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Pathology of the breast
Gábor Cserni
Lobules
Normal microscopic anatomy
Duct
Interlobular stroma
Intralobular stroma
Luminal epithelial cells
acini
Outer myoepithelial
cells – basal cells
Terminal ductulolobular unit
(TDLU)
Benign lesions
Kai Nielsen: Water Mother detail
Copenhagen Ny Carlsberg Glyptotek
INFLAMMATION - ACUTE MASTITIS
During the acute phase this is painful (red, hot,
oedematous)
• Bacterial (generally Staphylococcal) infections. Bacteria
gain access to the breast tissue through the ducts.
• Predisposing factors:
– inspissated secretions
– fissures in the nipples (during early weeks of nursing)
– dermatitis involving the nipple
• Bacteria may cause breast abscesses, or spread
throughout the entire breast. Healing may leave palpable
scars behind.
Plasma cell mastitis /
(MAMMARY) DUCT ECTASIA
The 2 lesions are likely to be related, the inflammatory phase
occurs in a younger population, therefore it is suggested to
precede ductectasia.
Nonbacterial inflammation associated with inspissation
of breast secretions in the main ducts (proposed
etiology).
– nipple discharge from multiple ducts is not uncommonly
caused by ductectasia
– the condition leads to periductal fibrosis, induration of the
breast substance, retraction of the skin or nipple mimicking
carcinoma
– the inspissated secretions may calcify and this can be
detected by mammography; sometimes this picture simulates
ductal carcinoma in situ
(MAMMARY) DUCT ECTASIA
Morphology:
The ectatic ducts contain inspissated secretory
material (also seen on gross examination),
granular debris and lipid laden macrophages.
The lining epithelium is generally destroyed.
There is a prominence of mononuclear
inflammatory cells, including plasma cells, the
latter vanishing with time (plasma cell mastitis →
ductectasia)
Periductal fibrosis
Occasionally granulomas may be formed in the
periductal stroma (these are foreign body related
granulomas associated with duct rupture).
FAT NECROSIS
It occurs after trauma, surgery or radiation therapy.
The initial necrosis results in inflammation and
fibrosis and can present as a hard mass,
clinically (sometimes mammographically)
resembling cancer.
Lipid laden (foamy) macrophages are the
carachteristic cells; lymphocytes are also
present
FIBROCYSTIC CHANGES
(Nonprolferative breast changes)
Present in over 50 % of women
Clinical manifestations:
• palpable lump, (can mimic benign tumors or
cancer)
• mammographic densities or calcifications
• nipple discharge
• can be a chance finding as „minimal changes”
Etiology:
• Unknown; appears to be due to minor Aberrations
of Normal Development and Involution (ANDI)
FIBROCYSTIC CHANGES (FCC)
Heterogeneous group of morphologic patterns
showing combinations of:
Fibrosis: stromal change with increase in
extralobular collagen
Cysts: dilatation of the acini of the lobules (lobular
architechture maintained); usually multifocal and
bilateral; apocrine metaplasia often associated
with cysts
Adenosis: increase of number of acini per lobule.
It is physiological during pregnancy and
lactation, but can be focally present in
nonlactating breasts
É. Kemény
„PROLIFERATIVE BREAST
DISEASE (w/o ATYPIA)”
• Partially overlaps with fibrocystic changes
• Includes epithelial proliferations like
– Usual type ductal hyperplasia: proliferation of ductal
epithelium (mild-moderate-florid)
– Sclerosing adenosis: proliferation of acini and
intralobular stroma resulting in the distorsion of the
normal architecture
– Papillomas: epithelial growth with fibrovascular cores
and dilation of the duct involved
„PROLIFERATIVE BREAST DISEASE”
- INTRADUCTAL PAPILLOMA
• LARGE DUCT PAPILLOMA (benign „tumor” of the breast)
- usually solitary papillary growth within a lactiferous duct
- rarely palpable
- serous or bloody discharge from the nipple (single duct)
fibrovascular cores covered by myoepithelial and epithelial cells
• MULTIPLE (SMALL DUCT / PERIPHERAL) PAPILLOMAS
- usually multiple ducts are involved
- can be palpable
Sclerosing papillomas may be confused with cancer
microscopically
Intraductal papilloma
FIBROADENOMA
The most common benign tumor of the female
breast
Biphasic (fibroepithelial) tumor with epithelial and
stromal component
Most often in the reproductive period.
