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[[Image:Breast_cancer.JPG|thumb|300px|Breast cancer at [[cut-up]]. (WC/John Hayman)]]
The article deals with '''invasive [[breast]] cancer''' and the evaluation of hormone receptor & HER2 status.  Non-invasive breast cancer is dealt with in ''[[non-invasive breast cancer]]''.
The article deals with '''invasive [[breast]] cancer''' and the evaluation of hormone receptor & HER2 status.  Non-invasive breast cancer is dealt with in ''[[non-invasive breast cancer]]''.


=Introduction=
=Introduction=
==Types of invasive breast cancer==
==Overview of invasive breast cancer subtypes==
Types:Ref.: <ref name=Ref_PBoD1143>{{Ref PBoD|1143}}</ref>
====Common epithelial subtypes====
*Ductal - also known as no specific type (NST) - 79%.
Type and percentage of breast carcinomas:<ref name=Ref_PBoD1143>{{Ref PBoD|1143}}</ref>
*Lobular 10%.
*[[Invasive ductal carcinoma of the breast|Ductal]] - [[AKA]] no special type (NST) - 79%.
*Cribriform (tubular) 6%.
*[[invasive lobular carcinoma|Lobular]] - 10%.
*Mucinous (colloid) 2%.
*[[Tubular carcinoma of the breast|Cribriform / tubular]] - 6%.
*Medullary 2%.  
*[[mucinous breast carcinoma|Mucinous]] (colloid) - 2%.
*Papillary 1%.
*[[medullary breast carcinoma|Medullary]] - 2%.  
*Metaplastic <1%.
*Papillary - 1%.
*[[Metaplastic breast carcinoma|Metaplastic]] - <1%.


Others:
===Common stromal types===
*Malignant [[phyllodes tumour]].
*[[Angiosarcoma]] - post-radiation ~ 10 years.<ref>URL: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html]. Accessed on: 28 November 2010.</ref>
*[[Angiosarcoma]] - post-radiation ~ 10 years.<ref>URL: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html]. Accessed on: 28 November 2010.</ref>
===Good prognosis subtypes===
Three good prognosis subtypes:<ref>URL: [http://emedicine.medscape.com/article/1947145-overview http://emedicine.medscape.com/article/1947145-overview]. Accessed on: 24 August 2012.</ref>
*Tubular carcinoma.
*Mucinous carcinoma.
*Papillary carcinoma.
==Comprehensive list of invasive breast cancer subtypes==
====Epithelial====
Counterparts of in situ lesions:
*[[Invasive ductal carcinoma of the breast|Invasive ductal carinoma]], not otherwise specified.
*[[Invasive lobular carcinoma]].
*[[Invasive cribriform carcinoma of the breast|Invasive cribriform carcinoma]].
*[[Invasive papillary carcinoma of the breast|Invasive papillary carcinoma]].
*[[Invasive micropapillary carcinoma of the breast|Invasive micropapillary carcinoma]].
Other epithelial tumours:
*[[Tubular carcinoma of the breast|Tubular carcinoma]].
*[[Medullary breast carcinoma|Medullary carcinoma]].
*[[Mucinous breast carcinoma|Mucinous carinoma]].
*[[Metaplastic breast carcinoma|Metaplastic carcinoma]].
*[[Neuroendocrine tumour]].
*[[Apocrine carcinoma of the breast|Apocrine carcinoma]].
*Lipid-rich carcinoma.
*[[Secretory breast carcinoma|Secretory carcinoma]].
*Oncocytic carcinoma.
*[[Glycogen-rich clear cell carcinoma of the breast|Glycogen-rich clear cell carcinoma]].
Epithelial tumours seen in the [[salivary gland]]:
*[[Adenoid cystic carcinoma of the breast]].
*[[Acinic cell carcinoma]].
*[[Carcinoma ex pleomorphic adenoma]].
Seen in the skin:
*[[Sebaceous carcinoma]].
Clinically diagnosed:
*Inflammatory carcinoma.
In situ lesions:
*[[Ductal carcinoma in situ]].
*[[Lobular carcinoma in situ]].
Proliferative lesions:
*[[Usual ductal hyperplasia]].
*[[Flat epithelial atypia]].
*[[Atypical ductal hyperplasia]].
Non-specific:
*Microinvasive carcinoma.
Papillary:
*[[Intraductal papilloma of the breast|Papilloma]].
*Atypical papilloma.
*Intraductal papillary carcinoma.
Adenomas:
*Ductal adenoma.
*[[Tubular adenoma of the breast|Tubular adenoma]].
*[[Lactating adenoma]].
*Apocrine adenoma.
*[[Pleomorphic adenoma]].
====Myoepithelial====
*Myoepitheliosis.
*Adenomyoepithelial adenosis.
*[[Adenomyoepithelioma]].
*Malignant adenomyoepithelioma.
====Mesenchymal tumours====
:See: ''[[Soft tissue lesions]]''.
====Fibroepithelial tumours====
*[[Fibroadenoma]].
*[[Phyllodes tumour]].
*Periductal stromal sarcoma, low grade.
*[[Mammary hamartoma]].
====Nipple lesions====
*[[Nipple adenoma]].
*Syringomatous adenoma.
*[[Paget disease of the breast]].
====Other====
*[[Lymphoma]].
*[[Metastasis]].


