Breast Pathology Flashcards
what signaling pathways play a major role in breast development?
Wnt
FGF
PTHrP (parathyroid hormone-related protein)
Poland syndrome
born with missing or underdeveloped muscles on one side of the body resulting in chest, shoulder, arm and hand abnormalities
milk line remnants/supernumerary nipples
failure of regression of the thickened ectodermal streaks during 2-3 months of development
polymastia
supernumerary nipples with breast tissue and ducts
accessory axillary breast tissue
in some women, the normal ductal system extends into the subcutaneous tissue of the axillary fossa
congenital nipple inversion
failure of the nipple to evert during development
acquired nipple inversion
may indicate invasive cancer or inflammatory nipple disease
lymphatic drainage of the lateral breast
external mammary –> scapular –> central –> axillary –> subclavicular
OR
interpectoral –> subclavicular
lymphatic drainage of medial breast
internal mammary nodes
what hormone stimulates breast development?
estrogen
physiologic breast changes during pregnancy
breast completely matures and becomes functional
lobules increase progressively in number and size
by the end of pregnancy, the breast is almost completely composed of lobules separated by a scant stroma
physiologic breast changes of pre-menopausal women
third decade
lobules and stroma start to involute and stroma is converted to adipose tissue
what are the two major epithelial structures of the breasts?
lobules and ducts
what are the two types of epithelial cells that make up a lobule/duct?
luminal cells
myoepithelial cells
what cell signaling pathways contribute to epithelial cells within the lobules/ducts?
calponin
a-smooth muscle actin
p63
CD10
what are the two types of stroma that make up breast tissue?
interlobular
intralobular
most common palpable benign lesions
cysts and fibroadenomas
most common palpable malignant lesions
invasive ductal carcinoma
what are mammographic densities and when are they concerning?
breast lesions that replace adipose tissue with radiodense tissue
concerning when they form irregular masses
what are mammographic calcifications and when are they concerning?
calcifications form on secretions, necrotic debris or hyalinized stroma
small, irregular, numerous and clustered calcifications are concerning
what percentage of invasive carcinomas are not detected by mammography?
10%
the reason why all papable masses require further investigation
you diagnose a breast “mass”, what’s the next step?
biopsy
acute mastitis
associated with first month of breastfeeding due to cracks and fissures in the nipples
what bacteria causes abscesses in the setting of mastitis?
staphylococci
what bacteria causes cellulitis in the setting of mastitis?
streptococci
squamous metaplasia of lactiferous ducts (SMOLD)
subareolar mass that mimics bacterial abscess
fistula tract often develops under the smooth muscle of the nipple
nipple inversion may also occur
which population is most at risk to developing SMOLD?
smokers due to vitamin A deficiency which alters ductal epithelium
duct ectasia
granulomatous and fibrotic inflammatory reaction due to duct rupture
*multiparous women in 5th-6th decade
clinical presentation of duct ectasia
palpable periareolar mass
white nipple secretions
skin retraction
*may resemble invasive carcinoma
clinical presentation of fat necrosis
painless, palpable mass
skin thickening or retraction
mammographic densities or calcifications
etiology of fat necrosis
breast trauma or surgery
lymphocytic mastopathy/sclerosing lymphocytic lobulitis
fibroinflammatory lesion secondary to autoimmune reaction
clinical presentation of lymphocytic mastopathy
hardened mass in women with DM1 or autoimmune thyroid disease
granulomatous lobular mastitis
rare disease that occurs in parous women
granulomas closely associated with lobules
cystic neutrophilic granulomatous mastitis
type of granulomatous mastitis caused by lipophilic Corynebacteria
which epithelial breast pathology has the highest risk of developing invasive carcinoma?
proliferative disease with atypia
ex: atypical ductal hyperplasia, atypical lobular hyperplasia
nonproliferative/fibrocystic changes
“lumps and bumps”
what morphologic changes are associated with fibrocystic changes?