Although benign, it may be associated with
proliferative changes and incur a slightly
increased (negligible) relative risk of cancer.
FIBROADENOMA
Clinically:
• well-circumscribed, palpable mass, may be multiple
• they grow in pregnancy (hormone sensitive tissues)
• with age fibroadenomas may calcify
Macroscopically:
• solitary (sometimes multiple), white, rubbery nodules,
from 1 to 10 cm in diameter
Microscopically:
• biphasic: stromal (cellular or sclerotic) + epithelial
(pericanalicular and / or intracanalicular patterns)
component
FIBROADENOMA
Patterns: pericanalicular – intracanalicular (generally mixed)
Biphasic:
stroma
pink i.e.
eosinophilic
epithelium
dark
É Kemény
PHYLLODES TUMOR
• Another biphasic (fibroepithelial) tumor characterised by
stromal cellularity and a leaf-like (phylloid or phyllodes)
pattern created by clefts and / or cyst formation
• Relatively rare
• Often occurs in the elderly, uncommon in the young
• Recurrence may occur in all subsets, if the excision is
incomplete
Benign (majority) > Borderline > Malignant
(some use a two tiered classification: low-grade vs high-grade)
Signs of malignancy:
• pleomorphism
• mitotic activity
• overgrowth of the stromal component
• invasion into adjacent breast tissue
• metastasis (often to lungs)
Phyllodes tumor
GYNECOMASTIA
Enlargement of the male breast due to the development of
breast parenchyma.
It is an important indicator of an imbalance between estrogens
and androgens.
Can be unilateral or bilateral
It may occur:
• during puberty
• in Klinefelter syndrome
• in liver cirrhosis
• as a side effect of drugs (marihuana, anabolic
steroids, androgen blockade, some psychoactive agents)
GYNECOMASTIA
Histology: proliferation of both stromal and
epithelial (generally ducts) components.
Lobules are only rarely seen.
Breast cancer (BC)
Rembrandt: Bathsheba in her bath (1654) - Louvre
Lifetime Probability of Developing Cancer, by
Site, Women, US, 2001-2003*
The most common
cancer in females
Site
Risk
All sites†
Breast
1 in 3 (100%)
1 in 8 (30% - 2017)
Lung & bronchus
1 in 16 (12%)
Colon & rectum
1 in 19 (8%)
Uterine corpus
1 in 40 (7%)
Non-Hodgkin lymphoma
1 in 55
Ovary
1 in 69
Melanoma
1 in 73
Pancreas
1 in 79
Urinary bladder
1 in 87
Uterine cervix
1 in 138
* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003.
† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.
Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.1.1 Statistical Research and Applications
Branch, NCI, 2006. http://srab.cancer.gov/devcan; ; ACS: Cancer Facts and Figures 2017
Breast cancer – general features
• Arises from the terminal ductulolobular units
• With screening programs (mammography) + ultrasonography
followed by fine-needle aspiration cytology or core biopsy many
cases are detected in an asymptomatic (non-palpable) stage
• Many tumors contain receptors for estrogen and progesterone
and may respond to hormonal manipulation
• Classification:
– Non-invasive (generally screen detected): ductal cc in situ,
lobular cc in situ
– Invasive: Invasive ductal cc no special type, invasive lobular
cc, less common types
BC Screening
• Before the advent of
breast cancer
screening programs
breast cancer was
mainly detected as a
symptomatic disease.