==Familial breast cancer==
==Familial breast cancer==
BRCA1 vs. BRCA2:<ref name=Ref_PBoD1133>{{Ref PBoD|1133}}</ref>
{{Main|Hereditary breast cancer}}
*BRCA1:
**Younger.
**Ovarian cancer.
**Worse types of breast cancer (e.g. triple negative breast cancer: PR-, ER-, HER2/neu-).
*BRCA2:
**Older.
**Like sporatic.
**Male [[breast cancer]].
*BOTH are associated with increased risk of (memory device ''CPP''):
**[[Colon cancer]].
**[[Prostate]].
**[[Pancreas]].


=Breast IHC=
=Breast IHC=
==Subtyping breast cancer==
==Molecular classification of ''invasive carcinoma''==
A molecular classification:<ref name=Ref_PCPBoD8_547>{{Ref PCPBoD8|547}}</ref>
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
! Type
! Percentage
! IHC
! Histology
! Prognosis/clinical
|-
| Luminal A
| ~45%
| ER+ PR+ HER2-
| well-differentiated
| good, chemo resistant
|-
| Luminal B
| 17%
| ER+ PR+ HER2+
| high grade
| poor, +/- chemo responsive
|-
| Normal breast-like
| ~8%
| ER+ PR+ (?) HER2-
| well-differentiated
| good
|-
| Basal-like
| ~20%
| ER- PR- HER2-
| poorly differentiated
| aggressive, may have good chemo response, classic for [[BRCA1]] mutation
|-
| HER2 positive
| ~10%
| ER- PR- (?) HER2+
| poorly differentiated
| poor
|}
 
The above is not applied clinically. A panel of [[immunostains]] ([[ER]], PR, HER2, EGFR, [[CK5/6]]) can reproduce the molecular groupings; however, these groupings originate from gene expression profiling studies<ref name=pmid19704256>{{Cite journal  | last1 = Tang | first1 = P. | last2 = Skinner | first2 = KA. | last3 = Hicks | first3 = DG. | title = Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready? | journal = Diagn Mol Pathol | volume = 18 | issue = 3 | pages = 125-32 | month = Sep | year = 2009 | doi = 10.1097/PDM.0b013e31818d107b | PMID = 19704256 }}</ref>
 
A newer classification outlines 10 subtypes based on molecular drivers identified by analysis of genomic and transcriptomic data from 2,000 breast tumors.<ref>{{Cite journal  | last1 = Curtis | first1 = C. | last2 = Shah | first2 = SP. | last3 = Chin | first3 = SF. | last4 = Turashvili | first4 = G. | last5 = Rueda | first5 = OM. | last6 = Dunning | first6 = MJ. | last7 = Speed | first7 = D. | last8 = Lynch | first8 = AG. | last9 = Samarajiwa | first9 = S. | title = The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. | journal = Nature | volume = 486 | issue = 7403 | pages = 346-52 | month = Jun | year = 2012 | doi = 10.1038/nature10983 | PMID = 22522925 }}</ref>
 
== Basal-like breast carcinoma==
 
 
*Overview:<ref>{{Cite journal  | last1 = Badve | first1 = S. | last2 = Dabbs | first2 = DJ. | last3 = Schnitt | first3 = SJ. | last4 = Baehner | first4 = FL. | last5 = Decker | first5 = T. | last6 = Eusebi | first6 = V. | last7 = Fox | first7 = SB. | last8 = Ichihara | first8 = S. | last9 = Jacquemier | first9 = J. | title = Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. | journal = Mod Pathol | volume = 24 | issue = 2 | pages = 157-67 | month = Feb | year = 2011 | doi = 10.1038/modpathol.2010.200 | PMID = 21076464 }}
</ref>
**A category of breast carcinomas defined by gene expression profiling.
**''Not used'' in clinical practice.
**Somewhere between 15-30% of breast carcinomas.
**Can be roughly be identified by immunohistochemistry - basal markers (CK14, p63, calponin, SMA).
**Not derived from myoepithelial cells, merely express a phenotype more in keeping with basal cells than ductal cells.
**Most triple negative (ER, PgR, Her-2); therefore cannot be treated with the usual therapeutic agents.
**There is an association in young women between basal-like breast cancer and BRCA1 mutation.
**Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
**Increased incidence in some populations - African-Americans, young women
**Sporadic basal-like cancers do not have a BRCA1 mutation but may have a dysfunctional BRCA1 pathway.
**p53 mutations are frequent.
 
*This molecular group includes a variety of morphologic phenotypes including:
**High grade [[invasive ductal carcinoma]] of no special type.
**Medullary-like carcinoma (a carcinoma with some but not all the features of medullary carcinoma).
**[[Medullary breast carcinoma|Medullary carcinoma]]
**[[Metaplastic breast carcinoma|Metaplastic carcinoma]].
**[[Adenoid cystic carcinoma of the breast|Adenoid cystic carcinoma]].
**[[Secretory carcinoma]].
 
*Classic morphological clues of a basal type cancer usually refer to medullary carcinoma features:
**Relatively circumscribed.
**Geographic necrosis.
**Abundant mitoses.
**Pushing margins.
**Central fibrosis or necrosis.
**High histological grade.
**Exceptionally high mitotic rate.
**Pushing borders.
**Conspicuous lymphocytic infiltrate.
 
*Behaviour:
**Basal-like breast cancer is a heterogeneous group.
**The behaviour of basal-like breast cancer appears to fall into two groups:
***The tumours that are by nature low grade (ie adenoid cystic carcinoma) and/or do not metastasise have a better prognosis than other types of breast carcinoma.
***The tumours with early metastasis that may behave more aggressively
****Hematogenous spread -greater tendency to metastasise to visceral sites (notably lung and brain) instead of to nodes and bone.
**Many have a complete response to chemotherapy and survival rates similar to typical breast cancer
**Non-complete response to chemotherapy is associated with low survival at 5 years.
 
