Breast - Precursor Lesions/Proliferative Entities Flashcards
What are the normal changes seen in the menstrual cycle?
1) Follicular Phase
Luminal epithelial cells with dark centrally located nuclei and eosinophilic cytoplasm
2) Luteal Phase
Vacuolation, ballooning of basal myoepithelial cells
3) Secretory Phase
Apical Snouts
Enlarged lumina
Eosinophilic secretory material
What are the changes seen in pregnancy and lactation?
Organoid enlargement and dilation of lobular units.
Luminal epithelial cells :
Vacuolated cytoplasm
Enlarged round nuclei
Prominant nucleoli
HOBNAIL pattern — (also seen in lactating adenoma)
Can see increased mitotic activity
What are the luminal markers for breast cells?
LMW cytokeratins - CK7, CK8/18, CK19
E-Cadherin (membranous) - loss is hallmark of lobular carcinoma
GCDFP-15 - gross cystic disease protein (cytoplasmic) - fairly specific, but usually patchy
Mammaglobin (cytoplasmic) - positive in 60% breast ca, but also stains gynae
GATA3 (nuclear) - highly sensitive,
**SOX10 **(nuclear) - enriched in triple negative breast Ca, but also stains melano and neuro
**ER and PR **(nuclear) - ER controls synthesis of PR
What are the myoepithelial markers?
P63 (nuclear)
P40 (nuclear)
Calponin (cytoplasmic)
SMA- smooth muscle actin (cytoplasmic)
SMMHC -smooth muscle myosin heavy chain (cytoplasmic)
CK14 (cytoplasmic)
S100 (nuclear and cytoplasmic)
**P63/P64 **and SMMHC are superior as they dont react with fibroblasts.
What markers would you use to identify breast primary in a metastasis?
GATA3 (>90%+, but not specific)
ER/PR (60% positive)
GCDFP (~60% positive)
Consider** SOX 10** in cases of triple negative breast Ca
Interpret ER/PR IHC
<1% nuclear staining - weak
1-10% nuclear staining - moderate
11%> - strong
If >1% of cells stain - positive
if <1% of cells stain - negative
1-10% is classed as low-positive - should be mentioned in the report as per ASCO/CAP 2020 guidelines
Interpret Her-2-Neu IHC
HER2 testing must be performed on every primary invasive carcinoma and on a metastatic site
No staining observed or incomplete faint / barely perceptible membrane staining within ≤ 10% of invasive tumor cells - Score 0 - Negative
Incomplete faint membrane staining and within > 10% of invasive tumor cells - Score +1 - Negative
Weak to moderate complete membrane staining observed in > 10% of invasive tumor cells - Score +2 - Equivocal
Tumor displays complete, intense circumferential membranous staining in > 10% of tumor cells - Score +3 - Positive
Interpret Fluoresecent in-situ hybridisation (FISH)
ASCO / CAP guidelines recommendations if initial HER2 testing by IHC results in equivocal values, reflex testing by FISH should be performed on the same specimen or an alternative specimen (eg lymph node).
Positive:
Single probe average HER2 copy number ≥ 6.0 signals/cell.
Dual probe HER2/CEP17 ratio ≥ 2.0 with any average HER2 copy number,
or HER2/CEP17 < 2.0 with an average HER2 copy number ≥ 6.0 signals / cell
Negative:
Single probe average HER2 copy number < 4.0 signals/cell.
Dual probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell
Borderline
Dual probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number 4.0 - 6.0 signals/cell
Count more cells or resample.
How would you differentiate Myoepithelial, myofibroblasts, and vessels?
SMA, Calponin, SMMHC, p63/p40
**Myoepithelial **- positive for all
Myofibroblasts - Positive for SMA, weakly for calponin
Vessels - Negative for p63/p40
This is why p63/p40 are better than SMA and calponin - less background noise
What is the immunoprofile of breast carcinoma (in general)?
CK7+
CK20-ve
GATA3
ER/PR
HER2
GCDFP-15
Mammaglobin
What is the immunoprofile of lobular carcinoma (in situ and infiltrative)?
Loss of E-Cadherin membranous staining
GCDFP-15
What is the immunoprofile of metaplastic breast carcinoma?
HMWCK (CK903 or CK5/6)
CK7
p63/p40
How can you differentiate between ALH/LCIS, ADH/DCIS, and UDH?
ALH/LCIS - lose e-cadherin, +ve HMWCK (CK903, CK5/6), +ve ER staining, cytoplasmic p120 catenin
ADH/DCIS- +ve e-cadherin, lose HMWCK (CK903, CK5/6), diffuse ER staining, **membranous **p120 catenin
UDH - +ve e-cadherin, +ve HMWCK, Patchy ER, Membranous p120 catenin
Describe Usual Duct Hyperplasia
- Admixture of cell types - epithelial, myoepithelial, apocrine
- Haphazard architecture
- Irregular slit like spaces
- Overlapping nuclei
- Nuclear grooves
- Pseudoinclusions
- Thin bridges
- Micropapillae with broad bases and narrow tips
What are the markers for for Usual Duct Hyperplasia
- Low molecular weight CKs (CK7)
- High molecular weight CKs (CK5/6)
- Heterogenous ER staining
What is Atypical Duct Hyperplasia?