• In the era of BC
screening many cases
are detected in an
asymptomatic (nonpalpable) stage; many
in the non-invasive or
„in situ” phase
Etiology
• Cause: unknown
• Important influences:
• Overexposure to estrogens and underexposure to
progesterone:
– nulliparous women or women having their first child after the age of 35
have an increased risk (action of progesteron in multiple pregnancies
followed by action of prolactin in breast feeding protect breast cells
against proliferative effect of estrogens)
– obesity - fat cells synthesize estrogens
• Genetic factors - 10% of cases are familial (e.g., inherited
BRCA1 or BRCA2 gene mutation)
• Atypical ductal or lobular hyperplasia
• Geographic variation: women from north-west Europe and
North America have higher risk compared to Asian, Hispanic
women
Morphology: DCIS
• Proliferation of tumor cells within (small) ducts and
lobules; bordered by myoepithelial cells and a
basement membrane; they do not invade through
these layers (=in situ, i.e. non invasive).
• The ducts may be completely filled with tumor cells
(solid pattern), or have central necrosis (comedo
pattern), which may calcify, rendering the lesion
mammographically detectable.
DCIS – comedo pattern
central necrosis
Myoepithalial cell marker immunostain
Paget’s disease of the nipple
• DCIS can spread from lactiferous ducts
into the contiguous skin of the nipple
without invading through the basement
membrane.
• The nipple appears ekzematous and
ulcerated.
Paget’s disease
LCIS (Lobular Carcinoma In Situ)
LCIS is characterized by a proliferation of small,
uniform and discohesive cells within ducts and
lobules.
LCIS is nearly always an incidental pathology
finding because it never forms a mass and is
rarely associated with calcifications.
LCIS
Uniform, dyscohesive cells fill and distend the acini in the lobule
Invasive carcinoma - histological types
• Invasive ductal carcinoma NST (No Special
Type) / NOS (Not Otherwised Specified)
(about 80% of the invasive cases)
• Special type carcinomas e.g.:
– Invasive lobular carcinoma (~ 10%)
Invasive ductal carcinoma
(NST / NOS)
• GROSS: firm, hard, irregular (sometimes
circumscribed), white masses
• MICRO: The tumor is composed of
malignant cells disposed in tubules,
cribriform structures, solid cell nests or
cords. Necrosis may be present.
• Dense stromal reaction may be present;
this is responsible for the hard consistency
of the tumor (scirrhous carcinoma).
Invasive ductal carcinoma
Positive resection
margin
Invasive lobular carcinoma
~10% of invasive carcinomas.
GROSS:
Tumors can be scirrhous or can have a diffusely infiltrating
pattern that is difficult to detect clinically and
mammographically. They may remain occult.
Invasive lobular carcinoma
More often
multifocal
and bilateral
than other
types of
breast
carcinoma.
Invasive lobular carcinoma
http://ioway.nativeweb.org/images/indianfile.jpg
Discohesive cells arranged in
„indian files”, or in „goose
lines”, often in a targetoid
pattern around normal ducts
Invasive lobular carcinoma
The lack of E-cadherin (silencing of the E-cadherin gene (CDH1)
by mutation or methylation) is believed to be responsible of the
distinct morphological pattern.
E-cadherin is a calcium dependent cell-to-cell adhesion molecule.
E-cadherin immunostain – no staining of tumor cells, positive membrane
staining of normal duct
Breast cancer spread
• Directly to skin and pectoral muscles
• To regional lymph nodes (somewhat dependent on the
primary tumor site)
– Axillary lymph nodes (most common; outer quadrant tumors)
– Internal mammary (parasternal) lymph nodes (less common;
more common with inner quadrant tumors)
– „Sentinel lymph nodes”: directly connected to the tumor, most
likely site of lymph node metastasis
• To distant sites:
Bones, lung, liver, skin, adrenals…etc
Invasive lobular carcinomas have a different pattern; predilection
meninges, serosal surfaces, ovary, uterus, other viscera and
bone marrow.