Other sources
Minireview: Basal-Like Breast Cancer: From Molecular Profiles to Targeted Therapies <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035993/>
 
== Triple Negative Breast Carcinoma ==
Features:<ref name=pmid21076464>{{Cite journal  | last1 = Badve | first1 = S. | last2 = Dabbs | first2 = DJ. | last3 = Schnitt | first3 = SJ. | last4 = Baehner | first4 = FL. | last5 = Decker | first5 = T. | last6 = Eusebi | first6 = V. | last7 = Fox | first7 = SB. | last8 = Ichihara | first8 = S. | last9 = Jacquemier | first9 = J. | title = Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. | journal = Mod Pathol | volume = 24 | issue = 2 | pages = 157-67 | month = Feb | year = 2011 | doi = 10.1038/modpathol.2010.200 | PMID = 21076464 }}</ref>
 
**A category of breast carcinomas defined by immunohistochemical/FISH expression of ER, PR and HER2.
**''Important to identify'' in clinical practice.
**About 15% of breast carcinomas.
**Important group due to a lack of tailored therapies for this group
***Some triple negatives also express androgen receptor and have and [apocrine carcinoma] morphology.<ref>{{Cite journal  | last1 = Niemeier | first1 = LA. | last2 = Dabbs | first2 = DJ. | last3 = Beriwal | first3 = S. | last4 = Striebel | first4 = JM. | last5 = Bhargava | first5 = R. | title = Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. | journal = Mod Pathol | volume = 23 | issue = 2 | pages = 205-12 | month = Feb | year = 2010 | doi = 10.1038/modpathol.2009.159 | PMID = 19898421 }}</ref>
****May respond to therapies targeting the androgen receptor.
***BCL11A overexpression recently identified as an oncogenic driver for some triple negatives <ref>{{Cite journal  | last1 = Khaled | first1 = WT. | last2 = Choon Lee | first2 = S. | last3 = Stingl | first3 = J. | last4 = Chen | first4 = X. | last5 = Raza Ali | first5 = H. | last6 = Rueda | first6 = OM. | last7 = Hadi | first7 = F. | last8 = Wang | first8 = J. | last9 = Yu | first9 = Y. | title = BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. | journal = Nat Commun | volume = 6 | issue =  | pages = 5987 | month =  | year = 2015 | doi = 10.1038/ncomms6987 | PMID = 25574598 }}</ref>
****Targeted therapies may include inhibitors of BCL11A.
**Triple-negative and basal-like phenotypes are not synonymous but overlap
***About 70% of triple-negative tumours are basal-like.
***About 70% of basal-like tumors are triple-negative tumours.
**Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
**Classic 'morphological clues' to a triple negative cancer usually refer to medullary carcinoma features.
 
==Immunostains for typing and diagnosis==
===DCIS versus LCIS===
Tabular comparison for DCIS versus LCIS:<ref name=Ref_BP275>{{Ref BP|275}}</ref><ref name=pmid18318578>{{cite journal |author=Yeh IT, Mies C |title=Application of immunohistochemistry to breast lesions |journal=Arch. Pathol. Lab. Med. |volume=132 |issue=3 |pages=349-58 |year=2008 |month=March |pmid=18318578 |doi= |url=http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=349}}</ref>
{| class="wikitable sortable"
!Disease
!E-cadherin
!Beta-catenin
!34betaE12
!CAM5.2 (CK8)
|-
|DCIS
| +ve
| +ve
| -ve
| +ve peripheral cytoplasm
|-
|LCIS
| -ve
| -ve
| +ve perinuclear
| +ve perinuclear
|}
 
===Invasive versus non-invasive===
Myoepithelial markers - typically lost in invasive carcinoma:<ref>{{Ref Lester3|88}}</ref>
{| class="wikitable sortable"
!Stain
!Location
!Notes
|-
| p63
| nuclear
| up to 10% of invasive tumours +ve<ref name=Ref_BP276>{{Ref BP|276}}</ref>
|-
| Smooth muscle actin (SMA)
| cytoplasmic
| stains myofibroblasts & blood vessels
|-
| Calponin
| cytoplasmic
| stains myofibroblasts & blood vessels
|-
| Smooth muscle myosin <br>heavy chain (SMM-HC)
| cytoplasmic
| stains myofibroblasts & blood vessels
|}


*DCIS vs LCIS:<ref>{{cite journal |author=Yeh IT, Mies C |title=Application of immunohistochemistry to breast lesions |journal=Arch. Pathol. Lab. Med. |volume=132 |issue=3 |pages=349-58 |year=2008 |month=March |pmid=18318578 |doi= |url=http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=349}}</ref>
Respecting findings that might indicate a more extensive search for microinvasion be undertaken in cases of pure ductal carcinoma in situ (DCIS), a recent study found 1) intermediate or high DCIS grade, 2) tumor thickness, and 3) diffuse peritumoral retraction clefts, but not such things as lymph node metastases, or HER2 score, independently increased the likelihood of finding a microinvasive component. <ref name=pmid28434924>{{cite journal |author=Mori K, Takeda M, Kodama Y, Kiyokawa H, Yasojima H, Mizutani M, Otani Y, Morikawa N, Masuda N, Mano M|title= Tumor thickness and histological features as predictors of invasive foci within preoperatively diagnosed ductal carcinoma in situ |journal=Human Pathology |volume=64 |issue= |pages=145-155 |year=2017 | pmid=28434924 |doi=10.1016/j.humpath.2017.04.004 }}</ref>
**E-cadherin (+ve DCIS, -ve LCIS).
**antibody 34betaE12 (+ve perinuclear LCIS, -ve DCIS).
**CAM5.2 (peripheral stain = DCIS, perinuclear stain = LCIS).
***CAM5.2 is against CK8.
**Beta-catenin (-LCIS, +DCIS).


