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Invasive breast cancer (view source)

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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]]''.


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====Common epithelial subtypes====
====Common epithelial subtypes====
Type and percentage of breast carcinomas:<ref name=Ref_PBoD1143>{{Ref PBoD|1143}}</ref>
Type and percentage of breast carcinomas:<ref name=Ref_PBoD1143>{{Ref PBoD|1143}}</ref>
*Ductal - [[AKA]] no special type (NST) - 79%.
*[[Invasive ductal carcinoma of the breast|Ductal]] - [[AKA]] no special type (NST) - 79%.
*[[invasive lobular carcinoma|Lobular]] - 10%.
*[[invasive lobular carcinoma|Lobular]] - 10%.
*Cribriform / tubular - 6%.
*[[Tubular carcinoma of the breast|Cribriform / tubular]] - 6%.
*[[mucinous breast carcinoma|Mucinous]] (colloid) - 2%.
*[[mucinous breast carcinoma|Mucinous]] (colloid) - 2%.
*[[medullary breast carcinoma|Medullary]] - 2%.  
*[[medullary breast carcinoma|Medullary]] - 2%.  
Line 28: Line 29:
*[[Invasive ductal carcinoma of the breast|Invasive ductal carinoma]], not otherwise specified.
*[[Invasive ductal carcinoma of the breast|Invasive ductal carinoma]], not otherwise specified.
*[[Invasive lobular carcinoma]].
*[[Invasive lobular carcinoma]].
*Invasive cribriform carcinoma.
*[[Invasive cribriform carcinoma of the breast|Invasive cribriform carcinoma]].
*[[Invasive papillary carcinoma of the breast|Invasive papillary carcinoma]].
*[[Invasive papillary carcinoma of the breast|Invasive papillary carcinoma]].
*[[Invasive micropapillary carcinoma of the breast|Invasive micropapillary carcinoma]].
*[[Invasive micropapillary carcinoma of the breast|Invasive micropapillary carcinoma]].
Line 45: Line 46:


Epithelial tumours seen in the [[salivary gland]]:
Epithelial tumours seen in the [[salivary gland]]:
*[[Adenoid cystic carcinoma]].
*[[Adenoid cystic carcinoma of the breast]].
*[[Acinic cell carcinoma]].
*[[Acinic cell carcinoma]].
*[[Carcinoma ex pleomorphic adenoma]].
*[[Carcinoma ex pleomorphic adenoma]].
Line 68: Line 69:


Papillary:
Papillary:
*[[Intraductal papilloma|Papilloma]].
*[[Intraductal papilloma of the breast|Papilloma]].
*Atypical papilloma.
*Atypical papilloma.
*Intraductal papillary carcinoma.
*Intraductal papillary carcinoma.
Line 104: Line 105:


==Familial breast cancer==
==Familial breast cancer==
BRCA1 vs. BRCA2:<ref name=Ref_PBoD8_1078>{{Ref PBoD8|1078}}</ref>
{{Main|Hereditary breast cancer}}
{| class="wikitable sortable"
| Gene
| Age
| Histology
| Other cancers
|-
| BRCA1
| younger
| worse types, e.g. triple negative breast ca.
| uterine tube
|-
| BRCA2
| older
| sporadic types
| stomach, melanoma, gallbladder, bile duct, pharynx
|}
 
Types of cancer assoc. with both BRCA1 and BRCA2:
*Ovarian, male breast, prostate, pancreas.


=Breast IHC=
=Breast IHC=
Line 157: Line 139:
| ER- PR- HER2-
| ER- PR- HER2-
| poorly differentiated
| poorly differentiated
| aggressive, may have good chemo response, classic for BRCA1 mutation
| aggressive, may have good chemo response, classic for [[BRCA1]] mutation
|-
|-
| HER2 positive
| HER2 positive
Line 166: Line 148:
|}
|}


The above is not applied clinically. [[IHC]] (ER, PR, HER2, EGFR, CK5/6) can reproduce the molecular groupings and has been proposed as a way to applied the classification.<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>
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]].


