Breast Pathology Robbins/Lecture Part 2 Flashcards
DCIS is treated _ as subsequent invasive carcinomas usually occur at the same site where as LCIS confers _ risk
locally
bilateral risk
white women are typically diagnosed with breast cancer around the age of? while black people and hispanic people are diagnosed with breast cancer when?
WW: 63
AW: 59
Hispanic: 56
why has the percentage of deaths from breast cancer decreased
mammography and other more effective treatment modalities
death rate mortality has not decreased in african american women (those who have the most risk of death)- this is due to unequal acess to care and that more aggresive breast cancers have a predilection for african americans
beyond female sex the major factors associated with an increase risk of breast cancer is?
hereditary factors, lifetime exposure to estrogen (early menses, late menopause), environmental factors, high breast density, radiation (high dose), obesity
what are the major factors that decrease the risk of breast cancer?
pregnancy prior to 20 years of age and prolonged breast feeding
the major risk factor for sporadic breast cancer are related to?
sporadic breast cancer is genetic/environmental factors/epigenetics
hormone exposure: gender, age at menarche and menopause, reproductive history, breast feeing, and exogenous estrogwns
familial breast cancer is?
25% of breast cancers
family history is present but negative for BRCA
hereditary breast cancer is?
10% of all breast cancers
BRCA1 or BRCA2 positive or TP53
the most important high penetrance susceptability genes for hereditary breast cancer are
tumor suppressor genes that typically regulate genomic stability and are involved in pro-growth signaling
BRCA1 and BRCA2
BRCA1 and BRCA2 are human genes that produce?
tumor suppresor proteins
tumor suppresor proteins help repair damaged DNA
- in a mutation DNA damage cannot be repaired properly and are more liekly to develop into cancer
mutations in BRCA1 and BRAC2 are responsible for _ percent of single gene familial breast cancers and about _ percent of all breast cancers
90%
3%
penetrance varies: the percentage of carriers who develop breast cancer varies)
it is believed that one quarter to one third of breast cancers occur due to inheritance of?
a susceptability gene
breast cancer is rare in women younger than _ and increases in incidence rapidly after age _
25
age 30
all breast cancers can be sperated into 3 major groups: what are they, and when does their incidence peak?
ER/luminal- peaks later in live around 65
HER2/ERBB2- plataeus later in life
TNBC-plateaus later in life
Describe the ER aka luminal positive pathway for breast cancer
- normal breast
- BRCA2 mutation
- 1q gain, 16q loss
- Flat epithelal atypia- precursor
- PIK3CA (signaling molecule) mutation
- atypical ductal hyperplasia- precursor
- DCIS- precursor
- invasive luminal cancer
dominant pathway of breast cancers 50-60% of all breast cancers
luminal cancers are high in ER and are also high in by negative feedback
PR
progesterone receptor
the major risk factor for luminal/ ER + cancer is?
estrogen exposure
estrogen increases local production of growth factors like TGFba, platelet derived growth factor, and expression of genes in breast epithelial cells stimulating proliferation
because estrogen increases cyclicly during reporductive years it has a direct correlation with what kind of breast cancer
luminal
treatment of luminal cancer
antiestrogenic therapy like tamoxifen
most luminal cancers metastisize to the ?
bone
do luminal cancers have a good prognosis?
yes, they respond well for decades to anti-estrogenic therapy, they are well differentiated and slow growing
well differentiated- look like normal cell type
describe the pathway for HER2+ breast cancers
- TP53 mutations
- HER2 amplification
- NO PRCURSOR
- DCIS
- HER+ cancer
20% of all breast cancers
her2 positive cancers arise through a pathway strongly associated with amplification of the ?
what chromosome?
HER2 gene on the chromosome 17q
HER2 also known as ERBB2 is a ?
receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stumulating RAS and P13K-AKT signaling pathways
HER2 cancers is the most common subtype of breast cancer in patients with germinal _ mutations.
this is known as?