*D2-40:<ref>{{cite journal |author=Ordóñez NG |title=Podoplanin: a novel diagnostic immunohistochemical marker |journal=Adv Anat Pathol |volume=13 |issue=2 |pages=83-8 |year=2006 |month=March |pmid=16670463 |doi=10.1097/01.pap.0000213007.48479.94 |url=}}</ref><ref>{{cite journal |author=Kahn HJ, Marks A |title=A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors |journal=Lab. Invest. |volume=82 |issue=9 |pages=1255-7 |year=2002 |month=September |pmid=12218087 |doi= |url=}}</ref>
===Usual ductal hyperplasia versus ductal carcinoma in situ===
**Monoclonal antibody to podoplanin.
Markers for UDH versus DCIS:<ref name=Ref_BP276>{{Ref BP|276}}</ref>
**Useful to assess lymphovascular invasion.
{| class="wikitable sortable"
!Disease
![[CK5/6]]
![[ER]]
|-
|UDH
| diffuse +ve
| patchy +ve
|-
|DCIS
| -ve
| diffuse +ve
|}


*ADH and DCIS:<ref name=Ref_Lester122>{{Ref Lester|122}}</ref>
===Lymphovascular invasion===
**E-cadherin.
{{Main|Lymphovascular invasion}}
***Present in most epithelial cells.
*D2-40 - marks the lymphatic spaces.<ref>{{cite journal |author=Ordóñez NG |title=Podoplanin: a novel diagnostic immunohistochemical marker |journal=Adv Anat Pathol |volume=13 |issue=2 |pages=83-8 |year=2006 |month=March |pmid=16670463 |doi=10.1097/01.pap.0000213007.48479.94 |url=}}</ref><ref>{{cite journal |author=Kahn HJ, Marks A |title=A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors |journal=Lab. Invest. |volume=82 |issue=9 |pages=1255-7 |year=2002 |month=September |pmid=12218087 |doi= |url=}}</ref>
***Lost in LCIS & invasive lobular carcinoma.
*CD31 - marks lymphovascular spaces.
**SMMHC (smooth muscle cell myosin heavy chain).
*CD34 - marks lymphovascular spaces, less specific than CD31.
***Marks myoepithelial cells.
 
===Lymph node metastases===
Immunostaining of sentinel lymph nodes to look for [[isolated tumour cells]] and small [[lymph node metastases]] may be done.
*CAM5.2 may be used.
*'''Not''' done routinely.


==Treatment-related markers - overview==
==Treatment-related markers - overview==
*Immunostaining of any sentinel lymph nodes - to look for isolated tumour cells and small lymph node mets.
**Sunnybrook uses ''CAM5.2''.
*ER (estrogen receptor).
*ER (estrogen receptor).
**Positive in most breast cancers; +ve in ~75-80%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
**Positive in most breast cancers; +ve in ~75-80%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
*PR (progesterone receptor).
*PR (progesterone receptor).
**Positive in most breast cancers; +ve in ~65-70%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
**Positive in most breast cancers; +ve in ~65-70%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
*HER2/neu.
*HER2/neu (HER2).
**Usually negative; -ve in 70-80%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
**Usually negative; -ve in 70-80%.<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
**Positivity association with a worse prognosis.
**Positivity associated with a worse prognosis.
**In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.<ref name=pmid22454081>{{Cite journal  | last1 = Gallardo | first1 = A. | last2 = Lerma | first2 = E. | last3 = Escuin | first3 = D. | last4 = Tibau | first4 = A. | last5 = Muñoz | first5 = J. | last6 = Ojeda | first6 = B. | last7 = Barnadas | first7 = A. | last8 = Adrover | first8 = E. | last9 = Sánchez-Tejada | first9 = L. | title = Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. | journal = Br J Cancer | volume = 106 | issue = 8 | pages = 1367-73 | month = Apr | year = 2012 | doi = 10.1038/bjc.2012.85 | PMID = 22454081 }}</ref><ref name=pmid22172323>{{Cite journal  | last1 = Jensen | first1 = JD. | last2 = Knoop | first2 = A. | last3 = Laenkholm | first3 = AV. | last4 = Grauslund | first4 = M. | last5 = Jensen | first5 = MB. | last6 = Santoni-Rugiu | first6 = E. | last7 = Andersson | first7 = M. | last8 = Ewertz | first8 = M. | title = PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. | journal = Ann Oncol | volume =  | issue =  | pages =  | month = Dec | year = 2011 | doi = 10.1093/annonc/mdr546 | PMID = 22172323 }}</ref>
 
