secretions and numerous
● Acute Bacterial Mastitis - 1st month of breastfeeding → due to cracks
lipid-laden macrophages
and fissures
● Erythematous and painful; fever is often present
○ Staphylococcus
■ Single or multiple abscesses
○ Streptococcus
■ Cellulitis
■ Diffuse
● Often treated with antibiotics and continues expression of milk

Figure 9. Acute mastitis

B. Squamous Metaplasia of Lactiferous Glands Figure 11. Duct ectasia of the breast
● AKA Subareolar Abscess, Periductal Mastitis, Zuska Disease
● Painful Erythematous subareolar mass
● If recurrent → may form fistula and nipple inversion
● 90% are smokers

3
 Figure 12:. Duct ectasia of the breast, light micrograph
D. Fat Necrosis
Figure 15. Sclerosing lymphocytic mastitis. There is thickening of basement
● May mimic cancer → painless palpable mass, skin thickening, membrane
retraction, mammographic densities and calcifications
● Due to breast trauma or surgeries

Figure 13. Fat necrosis with Multinucleated giant cells

Figure 16. Sclerosing lymphocytic mastitis. Note how the duct is surrounded
by lymphocytes.
F. Granulomatous Mastitis
● May be a manifestation of a systemic granulomatous diseases or
localized to the breast
● Granulomatous disease: TB, sarcoidosis, foreign body

Figure 14. Fat necrosis / also known as Balser's necrosis

● Debris
● Fats not well defined

E. Lymphocytic Mastopathy
● AKA Sclerosing Lymphocytic Lobulitis
● SIngle or multiple palpable masses or mammographic densities
● Densely collagenized stroma, atrophic ducts with thickened
basement membranes surrounded by prominent lymphocytic
infiltrate
● Common in women with type 1 DM, autoimmune thyroiditis → Figure 17. Skin lesions of a patient with idiopathic granulomatous mastitis.
hence hypothesized to have autoimmune basis Clinical presentation may mimic locally advanced breast carcinoma
● Must be distinguished from breast cancer

4
 Flat Epithelial Atypia
● “mukha siyang benign pero parang atypical na”
● cysts with mild cytologic atypia.
● associated with lesions that increase the risk of cancer.

Figure 18. Pathology slide demonstrating changes consistent with idiopathic

granulomatous mastitis. Typical features of idiopathic granulomatous mastitis
include tissue voids surrounded by granulomatous inflammation.

Figure 20. Flat Epithelial Atypia

Figure 19. Non Necrotizing granulomas surrounded by lymphocytes

V. BENIGN EPITHELIAL LESIONS
A. Nonproliferative Breast Changes
● AKA Fibrocystic Changes
● Hindi dumadami
o May changes sa breast pero hindi proliferation, hindi
dumadami ang epithelial cells, hindi dumadami iyong
stromal cells
● Not associated with increased risk of breast cancer
3 Principal Nonproliferative Morphologic Changes
1. CYSTIC CHANGE
● From the term itself: Cysts
● Often with apocrine metaplasia, dilation of lobules, blue
dome cyst
● Disappearance of mass after Fine Needle Aspiration
Biopsy (FNAB)
2. FIBROSIS
● From the term itself Fibrous
● Cyst that ruptures → chronic inflammation → fibrosis
3. ADENOSIS
Figure 21. 3 Principal Nonproliferative Morphologic Changes
● From the term “Adeno” it means Glands
● Increase in the number of acini per lobule Apocrine Metaplasia
● Normal feature of pregnancy ● benign breast condition and is sometimes considered part of or
● Lactational Adenomas: not a true neoplasm but exaggerated associated with fibrocystic change
response to gestational hormones ● characterized by dilated acini lined by columnar cells with
apocrine features

5
 B. Proliferative Breast Disease
● Proliferation of epithelial cells, without atypia
● From the term ‘Proliferative,’ it means dumadami ang epithelial
cells, pumapangit na
● Are associated with a small increase in the risk of subsequent
carcinoma in either breast