cystic
fibrosis
adenosis
adenosis
increase in the number of acini per lobule
*normal feature of pregnancy
lactational adenomas
palpable masses in pregnant or lactating women
*regress with cessation of breastfeeding
proliferative breast disease without atypia
characterized by proliferation of epithelial cells without cytologic atypia
associated with a small increased risk of invasive carcinoma
what morphologic changes are associated with proliferative breast disease without atypia?
epithelial hyperplasia sclerosing adenosis complex sclerosing lesion papilloma gynecomastia
clinical presentation of large duct papillomas
nipple discharge - serous or serosanguinous
proliferative breast disease with atypia
clonal lesion characterized by proliferations of either ductal or lobular epithelial cells
have some but not all histo features of carcinoma in situ
associated with a moderate increase in risk of carcinoma
what morphologic changes are associated with proliferative breast disease with atypia?
atypical ductal hyperplasia (ADH)
atypical lobular hyperplasia (ALH)
what features are shared between ADH and ALH
express high levels of estrogen receptors (ER)
have a low rate of proliferation
may have acquired chromosomal aberrations such as losses of 16q, 17p or gains of 1q
feature specific to ALH
loss of E-cadherin expression
*shared feature with LCIS
feature specific to ADH
absence of cytokeratin 5/6 and diffuse positivity for ER
3 major groups of breast cancers
ER+, HER2- (luminal)
HER2+
ER-, HER2- (triple negative)
characteristics of hereditary breast cancer
AD trait high penetrance early onset bilateral or multifocal cancers multiple primary cancers
characteristics of familial breast cancer
low penetrance
variable age of onset
may result from common genetic background, similar environment or lifestyle factors
which genes are associated with the highest susceptibility for breast cancer
BRCA1 –> Ch 17
BRCA2 –> Ch 13
what is the most common pathogenesis of breast cancer
sporadic (65%)
histological subtypes of low proliferation luminal breast cancers
tubular
grade 1 or 2 lobular
mucinous
papillary
histological subtype of high proliferation luminal breast cancers
grade 3 lobular
histological subtype of HER2+ breast cancer
apocrine
micropapillary
histological subtypes of triple-negative breast cancers
medullary features
metaplastic
most common gene mutations in all types of breast cancer
PIK3CA
TP53
low proliferation luminal cancer
40-50%
older women and men
low grade with low recurrence rate
mets usually to bone
*responds well to antiestrogenic drugs
high proliferation luminal cancer
10%
increased nuclear staining for Ki67
most common form associated with BRCA2
how does estrogen contribute to luminal breast cancer
increases local production of growth factors
stimulates breast growth
proliferation leads to accumulated DNA damage
stimulates growth of premalignant or malignant cells
recurrence pattern for luminal breast cancer
lowest rate of recurrence in the first 10 years
but recurrences continue with a steady rate over a long period of time
recurrence pattern for HER2 breast cancer
mixed pattern with both early and late peaks
*late peak may be due to acquired resistance to therapy
recurrence pattern for triple-negative breast cancer
occur within the first 8 years
*recurrences after this time are rare
HER2 breast cancer
10-20% of all breast cancer
poorly differentiated
gene expression largely based on ER status
*most common subtype in patients with Li-Fraumeni syndrome (TP53 mutation)
HER2 physiological role
receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis
proto-oncogene for HER2
ERBB2
*amplification leads to overexpression of HER2
HER2 breast cancer treatment
trastuzumab (Herceptin)
*MoAb that binds and inhibits HER2
triple-negative breast cancer
“basal-like” cancer –> expressed in basally located myoepithelial cells
estrogen-independent pathway and not associated with HER2 overexpression
young premenopausal women especially AA and Hispanics
likely to present as palpable mass between mammograms due to high proliferation
BRCA1 association
carcinoma in situ
clonal proliferation that is confined to ducts and lobules
no extension beyond basement membrane
myoepithelial cells preserved
ductal (DCIS) or lobular (LCIS)
how is carcinoma in situ detected on mammogram?