Notes:
*Male breast cancer is usually hormone receptor positive (~97%), and HER2 positivity is quite rare (~6%).<ref name=pmid24080492>{{Cite journal  | last1 = Schildhaus | first1 = HU. | last2 = Schroeder | first2 = L. | last3 = Merkelbach-Bruse | first3 = S. | last4 = Binot | first4 = E. | last5 = Büttner | first5 = R. | last6 = Kuhn | first6 = W. | last7 = Rudlowski | first7 = C. | title = Therapeutic strategies in male breast cancer: Clinical implications of chromosome 17 gene alterations and molecular subtypes. | journal = Breast | volume =  | issue =  | pages =  | month = Sep | year = 2013 | doi = 10.1016/j.breast.2013.08.008 | PMID = 24080492 }}</ref>
*ASCO/CAP guidelines recommend that cold ischemia time be <1 hour.<ref name=pmid22460807 >{{Cite journal  | last1 = Yildiz-Aktas | first1 = IZ. | last2 = Dabbs | first2 = DJ. | last3 = Bhargava | first3 = R. | title = The effect of cold ischemic time on the immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 expression in invasive breast carcinoma. | journal = Mod Pathol | volume = 25 | issue = 8 | pages = 1098-105 | month = Aug | year = 2012 | doi = 10.1038/modpathol.2012.59 | PMID = 22460807 }}</ref>


===ER & PR scoring<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>===
===ER & PR scoring===
Nuclear staining:<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
*Give a percentage, i.e. 0-100%.
*Give a percentage, i.e. 0-100%.
**Important cut points: 1% and 10%.  
**Important cut points: 1% and 10%.  
Line 71: Line 317:
*Normal breast epithelial cells have a patchy staining for ER and PR.
*Normal breast epithelial cells have a patchy staining for ER and PR.
*Evaluated on the invasive component.
*Evaluated on the invasive component.
===HER2 scoring<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>===
===HER2 scoring===
{| class="wikitable"
Immunohistochemical based testing:<ref name=pmid24382093>{{Cite journal  | last1 = Rakha | first1 = EA. | last2 = Starczynski | first2 = J. | last3 = Lee | first3 = AH. | last4 = Ellis | first4 = IO. | title = The updated ASCO/CAP guideline recommendations for HER2 testing in the management of invasive breast cancer: a critical review of their implications for routine practice. | journal = Histopathology | volume = 64 | issue = 5 | pages = 609-15 | month = Apr | year = 2014 | doi = 10.1111/his.12357 | PMID = 24382093 }}</ref><ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf]. Accessed on: October 7, 2014.</ref>
| '''Score'''
{| class="wikitable sortable"
| '''Staining intensity'''
! Score
| '''Cells stained (%)'''
! Staining intensity
| '''Membrane staining'''
! Cells stained (%)
| '''Management'''
! Membrane staining
| '''Percentage of cases'''
! Management
! Percentage of cases
|-
|-
| '''0'''
| '''0'''
| nil
| no staining/barely visible
| <10%
| '''≤10%'''
| incomplete
| '''incomplete'''
| No HER2 blocker
| No HER2 blocker
| ~60%
| ~60%
|-
|-
| '''1+'''
| '''1+'''
| minimum
| minimal/barely visible
| >10%
| '''>10%'''
| incomplete
| '''incomplete'''
| No HER2 blocker
| No HER2 blocker
| ~10%
| ~10%
|-
|-
| '''2+'''
| '''2+'''
| weak
| weak-to-moderate
| >10%
| '''>10%'''
| complete
| '''incomplete''' (circumferential)
| Needs [[SISH]] or [[FISH]]
| ~10% †
|-
| '''2+'''
| intense
| '''≤10%'''
| '''complete'''
| Needs [[SISH]] or [[FISH]]
| Needs [[SISH]] or [[FISH]]
| ~10%
| ~10% †
|-
|-
| '''3+'''
| '''3+'''
| strong
| intense staining
| >10%
| '''>10%''' ‡
| complete
| '''complete'''
| HER2 blocker
| HER2 blocker
| ~20%
| ~20%
|}
|}


Notes:
Note for IHC:
*Normal breast epithelial cells do not stain with HER2.
*Normal breast epithelial cells do not stain with HER2.
*Evaluated on the invasive component.
*Evaluated on the invasive component.
*SISH = silver [[in situ hybridization]].
*SISH = silver [[in situ hybridization]].
*FISH = fluorescence in situ hybridization.
*FISH = fluorescence in situ hybridization.
*† Together approximately 10%.
*‡ The cut point was 10%, changed to 30% and then changed back to 10%.<ref name=pmid24382093/>
ISH based testing:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf]. Accessed on: October 7, 2014.</ref>
{| class="wikitable sortable"
! Result
! Ratio criteria
! Gene copy number criteria
|-
| Positive
| ≥2.0 HER2/CEP17
| ≥6.0 copies of HER2/cell
|-
| Equivocal
| <2.0 HER2/CEP17 (required)
| 4.0-6.0 copies of HER2/cell
|-
| Negative
| <2.0 HER2/CEP17
| <4.0 copies of HER2/cell
|}
Note for ISH:
*Can be called ''positive'' based on either ''ratio criteria'' or ''gene copy number criteria''.


===Clinical===
===Clinical===
Line 120: Line 397:


=Characteristics of the subtypes=
=Characteristics of the subtypes=
==Ductal carcinoma==
==Invasive ductal carcinoma of the breast==
*[[AKA]] "NST" = No Specific Type.
*[[AKA]] "NST" = No Specific Type.
*[[AKA]] ''invasive mammary carcinoma''.
{{Main|Invasive ductal carcinoma of the breast}}


===Microscopic===
==Invasive lobular carcinoma==
Features:
*Abbreviated ''ILC''.
*Cohesive cells - forming ducts or in sheets.
*[[AKA]] ''lobular carcinoma''.
*Nuclear pleomorphism.
{{Main|Invasive lobular carcinoma}}
 
Clinical
*Typically: ER+, PR+, HER2-.