Several Morphologically Distinct Patterns

1. Epithelial Hyperplasia
● AKA Usual Ductal Hyperplasia
● 2 forms: Usual and Atypical
o Atypical Ductal Hyperplasia: cells look more
distorted and abnormal
● Increased numbers of both luminal and myoepithelial
cell types, myoepithelial still intact

Figure 24. Papilloma, presence of dilated duct

Figure 22. Epithelial Hyperplasia or Usual Ductal hyperplasia

2. Sclerosing Adenosis
● Increased number of acini that are compressed and
distorted in the central portion of the lesion Figure 25. Papilloma. Note the presence of the dilated duct
● Stromal fibrosis completely compresses the lumens →
4. Complex Sclerosing Lesion
pattern that superficially resembles invasive carcinoma
● Have components of sclerosing adenosis, papilloma, and
epithelial hyperplasia
● Radial Sclerosing Lesion
o “Radial scar”
o Closely mimics invasive carcinoma mammographically,
grossly, and histologically.
o A misnomer, as it is not associated with prior trauma or
surgery.
o Stellate-like, focused or direction towards the center

Figure 23: Sclerosing Adenosis

3. Papilloma
● Grow within a dilated duct, composed of multiple
branching fibrovascular cores
● Epithelial hyperplasia and apocrine metaplasia are
frequently present
Figure 26. Complex Sclerosing Lesion

6
 ● 2 types:
1. Atypical Ductal Hyperplasia
■ consists of a relatively monomorphic proliferation of regularly
spaced cells, sometimes forming cribriform spaces.
■ Distinguished from DCIS in that it only partially fills involved
ducts

Figure 27. Radial Sclerosing Lesion

Gynecomastia
● enlargement of the male breast
Figure
● the only benign lesion seen with any frequency in the male breast 30. Atypical Ductal Hyperplasia
→ imbalance between estrogens
○ e.g. Cirrhosis 2. Atypical Lobular Hyperplasia
● button-like subareolar enlargement and may be unilateral or bilateral ■ consists of cells identical to those of lobular carcinoma in situ
● Increase in dense collagenous connective tissue associated with ■ cells do not fill or distend more than 50% of the acini within a
epithelial hyperplasia of the duct lining lobule.

Figure 28. Gynecomastia Figure 31. Atypical Lobular Hyperplasia

VI. CARCINOMA OF THE BREAST

A. Atypical Ductal And Atypical Lobular
● Almost all breast malignancies are Adenocarcinomas
● The terms ductal and lobular are still used to describe subsets of
both in situ and invasive carcinomas, but mots evidence suggests all
breast carcinomas arise from cells in the terminal duct lobular unit
○ Pinapastain pa rin para sure kung ano yung origin niya
● The most important risk factors are gender (99% of those affected are
female), age, lifetime exposure to estrogen, genetic inheritance, and
to a lesser extent, environmental and lifestyle factors
○ Specifically, delayed childbearing, fewer pregnancies, and reduced
breastfeeding
Figure 29. Gynecomastia, increased dense collagenous stroma

DUCTAL LOBULAR
C. Atypical Hyperplasia
● AKA Proliferative Breast Disease with Atypia Atypical Ductal hyperplasia Atypical lobular hyperplasia
● A clonal proliferation having some, but not all, of the histologic ↓ ↓
features of carcinoma in situ. Ductal carcinoma in situ Lobular carcinoma in situ (LCIS)
● Associated with a moderately increased risk of carcinoma (DCIS) ↓
↓ Invasive lobular carcinoma
● High levels of Estrogen receptor (ER)
Invasive ductal carcinoma
● Traditionally, Ductal or Lobular classification only, now changing due
to the advent of molecular testing
● based on studies, cancers starts usually at the terminal ducts

7
 Cribriform DCIS Cookie cutter-like spaces 🍪

Figure 32. Microanatomy of normal adult female breast tissue showing ducts
(TD) and lobules (L).