==Subtyping breast cancer==
*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.


*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>
*Behaviour:  
**E-cadherin (+ve DCIS, -ve LCIS).  
**Basal-like breast cancer is a heterogeneous group.
**antibody 34betaE12 (+ve perinuclear LCIS, -ve DCIS).
**The behaviour of basal-like breast cancer appears to fall into two groups:
**CAM5.2 (peripheral stain = DCIS, perinuclear stain = LCIS).
***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.
***CAM5.2 is against CK8.
***The tumours with early metastasis that may behave more aggressively
**Beta-catenin (-LCIS, +DCIS).
****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.


*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>
Other sources
**Monoclonal antibody to podoplanin.
Minireview: Basal-Like Breast Cancer: From Molecular Profiles to Targeted Therapies <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035993/>
**Useful to assess lymphovascular invasion.


*ADH and DCIS:<ref name=Ref_Lester122>{{Ref Lester|122}}</ref>
== Triple Negative Breast Carcinoma ==
**E-cadherin.
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>
***Present in most epithelial cells.
 
***Lost in LCIS & invasive lobular carcinoma.
**A category of breast carcinomas defined by immunohistochemical/FISH expression of ER, PR and HER2.
**SMMHC (smooth muscle cell myosin heavy chain).
**''Important to identify'' in clinical practice.
***Marks myoepithelial cells.
**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
|}
 
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>
 
===Usual ductal hyperplasia versus ductal carcinoma in situ===
Markers for UDH versus DCIS:<ref name=Ref_BP276>{{Ref BP|276}}</ref>
{| class="wikitable sortable"
!Disease
![[CK5/6]]
![[ER]]
|-
|UDH
| diffuse +ve
| patchy +ve
|-
|DCIS
| -ve
| diffuse +ve
|}
 
===Lymphovascular invasion===
{{Main|Lymphovascular invasion}}
*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>
*CD31 - marks lymphovascular spaces.
*CD34 - marks lymphovascular spaces, less specific than CD31.
 
===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 209: Line 318:
*Evaluated on the invasive component.
*Evaluated on the invasive component.
===HER2 scoring===  
===HER2 scoring===  
Immunohistochemical based testing:<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref><ref name=Lester3_87>{{Ref Lester3|87}}</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: 27 November 2011.</ref>
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>
{| class="wikitable"
{| class="wikitable sortable"
| '''Score'''
! Score
| '''Staining intensity'''
! Staining intensity
| '''Cells stained (%)'''
! Cells stained (%)
| '''Membrane staining'''
! Membrane staining
| '''Management'''
! Management
| '''Percentage of cases'''
! 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+'''
| uniform staining (used to be ''strong'')
| intense staining  
| >30% (used to ''>10%'')
| '''>10%''' ‡
| complete
| '''complete'''
| HER2 blocker
| HER2 blocker
| ~20%
| ~20%
|}
|}


Notes 1:
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 name=Lester3_87>{{Ref Lester3|87}}</ref>
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"
{| class="wikitable sortable"
| '''Result'''
! Result
| '''Ratio criteria'''
! Ratio criteria
| '''Gene copy number criteria'''
! Gene copy number criteria
|-
|-
| Positive
| Positive
| >2.2 HER2/CEP17
| ≥2.0 HER2/CEP17
| >6.0 copies of HER2/cell
| ≥6.0 copies of HER2/cell
|-
|-
| Equivocal
| Equivocal
| 1.8-2.2 HER2/CEP17
| <2.0 HER2/CEP17 (required)
| 4.0-6.0 copies of HER2/cell
| 4.0-6.0 copies of HER2/cell
|-  
|-  
| Negative
| Negative
| <1.8 HER2/CEP17
| <2.0 HER2/CEP17
| <4.0 copies of HER2/cell
| <4.0 copies of HER2/cell
|}
|}
Notes 2:
Note for ISH:
*Can be called ''positive'' based on either ''ratio criteria'' or ''gene copy number criteria''.
*Can be called ''positive'' based on either ''ratio criteria'' or ''gene copy number criteria''.