Breast cancer – prognostic factors
•
Prognostic factors: parameters which affect the
outcome of the disease (without treatment)
1. Distant metastasis (Stage IV disease). The presence
of distant metastases infers the worst prognosis
2. Lymph node metastases (The most important
prognostic factor in those without evident distant
metastasis) With increasing numbers of involved
lymph nodes the prognosis worsens:
- Node-negative tumors have 70-80% 10-y-survival
- Node-positive tumors >9 positive nodes have 1015% 10-y-survival
Breast cancer – prognostic factors (ctd)
3. Tumor size (the larger the tumor, the worse the
prognosis)
4. Tumor stage (the first 3 factors are combined in
the TNM classification and in the STAGEs of
the disease) 0 (in situ) - IV
5. Tumor histologic grade (breast cancers are
graded in a 3-tiered system on the basis of
their tubule formation, nuclear pleomorphism
and mitotic rate: grade 1 – well differentiated,
grade 2 – moderately differentiated, grade 3 –
poorly differentiated)
6. Lymphatic or vascular / (lympho)vascular
invasion; its presence is an adverse sign
Breast cancer – prognostic factors (ctd)
7. Estrogen and progesterone receptor (ER,
PR) status: ER and PR positive tumors
have somewhat better prognosis and are
likely to react to hormonal treatment (ER
and PR status is also a predictive marker
– i.e. predicts the responsiveness to a
given therapy; hormonal treatment here)
ER+ breast cancer (nuclear)
Breast cancer – prognostic factors (ctd)
8. HER-2 (c-erb-B2; NEU) status. HER-2 is an
oncogen; it is amplified in 15-20% of breast
cancers; the gene amplification is paralleled by
protein overexpression. HER-2 positive tumors
have worse prognosis.
The HER-2 status is predictive of the response to
targeted therapy against the HER-2
oncoprotein (trastuzumab; humanized
monoclonal antibody – the 1st targeted therapy
agent for solid tumors)
HER-2
Immunohistochemistry:
Protein overexpression (membrane)
Chromogenic in situ hybridisation:
Gene amplification
Different biologies and therapeutic
groups according to ER, (PR) & HER2
• Better prognosis
• ER+ HER2- (low
proliferation)
• Worse prognosis
• ER+ HER2- (high
proliferation)
• HER2+ (ER+ or ER-)
• ER- (PR-) HER2(triple negative)
Special presentations of breast
cancer
INFLAMMATORY CARCINOMA
Cancer, clinically presenting as inflammation (peau
d’orange sign – resulting from oedema; or frank
redness, inflammation)
This must be suspected in all cases of „mastitis” in
non lactating women.
This is generally associated with dermal lymphatic
vessel invasion, although this latter (without the
clinical symptoms) is not sufficient for diagnosing
inflammatory carcinoma
Poor associated prognosis; this is generally not a
surgical disease in this stage
Special presentations of breast
cancer
MALE BREAST CANCER
Often associated with BRCA2 mutations
In men carcinomas tend to invade skin
and chest wall earlier as there is much
less amount of surrounding breast tissue.
Matched by stage, prognosis is similar in
men and women
Other malignancies
• Malignant phyllodes tumors can contain
areas of liposarcoma or fibrosarcoma or
even heterologous elements like
chondrosarcoma, osteosarcoma
• Other sarcomas: e.g. Angiosarcoma (can
be a consequence of radiotherapy)
• Lymphoma
• Metastases (e.g. melanoma)
Michelangelo: Night – Toomb of Guiliano Medici (1526-31) - Florence
Summary of lesions
• Benign
Malignant
– Acute mastitis
– Plasma cell mastitis
/ Mammary ductectasia
– Fat necrosis
– Fibrocystic changes
proliferative breast disease
– Intraductal papilloma
– Fibroadenoma
– Benign phyllodes tumor
– Gynecomastia
- In situ carcinomas (CIS):
Ductal CIS (DCIS)
Lobular CIS (LCIS)
Paget’s disease of the nipple
- Invasive carcinomas:
Invasive ductal carcinoma nst
Invasive lobular carcinoma
- Malignant phyllodes tumor
- Other malignancies: e.g.
Angiosarcoma
Borderline phyllodes tumor