Micropapillary Complex bulbous protrusions without

DCIS fibrovascular cores

Figure 33. Breast anatomy

Papillary DCIS True papillae with fibrovascular cores

B. Carcinoma In-Situ
● Cancer na, kaya lang intact pa yung basement membrane
● Literally “carcinoma in its original place”
○ Confined within ducts and lobules by a basement membrane
● Has no capacity to metastasize BUT has increased risk of developing
into invasive breast carcinoma
● It is now recognized that these growth patterns are not related to the
cell of origin, but rather reflect differences in tumor cell genetics and
biology
● Paget disease
○ Malignant cells (paget cells) extend from DCIS within the ductal
Ductal Carcinoma In Situ (DCIS) system via the lactiferous sinuses into nipple skin without crossing
● Myoepithelial cells are preserved in involved ducts/lobules, although the basement membrane
they may be diminished in number
● Almost always detected by mammography → calcifications
associated with secretory material or necrosis
● Forms:

Comedo DCIS Tumor cells with pleomorphic, high-grade

nuclei and areas of central necrosis

8
 VII. INVASIVE BREAST CARCINOMA
Table 1. Division of Invasive Breast Carcinoma
No Special Type (NST) Special Histologic Types

Invasive Ductal Carcinoma Invasive Lobular Carcinoma

Mucinous (Colloid) Carcinoma
Tubular Carcinoma
PapillaryCarcinoma
Apocrine Carcinoma
Micropapillary Carcinoma
Figure 34. Paget’s disease Carcinoma with medullary pattern
Metaplastic Carcinoma
● Mastectomy is curative in greater than 95% of women Secretory Carcinoma
● Postoperative radiation therapy and tamoxifen also reduce the risk of Inflammatory Carcinoma
recurrence
Lobular Carcinoma In Situ (LCIS)
● Clonal proliferation of cells within ducts and lobules that grow in a
dyscohesive fashion → loss of cellular adhesion due to
dysfunction of E-cadherin (all lobular)
○ E-cadherin is responsible sa pagdikit dikit ng cells
● Incidental biopsy finding → rarely associated with calcifications or
stromal reactions that produce mammographic densities
○ LCIS is bilateral in 20 to 40% of cases
○ DCIS is bilateral in 10 to 20% of cases
● Mucin-positive signet ring cells are commonly present
● Paget disease (involvement of nipple skin) does not occur
● It is unclear if surgical removal of the identified lesion lowers risk →
→ bilateral prophylactic mastectomy

Figure 35. Lobular Carcinoma In Situ (Dark brown in the figure are
E-cadherins) Figure 37. Invasive breast carcinoma (spreading through the stroma, not
well-defined)
Invasive Ductal Carcinoma
Invasive/Infiltrating Breast Carcinoma of No Special Type (NST)
● Mammographic and gross appearance varies widely depending on
the stromal reaction to the tumor
○ Imaging - most commonly present as hard, irregular, radiodense
mass
○ Gross - typically produce a characteristic grating sound,
deceptively well-circumscribed
○ Microscopic - sheets of tumor cells with scant stromal reaction or
ingle tumor cells infiltrating otherwise unremarkable fibrofatty tissue
● Graded using the Nottingham Histologic Score (Tubule formation,
Nuclear pleomorphism, Mitotic rate)

Figure 36. Signet ring cell pattern of LCIS (Arrows indicate LCIS cells that
breach through the basal lamina)

9
 Figure 40. Aldred Score. No need to memorize.

ely? kaw na ba mag export to pdf?