TP53 mutations
Li-Fraumeni syndrome- sarcomas, leukemia, brain tumors
can HER cancers be ER positive?
yea or not, dont get too confused with this
if it is ER positive it has a better prognosis than if it was negative
the only common molecular mechanism for HER2 overexpression is?
gene amplification
they have complex interchromosomal rearrangements, high mutational load
HER2 carcinomas are diagnosed by?
detecting HER2 overexpression with immunochemistry or HER2 gene amplification by insitu hybridization
how do we treat HER2 cancers
with antibodies that bind and block HER2 activity (HER2 targeted therapy)
Decribe the TNBC pathway
- BRCA1 mutation
- TP53 mutation
- P53 signature
- BRCA1 inactivation
- DCIS
- Triple Negative Breast Cancer
estrogen independent pathway and no HER2 amplification- 15% of all breast cancers
TNBC have a _ like gene expression because many of the genes that comprise this signature are normally expressed in basally located myoepitheleal cells
basal-like
possible precursor lesion for TNBC ?
lobular epithelial cells that are ER negative and p53 positive
resemble serous tubal intraepithelial corcinoma in the fallopian tube with a BRCA1 mutation
TNBC shares genetic features with what?
serous ovarian carcinomas and serous tubal intraepitheal carcinomas
TBNC is more likely to present with? (different than luminal cancer)
palpable mass: less likely to be detected on mammography because it grows in the period betwen screenings
how do we treat TNBC and do they recurr
cytotoxic therapy
yes they reoccur (first 8 years after diagnosis)
TNBC mestasizes where?
brain and visceral sites
agreesive tumors that typically end in death
what approaches have been made to subclassify breast cancer into clinically meaningful subtypes
- circos plots of genomic abnormalities
- mRNA gene spression profiles (red= more mutations)
- immuno-histochemistry for specific proteins
- respective morphology
what immunochemistry proteins are spescific for luminal cancer, HER2+ cancers, and TNBC
luminal: ER and Ki67
HER2: HER2
TNBC: basal keratins
_ breast cancers have the lowest rate of recurences in the first 10 years
luminal
almost all recurrences of _ breast cancer occur within the first 8 years
TNBC
_ breast cancers show a mixed pattern with both early and late peaks of reoccurence
HER2+ cancers
late peak: due to aquired resistance?
describe the spectrum of luminal cancers
there are different histological grades and proliferation rates for luminal cancer
luminal A- low proliferation with ER+ and PR+ which are well differentiated and slow growing
luminal B- high proliferation has low ER+ and absent PR+ are more aggressive luminal tumors
PR is upregualted by estrogen and ER
luminal B has association with what mutation, and staining for what?
BRCA2
Ki67 staining
does luminal A or luminal B metastize to bone
luminal A
how do luminal A and luminal B differ in reponse to treatment?
luminal A has a good response to anti-estrogenic therapy
luminal B- 10% need chemotherapy
luminal B has higher expression of genes related to cellular proliferation
how does estrogen promote luminal breast cancer?
increases local growth factors like TGFBa, platelet derived growth factor, fibroblast growth factor, and stimulates breast growth
the proliferation of breast epithelium leads to accumulated _ damage
DNA
repeated _ increase the risk of developing cancer and damage may become fixed
cycles
once premalignant and malignant changes are present in luminal cancers _ stimulate growth of these cells and aid in tumor development
hormones (estrogen futher complicated/develops the cancer)
is there a morphologic pattern associated with HER2 cancers?
no
poorly differentiated
variation in gene expression among HER2 cancers is largely based on?
ER status and differing lecels of expression of ER related genes
what pharmaceutical agent can help treat HER2+ cancers
herceptin (it is a monoclonal antibody that inhibits HER2)
not all respond to targeted therapy because resistance can occur
who is most likely to get TNBC
african american women, hsitpanics, young premenopausal women
due to high proliferation and rapid growth TNBC are likely to present with palpable mass in the interbal between mammographic screenings
just know that (one year they are fine, the next year they have a large mass)
almost all breast malignancies are _ (SCC/Adenocarcinomas)
adenocarcinomas
all breast carcinomas arise from cells in the?
TDLU
carcinoma in situ by definiton is?
2 parameters-
a clonal proliferaction that is confied to ducts and lobules
with NO extension beyond the basement membrane and the myoepithleal cells are preserved
DCIS is detected mammographically as?
micro Ca+ calcificatons that extend throughout the duct system
NOT as a mass!!