==Lobular carcinoma==
==Medullary breast carcinoma==
===General===
*[[AKA]] ''medullary carcinoma of the breast''.
*May be associated with a CDH-1 mutation - seen in diffuse type [[stomach|gastric]] cancer.<ref>URL: [http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33006 http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33006]. Accessed on: 19 April 2011.</ref>
{{Main|Medullary breast carcinoma}}


===Microscopic===
==Tubular carcinoma of the breast==
Features:
*[[AKA]] ''tubular carcinoma''.
*"Single file" - cell line-up in a row.
{{Main|Tubular carcinoma of the breast}}
**Cell should not be cohesive -- lymphoma should briefly come to mind.
***primary lymphoma of the breast exists... but it is extremely rare.
*NO gland formation.
**If it forms glands... it is more likely NST.
*May have [[signet ring cell|signet ring]] morphology.
*NO [[desmoplastic reaction]], i.e. the stroma surrounding the tumour cells should look benign and undisturbed.


Note:
==Metaplastic breast carcinoma==
*commonly have low grade nuclear features
*[[AKA]] ''metaplastic carcinoma''.
{{Main|Metaplastic breast carcinoma}}


Subclassification:
==Invasive micropapillary carcinoma of the breast==
*Classic lobular carcinoma.
*[[AKA]] ''micropapillary carcinoma''.
**Low nuclear grade - NO significant variation of nucleus size.
{{Main|Invasive micropapillary carcinoma of the breast}}
*Pleomorphic lobular carcinoma.
**Significant nuclear atypia.
Note: Some pathologist grade lobular carcinoma like other types and avoid the term "pleomorphic lobular carcinoma."<ref>MUA. Jan 22, 2009.</ref>


==Medullary carcinoma==
==Apocrine carcinoma of the breast==
===General===
{{Main|Apocrine carcinoma of the breast}}
*Some pathologists don't believe this exists.


Epidemiology:
==Mucinous breast carcinoma==
*Thought to have a better prognosis that no special type (NST).
*[[AKA]] ''mucinous carcinoma of the breast'', [[AKA]] ''colloid carcinoma of the breast''.
*Association with BRCA1 mutations.
{{Main|Mucinous breast carcinoma}}


===Microscopic===
==Adenoid cystic carcinoma of the breast==
Features:
*[[AKA]] ''breast adenoid cystic carcinoma''.
#Lesion has well-circumscribed border.
{{Main|Adenoid cystic carcinoma of the breast}}
#Syncytial growth pattern = clumps of cells with poorly defined cell borders.
#Lymphocytic infiltrate.
#High nuclear grade (as per Nottingham grading system).
#No tubule formation.


==Tubular carcinoma==
==Intracystic papillary breast carcinoma==
===General===
*[[AKA]] ''encapsulated or encysted papillary carcinoma of the breast'', abbreviated ''EPC''.
Epidemiology:
{{Main|Intracystic papillary breast carcinoma}}
*Typically excellent prognosis.
*Hormone receptors commonly present.


===Microscopic===
==Glycogen-rich clear cell carcinoma of the breast==
Features:<ref name=Ref_PBoD1146>{{Ref PBoD|1146}}</ref><ref>URL: [http://www.bweems.com/nsj3mp2.jpg http://www.bweems.com/nsj3mp2.jpg].</ref><ref>URL: [http://surgpathcriteria.stanford.edu/breast/tubularcabr/ http://surgpathcriteria.stanford.edu/breast/tubularcabr/].</ref>
*Abbreviated ''GRCC''.
*Well-formed tubules.
{{Main|Glycogen-rich clear cell carcinoma of the breast}}
*Myoepithelial cells absent.
*+/- Cribriform spaces.
*Apocrine snouts typical.
*+/- Calcification.
*Angled ducts common: "prows" - important feature (low power).
*Looks benign to the uninitiated -- '''IMPORTANT'''.


ASIDE: prow = front of a ship.  
==Secretory carcinoma of the breast==
*[[AKA]] ''secretory breast carcinoma'', abbreviated ''SBC''.
{{Main|Secretory carcinoma of the breast}}


DDx:
==Invasive cribriform carcinoma of the breast==
*[[sclerosing adenosis|Benign sclerosing lesion]].
{{Main|Invasive cribriform carcinoma of the breast}}


==Metaplastic carcinoma==
==Invasive papillary carcinoma of the breast==
===General===
{{Main|Invasive papillary carcinoma of the breast}}
*May be difficult to diagnosis.
*Should '''not''' be confused with the indolent behaving [[intracystic papillary carcinoma of the breast]], also known as ''encapsulated papillary carcinoma of the breast''.
*Prognosis - poor.
 
===Microscopic===
Features:<ref name=metaplastic>URL: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html]. Accessed on: 28 November 2010.</ref>
*Spindle cells ''or'' squamoid cells ''or'' other malignant mesenchymal elements.
*+/-Adenocarcinoma.
 
Images: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html Metaplastic carcinoma (breastpathology.info)].<ref name=metaplastic>URL: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html]. Accessed on: 28 November 2010.</ref>


=Grading breast cancer=
=Grading breast cancer=
Most common system: ''Nottingham'' (aka Scarff-Bloom-Richardson) which is based on:
{{Main|Breast cancer grading}}
#Nuclear grade.
#*Small, regular (1.5-2x RBC dia.) = 1.
#*Moderated variability = 2.
#*Marked variation (>2.5x RBC dia.) = 3.
# Tubule formation.
#*Majority of tumour - tubules >75% = 1.
#*Moderate - 10% to 75% = 2.
#*Minimal <10% = 3.
# Mitotic rate.
#*0-5 mitosis/10 [[HPF]] (1.52 mm^2 --or-- 0.0152 mm^2 * 10) = 1.
#*6-10 mitosis/10 HPF (1.52 mm^2) = 2.
#*>11 mitosis/10 HPF (1.52 mm^2) = 3.
Mnemonic: ''TMN'' = tubule formation, mitotic rate, nuclear grade.