BRCA1 AND BRCA2

● 80% to 90% of single gene familial breast cancers
● 3% to 6% of all breast cancers
● most carriers develop breast cancer by the age of 70 years

BRCA1 BRCA2

● Chromosome 17q21* ● Chromosome 13q12.3*

● Markedly increase the risk of ● Smaller risk for ovarian
ovarian carcinoma carcinoma
● Are at higher risk for other ● More frequent with male
epithelial cancers such as breast cancer
prostatic and pancreatic ● BRCA2-associated breast
carcinoma carcinomas aso tend to be
● BRCA1-associated breast poorly differentiated → often
cancers are commonly poorly ER positive
differentiated → TNBC
Figure 38.Morphological variants of the main subtypes of invasive breast
carcinoma (A) medullary carcinoma; (B) metaplastic carcinoma; (C) apocrine *Di naman daw tatanong ni Doc
carcinoma; (D) mucinous carcinoma; (E) cribriform carcinoma; (F) tubular
carcinoma; (G) neuroendocrine carcinoma; (H) classic lobular carcinoma; and
(I) pleomorphic lobular carcinoma.

B. Molecular classification of breast carcinoma

Figure 41. Estrogen Receptor Pathways

Figure 39. Estrogen receptor, progesterone receptor, herceptin receptor 2
● ER+, Her2-
○ aka “LUMINAL” cancers
● Her2+, ER +/-
○ aka “HER2” cancers
● ER-, Her2-
○ aka “TRIPLE NEGATIVE” breast cancers (TNBC)
● Pag positive PR most likely positive na din ER

Figure 42. Summary.Tandaan daw tong table

10
 B. Intralobular Stromal Tumors

Figure 46. Fibroadenoma (microscopic). Pericanalicular pattern (left) and

intracanalicular pattern (right)

Figure 43. Interlobular and Intralobular stroma PHYLLODES TUMOR

● AKA Cystosarcoma phyllodes (not used anymore) → not cystic and
mostly are benign
○ Benign behavior- MED12 mutations
○ Malignant behavior- additional mutations such as TERT
● Phyllodes- greek term for “leaflike” → due to the presence of nodules
of proliferating stroma covered by epithelium
● Phyllodes tumor is distinguished from fibroadenoma on the basis of
○ Higher cellularity
○ Higher mitotic rate
○ Nuclear pleomorphism
○ Stromal overgrowth
○ Infiltrative borders

Figure 44. Stromal tumor. (TG: Tandaan daw MED12)

FIBROADENOMA
● The most common benign tumor of the female breast → 20s-30s
● Palpable mass → young women
● Mammographic density or clustered calcifications —> older women
● Gross: well-circumscribed, rubbery, grayish white nodules that bulge
above the surrounding tissue
● Microscopic:
○ Stroma- delicate and often myxoid Figure 47. Phyllodes tumor (gross)
○ Epithelium
■ Surrounded by stroma (pericanalicular pattern)
■ Compressed or distorted (intracanalicular pattern)
● Hormonally responsive and may grow in size during pregnancy and
regress after menopause
● Slightly increased risk of carcinoma

Figure 48. Phyllodes tumor (microscopic)

Figure 45. fibroadenoma gross

11
 Figure 49. Qualifier table for phyllodes tumor

FIBROADENOMA VS. PHYLLODES TUMOR

Fibroadenoma Phyllodes Tumor

Cellularity Less cellular More cellular

Mitotic rate present

Nuclear pleomorphism less pronounced more pronounced

Stromal overgrowth less stroma More stroma

Infiltrative borders less more

B. Interlobular Stromal Tumors

MYOFIBROBLASTOMA
● Consists of myofibroblasts
● Only breast tumor that is equally common in males
LIPOMAS
● Fat-containing lesions
FIBROMATOSIS
● Clonal proliferation of fibroblasts and myofibroblasts
● Locally aggressive but does not metastasize
ANGIOSARCOMA
● Associated with radiation therapy or chronic edema

References
● Dr. Lamata-Porras’ Lecture And Powerpoint Slides

12