DCIS can present as a mass (usually just calcium) if ?
if it is associatd with fibrosis or nipple discharge
what is the nautral history of DCIS?
difficult to determine: mastectomy and radiation is curative
how many people with DCIS end up dying from metastasis
1-3%
the deposittion of CA+ is variable and some might be missed?
risk factor for DCIS to reoccur?
high nuclear grade and necrosis
extend of disease
positive surgical marigins
what can decrease the rate of recurrence of DCIS
radiation and tamoxifen (along with ressection)
what is the most common type of DCIS
comedo type
comedo type DCIS presents as?
on mammography
linear brnaching og calification
on histology comedo type DCIS present with what 2 things?
- tumor cells with pleomorphic high grade nuclei
- central area of necrosis + calcifications in the ducts
pagets disease of the nipple arises from
malignant cells in the duct involved with DCIS
pathology of pagets disease of the nipple
DCIS in the duct ectends within the duct system vua the lactiferous sinuses into the nipple skin without crossinf the basement membrane
tumor cells disrupt the normal epitheliam barrier and allos extracellular fluid to seep out onto the nipple surface
paget cells are redilty detected by?
nipple biopsy or cytologic preparatios of exudate
clinical presentation of pagets disease of the nipple
unilateral erythematous eruption of a scale crust on the breast with pruritis
palpable mass?
commonly mistaken for eczema
paget disease of the nipple carcinomas (mass and are invasive) are assocated with what subtype of cancer?
ER negative and HER positive
lobular carcinoma insitu is a clonal proliferation of cells that growa in a discohesive patter due to mutations in?
CDH1 that leads to a loss of tumor suppressor adhesion protein E-cadherin
CDH1 mutation
E-cadherin negative
bilateral
does LCIS have mammographic findings?
typically no
LCIS almost always expresses what subtype of cancer
ER and PR positive
HER2 negative
_ incidence has not changed since mammographic screening
LCIS
how does LCIS look morphologically?
samll rounded, loosely cohesive cells that ill and expand in the acini of a lobule
LCIS cell extend into the adjacent duct by _ spread
pagetoid
pagetoid: spread of neoplastic cells between the basement membrane and overlying luminal cells
_ cells are commonly present in LCIS
mucin positive signet ring cells
larger breast carcinomas may invade the _ muscle and become fixed to the chest wall or invade the _ which causes retraction and dimpling of the skin
pectoralis
dermis
when the breast tumor involves the central protion of the breast retraction of the _ may develop
nipple
breast carcinomas have a wide variety of morphologic apperance: 1/3 are and 2/3 are
1/3: special histological types
2/3: ductal/no special type NST/NOS
invasive carcinoma is graded using the _ score
Nottingham Histologic Score
invasive carcinomas of the breast are scored for _, _, and _
tubular formation
nuclear pleomorphism
mitotic rate
what are the multiple subtypes of invasive breast carcinoma that are recognised by distincitve morphologies
5 of them
- lobular carcinoma
- medullary carcinoma
- mucinous/colloid carcinoma
- tubular carcinoma
- inflammtory carcinoma
lobular carcinoma has a loss of _ and has characteristic mestatasis where?
CHD1 (Ecadherin)
metastasize to peritoniem, retroperitoneum, leptomeninges, GI tract, and ovaries/uterus
like LCIS
medullary pattern carcinomas are of interest because they look like they have a _ mutation
BRCA1 hypermythlation mutation
similar to TNBC but have a better prognosis
why do medullary pattern carcinomas have a better prognosis than TNBC?
they have a large number of infiltrating lymphocytes suggesting improved outcomes may be related to the host immune system response
mucinous/colloid carcinoma is soft and rubbery and has a consitency of?
pale gray blue gelatin
how do mucinous carcinomas look histologically
tumor cells arranged in clusters within large lakes of mucin
inflammatory carcinomas have higher incidence in?
african americans
presentation of inflammtory carcinomas and prognosis
peau d’orange from extensive plussing of lymp spaces with carcinoma cells
poor prognosis
cancer cells plug the dermis
male breast cancer is usually at _ stage at presentation
high
risk factors for male breast cancer
estrogen exposure
in the absence of adequate surgery the majority of patients with breast cancer die wtih extensive local disease causing ulceration of the skin. _ is a dreaded complication of breast cancer (skin involvement)
carcinoma en cuirasse (carcinoma of the breastplate)
invasive carcinoma of no special type looks like what?
haphazard stromal invasion, irregular margins on immaging, exuberant demoplsatic stromal response (very hard like cutting a carrot)