Notes:
=Staging breast cancer=
*Elston & Ellis devised the system that is used.<ref name=pmid12405945>{{cite journal |author=Elston CW, Ellis IO |title=Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403-410 |journal=Histopathology |volume=41 |issue=3A |pages=151–2, discussion 152–3 |year=2002 |month=September |pmid=12405945 |doi= |url=}}</ref> They also wrote a follow-up article in 2002.<ref name=pmid1757079>{{cite journal |author=Elston CW, Ellis IO |title=Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up |journal=Histopathology |volume=19 |issue=5 |pages=403–10 |year=1991 |month=November |pmid=1757079 |doi= |url=}}</ref>
{{Main|Breast cancer staging}}


==Note about mitosis counting==
=Lymphovascular invasion=
*One MUST adjust for the size of the field of view.
{{Main|Lymphovascular invasion}}
In the context of breast pathology, the Rosen criteria for LVI are widely excepted, and are as follows:<ref name=pmid6674861>{{Cite journal  | last1 = Rosen | first1 = PP. | title = Tumor emboli in intramammary lymphatics in breast carcinoma: pathologic criteria for diagnosis and clinical significance. | journal = Pathol Annu | volume = 18 Pt 2 | issue =  | pages = 215-32 | month =  | year = 1983 | doi = | PMID = 6674861 }}</ref><ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf]. Accessed on: 5 August 2011.</ref>
#Must be outside of the tumour proper.
#*LVI is usually very close -- typically within 0.1 cm.
#Contour of cells should differ from possible vessel wall.
#*DCIS with retraction artifact mimicing LVI has a contour that matches its surrounding fibrous tissue.
#Endothelium (usu. flat) should be visible.
#Lymphatics are found adjacent to [[blood vessels]] - vessels should be present in the vicinity.


*Most of the Resident scopes have an eye piece diameter of 22 mm. Therefore, the field diameter at 40 X is approximately 22 mm / 40 X ~= 0.55 mm and the field of view is pi/4*(0.55 mm)^2 = 0.2376 mm^2.
Memory device ''LUBE-O'':
**Thus, on a resident scope (with a FOV of 0.2376 mm^2) one should sample 6 or 7 fields of view (FsOV).
*'''L'''VI has a '''U'''nique contour, '''B'''lood vessels and '''E'''ndothelium in the vicinity, and is '''O'''utside of the tumour.
***Calculation: 1.52 mm^2 (sampling area) / 0.2376 mm^2 (area / FOV ) = 6.40 FsOV.


*'''RANT''': Sampling 10 fields, where the field of view (FOV) is 0.152 mm^2, is ''not'' the same as sampling ten fields, where the FOV is 0.312 mm^2.  It surprises me that Elston & Ellis ignore the fact that "10 HPFs" on different microscopes represent different sample areas and that they do ''not'' standardize the sampling area.
Note:
 
*LVI does not affect the stage.
==Calculating Nottingham score==
*Grade I = 3-5 points.
*Grade II = 6-7 points.
*Grade III = 8-9 points.
 
Notes:
*I've found most tumours are grade II. 
*The mitotic score is usually 1/3.
*The nuclear score is rarely 1/3 -- even in the tubular subtype.<ref>MUA. 20 January 2009.</ref>
 
=Staging breast cancer=
Definitions:<ref>URL: [http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging]. Accessed on: 8 July 2010.</ref>
*Isolated tumour cells: <=0.2 mm ''and'' <200 cells.
*Micrometastasis: <=0.2 cm ''and'' ( >0.2 mm ''or'' >=200 cells ).
 
Tumour:<ref>URL: [http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging]. Accessed on: 8 July 2010.</ref><ref>URL: [http://www.cancerhelp.org.uk/type/breast-cancer/treatment/tnm-breast-cancer-staging http://www.cancerhelp.org.uk/type/breast-cancer/treatment/tnm-breast-cancer-staging]. Accessed on: 9 July 2010.</ref>
*pT1: <= 2 cm.
**pT1mic <= 0.1 cm.
**pT1a > 0.1 cm ''and'' <= 0.5 cm.
**pT1b > 0.5 cm ''and'' <= 1.0 cm.
**pT1c > 1.0 cm ''and'' <= 2.0 cm.
*pT2: > 2 cm and <= 5 cm
*pT3: > 5 cm.
*pT4: chest wall or skin involvement.
 
Lymph nodes:<ref>URL: [http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging]. Accessed on: 8 July 2010.</ref>
*pN0: nil.
**pN0(i+): <=0.2 mm ''and'' <200 cells.
*pN1: 1-3 axillary LNs ''or'' internal mammary LNs.
**pN1mi: <=0.2 cm ''and'' ( >0.2 mm ''or'' >=200 cells ).
**pN1a.
**pN1b.
**PN1c.
*pN2 4-9 positive LNs; internal mammary LNs ''or'' axillary LNs.
*pN3.