- Monoclonal
- Neoplastic proliferation of evenly spaced epithelial cells
- Cribriform architecture
- Bridging
- Micropapillae
- If >2mm or 2 duct spaces, is classed as DCIS
What are the markers for Atypical Ductal Hyperplasia?
- Low molecular weight CK - 8, 18, 19
- Strong, uniform ER staining
- **Negative **for High molecular weigh CK (5/6)
What’s the treatment for ADH?
If found on biopsy -> surgical excision to exclude DCIS/Invasive
If found on excision -> No further treatment required
Describe DCIS
- Monoclonal
- Neoplastic proliferation of epithelial cells of ductal origin.
- Morphological appearance defines the grade… not architecture
- Can involve lobules - cancerisation of the lobules
- No specific size requirement, unlike ADH
- Majority or non-palpable
- Found on mammo with linear calcifications
- High grade associated with - stromal fibosis, sclerosis, infiltrative lymphocytes
What is the treatment of DCIS?
Excision with wide negative margins
+/- radiation therapy
+/- hormone therapy
What are the markers for DCIS?
- ER/PR positive in a clonal pattern (more frequently negative in high grade)
- HER2 - variable
- Negative for CK5/6
- E-Cadherin retained
- Myoepithelial cells - p40, p63, SMMS, calponin, CK5/6 and CK5
Myoepithelial cell layer surrounding ducts spaces containing DCIS is intact, but may be attenuated especially in high grade DCIS
What are the important prognostic factors for DCIS?
- Positive surgical margins
- high nuclear grade
- large lesion size
- comedo necrosis
- young age (< 45 years)
What are the molecular mutations for DCIS?
- PIK3CA (about 25%)
- TP53 (10-15%)
- GATA3 (about 10%)
What are the cytogenetics for LOW GRADE DCIS?
LOSSES:
16q, 17p
GAINS:
1p
What are the cytogenetics for HIGH GRADE DCIS?
LOSSES:
8p, 11q, 13q, 14q
GAINS:
5p, 8q, 17q
What are the architectural growth patterns of DCIS?
Cribriform:
Fenestrated proliferation with multiple, round, rigid extracellular lumens with punched out appearance
Roman bridges
Micropapillary:
Papillary fronds and tufts lacking fibrovascular cores projecting into duct lumen
Papillae often have club shaped cells comprising the micropapillae are uniform in appearance
Papillary:
Papillary fronds containing prominent fibrovascular septa projecting into duct lumen, papillary cores generally lack myoepithelial cell layer
Solid:
Lumen of ducts or lobules filled with sheets of cohesive cells
Cells are evenly spaced especially in low or intermediate grade DCIS
Flat or clinging:
1 - 2 layers of generally high grade malignant cells lining a gland with a large empty lumen
Comedo:
Central expansile necrosis containing cellular debris, generally associated with high grade DCIS, frequently associated with coarse microcalcifications
What is the Van Nuys Prognostic Index (VNPI)?
he VNPI was an attempt to objectively determine the aggressiveness of DCIS in terms of the likelihood of ‘local recurrence’ following ‘breast conserving’ surgeries.
Describe Atypical Lobular Hyperplasia
- small proliferation of discohesive, monomorphic epithelial cells.
- may show pagetoid spread through ductal spaces
- cytologically similar to LCIS… but limited to <1/2 duct
- common in premenopausal women
- Non-obligate precurser lesion
Describe lobular carcinoma in situ
More that 50% of acini are filled with/expanded by the neoplastic cells
Non obligate precursor lesion
Most often not associated with mammographic findings
Increased incidence in owmen who are post meno-pausal on HRT
CLASSIC
* Discohesive, monomorphic epithelial cells.
* Originate from TDLU
* >50% acini are filled and expanded, moften >8 cells thick
PLEOMORPHIC
* Large epithelial cells
* Marked nuclear pleomorphism
* May see nucleoi, mitoses, intracytoplasmic vacuoles
FLORID
* Confluent, mass like lesion
* Little or no intervening stroma between distended TDLU
* often 50 cells thick
Intracytoplasmic vacuole - ** MUCICARMINE**positive (special stain)
What is the treatment for LCIS
If CLASSIC on core biopsy:
No need to excise
if CLASSIC on excision:
No need for clear margins
if PLEOMORPHIC or FLORID:
excise with negative margins due to increased genomic instability and aggressive behaviour
Tamoxifen - reduced subsequent risk of ER+ by 50%
Explain membranous IHC for normal epithelium, lobular neoplasia, DCIS
NORMAL EPITHELIUM:
Membrane +ve for E-cad, p120 catenin, B-catenin
DCIS:
**Membrane +ve **for E-cad, p120 catenin, B-catenin
LOBULAR NEOPLASIA:
-ve for E-cad, Cytoplasmic +ve for p120 catenin, **loses membrane **B-catenin
What are the risks for invasive cancer with each in situ breast entity?
UDH:
2-fold increase risk for breast cancer
ADH:
4 to 5-fold increase risk for breast cancer
DCIS:
10x relative risk of invasive disease in ipsilateral breast
40% progress to invasive if left untreated
ALH:
4 to 5-fold increase risk for breast cancer
Life time risk is 15%
67% cancer occurs in ipsilateral breast, 33% in contralateral breast
LCIS:
8-10 fold relative risk for invasive breast cancer
remember Tamoxifen reduced risk by 50% om ER+ve LCIS