micro Ca++ or periductal fibrosis
describe the progression from normal breast tissue to luminal cancer (ER+)
germline BRCA2 mutation –> flat epithelial atypia
PIK3CA mutation –> atypical ductal hyperplasia
ADH –> DCIS –> invasive cancer
describe the progression from normal breast tissue to HER2 cancer
germline TP53 mutation + HER2 amplification –> atypical apocrine adenosis –> DCIS –> invasive cancer
describe the progression from normal breast tissue to triple-negative cancer
germline BRCA1 mutation + TP53 mutation + BRCA1 inactivation –> DCIS –> invasive cancer
treatment for DCIS
lumpectomy vs mastectomy + chemo
post-op radiation + tamoxifen
risk factors for DCIS progression
nuclear grade and necrosis
extent of disease
positive surgical margins
paget disease of the nipple
rare manifestation of breast cancer that presents as unilateral erythematous eruption with scale crust
what is the MOA of paget disease
malignant cells extend from DCIS within the ductal system via the lactiferous sinuses into the nipple skin without crossing the basement membrane
tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out
which cancer gene is associated with Paget disease?
HER2
lobular carcinoma in situ
clonal proliferation of cells that grow in a discohesive fashion due to mutation in CDH1 that leads to loss of E-cadherin
always incidental finding (no mammogram findings)
bilateral in 20-40% of cases
risk factor for invasive cancer
ER+, HER2-
lobular carcinoma pattern of metastasis
peritoneum and retroperitoneum
leptomeninges
GI tract
ovaries and uterus
carcinoma of medullary pattern
associated with hypermethylation of BRCA1 (NOT germline)
associated with infiltrating T-cells
better prognosis than poorly differentiated carcinomas
inflammatory carcinoma
3% of breast cancers
higher incidence in AA
very poor prognosis
what skin finding is associated with inflammatory carcinoma?
peau d-orange –> due to extensive plugging of lymphovascular spaces of the dermis with carcinoma cells
stage 0 breast cancer
DCIS
no mets
97% survival
stage 1 breast cancer
invasive CA ≤ 2cm
no mets
87% survival
stage 2 breast cancer
invasive CA > 2cm + 1-3 LNs involved
invasive CA > 2cm but ≤ 5 cm + 0-3 LNs involved
65% survival
stage 3 breast cancer
invasive CA > 5cm with or without LNs
any size invasive CA + ≥ 4 LNs involved
inflammatory CA with or without LNs
40% survival
stage 4 breast cancer
any size CA with or without LN + distal mets
5% survival
carcinoma en cuirasse
extensive local disease, causing ulceration to the skin
occurs in untreated breast cancer
gynecomastia
only benign lesion of the male breast
estrogen/androgen imbalance that leads to stimulation of breast tissue
subareolar enlargement that may be bilateral
causes of gynecomastia
liver disease decreased testosterone drugs XXY karyotype testicular neoplasms
mnemonic for drugs causing gynecomastia
DISCOS
digoxin isoniazid spironolactone cimetidine o = estr"o"gens stilboestrol
what is the lifetime risk of a male developing breast cancer?
0.11%
fibroadenoma
most common benign tumor of the female breast
caused by mutations in MED12
what drug is associated with the formation of fibroadenoma?
cyclosporine A given post-renal transplant
are fibroadenomas associated with an increased risk of carcinoma?
yes - even higher if “complex” features are present
ex: large cysts, sclerosing adenosis, calcifications, or apocrine changes
phyllodes tumor
similar to fibroadenoma however has higher cellularity, higher mitotic rate, nuclear pleomorphism, stromal overgrowth and infiltrative borders
high-grade are malignant whereas low grade resemble fibroadenoma
what benign lesions arise within the breast stroma?
myofibroblastoma
lipomas
fibromatosis
what is the most common malignant stromal tumor?
angiosarcoma
*associated with prior radiation or Stewart-Treves syndrome
what secondary malignancies may arise in the breast?
lymphoma
skin
mets from another site