=Other=
=Other=
Line 291: Line 498:
IHC & DDx:  
IHC & DDx:  
*See ''[[Paget disease]]''.
*See ''[[Paget disease]]''.
==Sentinel lymph node biopsy==
===General===
*Used for staging, positive LNs = poorer prognosis.
Notes:
*There is '''no''' mortality benefit from axillary lymph node dissection, i.e. positive axillary lymph nodes can be left in situ without affecting outcome.<ref>{{cite journal |author=Giuliano AE, Hunt KK, Ballman KV, ''et al.'' |title=Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial |journal=JAMA |volume=305 |issue=6 |pages=569–75 |year=2011 |month=February |pmid=21304082 |doi=10.1001/jama.2011.90 |url=}}</ref>
**This does not negate the fact that a positive sentinel LN biopsy (vs. negative sentinel LN biopsy) portends a poorer prognosis.
===Microscopic===
Features:
*Atypical cells.
**Nuclear changes of malignancy:
***Nuclear enlargement + variation in size.
***Variation in shape.
***Hyperchromasia and variation in staining.
**Usually in the subcapsular sinuses.
Pitfalls:
*Naevus cell rests.<ref>URL: [http://www.breastpathology.info/Case_of_the_month/2007/COTM_1107%20discussion.html http://www.breastpathology.info/Case_of_the_month/2007/COTM_1107%20discussion.html]. Accessed on: 28 November 2010.</ref>
===IHC===
Some hospitals use:
*CAM5.2 (LMWK) - to look for isolated tumour cells and small lymph node metstases.


==Trivia==
==Trivia==
===Tumour size and lymph node metastases===
===Tumour size and lymph node metastases===
There is a paper<ref name=pmid18483831>{{Cite journal  | last1 = Porembka | first1 = MR. | last2 = Abraham | first2 = RL. | last3 = Sefko | first3 = JA. | last4 = Deshpande | first4 = AD. | last5 = Jeffe | first5 = DB. | last6 = Margenthaler | first6 = JA. | title = Factors associated with lymph node assessment in ductal carcinoma in situ: analysis of 1988-2002 seer data. | journal = Ann Surg Oncol | volume = 15 | issue = 10 | pages = 2709-19 | month = Oct | year = 2008 | doi = 10.1245/s10434-008-9947-5 | PMID = 18483831 | url=http://onlinelibrary.wiley.com/doi/10.1002/cncr.24592/pdf}}</ref> that predicts LN mets based on tumour size.
There is a paper<ref name=pmid18483831>{{Cite journal  | last1 = Porembka | first1 = MR. | last2 = Abraham | first2 = RL. | last3 = Sefko | first3 = JA. | last4 = Deshpande | first4 = AD. | last5 = Jeffe | first5 = DB. | last6 = Margenthaler | first6 = JA. | title = Factors associated with lymph node assessment in ductal carcinoma in situ: analysis of 1988-2002 seer data. | journal = Ann Surg Oncol | volume = 15 | issue = 10 | pages = 2709-19 | month = Oct | year = 2008 | doi = 10.1245/s10434-008-9947-5 | PMID = 18483831 | url=http://onlinelibrary.wiley.com/doi/10.1002/cncr.24592/pdf}}</ref> that calculates the probability of [[lymph node]] mets based on tumour size. The developed formula is:


:<math>L_{To-Nodes}=1-exp(-Q_n D^Z)</math>
:<math>L_{To-Nodes}=1-exp(-Q_n D^Z)</math>
Line 352: Line 535:
| 50            || 62 %
| 50            || 62 %
|}
|}
===Natural history===
There is a theory that up to 22% of small (radiographically detected) breast tumours regress, based on an analysis in a large population.<ref name=pmid19029493>{{Cite journal  | last1 = Zahl | first1 = PH. | last2 = Maehlen | first2 = J. | last3 = Welch | first3 = HG. | title = The natural history of invasive breast cancers detected by screening mammography. | journal = Arch Intern Med | volume = 168 | issue = 21 | pages = 2311-6 | month = Nov | year = 2008 | doi = 10.1001/archinte.168.21.2311 | PMID = 19029493 }}</ref>  The study is supported by NCI's SEER data.<ref name=pmid19468099>{{Cite journal  | last1 = Jatoi | first1 = I. | last2 = Anderson | first2 = WF. | title = Breast cancer overdiagnosis with screening mammography. | journal = Arch Intern Med | volume = 169 | issue = 10 | pages = 999-1000, author reply 1000-1 | month = May | year = 2009 | doi = 10.1001/archinternmed.2009.95 | PMID = 19468099 }}</ref> Also, it generated many comments.<ref name=pmid19029493/>
===Missed macrometastases===
The effect of missed macrometastases is small; this implies using [[IHC]] to look for isolated tumour cells is money that isn't well spent.<ref name=pmid21247310>{{Cite journal  | last1 = Weaver | first1 = DL. | last2 = Ashikaga | first2 = T. | last3 = Krag | first3 = DN. | last4 = Skelly | first4 = JM. | last5 = Anderson | first5 = SJ. | last6 = Harlow | first6 = SP. | last7 = Julian | first7 = TB. | last8 = Mamounas | first8 = EP. | last9 = Wolmark | first9 = N. | title = Effect of occult metastases on survival in node-negative breast cancer. | journal = N Engl J Med | volume = 364 | issue = 5 | pages = 412-21 | month = Feb | year = 2011 | doi = 10.1056/NEJMoa1008108 | PMID = 21247310 }}</ref>


=See also=
=See also=
Line 359: Line 548:
=References=
=References=
{{reflist|2}}
{{reflist|2}}
=External links=
*[http://ww5.komen.org/BreastCancer/SubtypesofBreastCancer.html About breast cancer - molecular subtypes (komen.org)].


[[Category:Breast pathology]]
[[Category:Breast pathology]]
[[Category:Invasive breast cancer]]
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