Line 282: Line 400:
*[[AKA]] "NST" = No Specific Type.
*[[AKA]] "NST" = No Specific Type.
*[[AKA]] ''invasive mammary carcinoma''.
*[[AKA]] ''invasive mammary carcinoma''.
===General===
{{Main|Invasive ductal carcinoma of the breast}}
*Most common type of invasive breast cancer.
 
===Microscopic===
Features:
*Atypical cells:
**Usually >2x RBC diameter.
**Nucleoli common.
**Forming ducts ''or'' sheets.
**+/-Mitoses.
**+/-Necrosis.
*Evidence of invasion:
**Atypical nucleus adjacent to adipocyte - '''diagnostic'''.
**"Infiltrative" pattern:
***Small glands of variable size within desmoplastic stroma.
***Glands lined by a single layer of cells.
 
DDx:
*[[DCIS]].
*[[Invasive lobular carcinoma]].
 
===IHC===
Myoepithelial markers - '''diagnostic''' for invasion:
*SMMS -ve.
*p63 -ve.
 
Prognostic markers - may be useful for metastates:
*ER +ve (diffuse).
*PR +ve (diffuse).
*HER2 -ve.


==Invasive lobular carcinoma==
==Invasive lobular carcinoma==
*Abbreviated ''ILC''.
*Abbreviated ''ILC''.
*[[AKA]] ''lobular carcinoma''.
*[[AKA]] ''lobular carcinoma''.
===General===
{{Main|Invasive lobular carcinoma}}
*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>
 
===Microscopic===
Features:
*"Single file" - cell line-up in a row.
**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:
*commonly have low grade nuclear features
 
Images:
*[http://commons.wikimedia.org/wiki/File:Lobular_carcinoma_-_low_mag.jpg Lobular carcinoma - low mag. (WC)].
*[http://commons.wikimedia.org/wiki/File:Lobular_carcinoma_-_high_mag.jpg Lobular carcinoma - high mag. (WC)].
*[http://commons.wikimedia.org/wiki/File:Breast_invasive_lobular_carcinoma_%281%29.jpg Lobular carcinoma - 1 (WC)].
*[http://commons.wikimedia.org/wiki/File:Breast_invasive_lobular_carcinoma_%282%29.jpg Lobular carcinoma - 2 (WC)].
 
Subclassification:
*Classic lobular carcinoma.
**Low nuclear grade - NO significant variation of nucleus size.
*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 breast carcinoma==
==Medullary breast carcinoma==
*[[AKA]] ''medullary carcinoma of the breast''.
*[[AKA]] ''medullary carcinoma of the breast''.
===General===
{{Main|Medullary breast carcinoma}}
*Some pathologists don't believe this exists.
 
Epidemiology:
*Thought to have a better prognosis that no special type (NST).
*Association with BRCA1 mutations.
 
===Microscopic===
Features:
#Lesion has well-circumscribed border.
#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 of the breast==
==Tubular carcinoma of the breast==
*[[AKA]] ''tubular carcinoma''.
*[[AKA]] ''tubular carcinoma''.
===General===
{{Main|Tubular carcinoma of the breast}}
Epidemiology:
*Typically excellent prognosis.
*Hormone receptors commonly present (ER +ve, PR +ve).
*Usually HER2 -ve.
*Classically seen in post-menopausal women.
 
Note:
*May be seen in association with [[lobular carcinoma in situ]] and columnar cell lesions - known as '''Rosen triad'''.<ref name=pmid18434766>{{Cite journal  | last1 = Brandt | first1 = SM. | last2 = Young | first2 = GQ. | last3 = Hoda | first3 = SA. | title = The "Rosen Triad": tubular carcinoma, lobular carcinoma in situ, and columnar cell lesions. | journal = Adv Anat Pathol | volume = 15 | issue = 3 | pages = 140-6 | month = May | year = 2008 | doi = 10.1097/PAP.0b013e31816ff313 | PMID = 18434766 }}</ref>
**Memory device ''TLC'' = '''T'''ubular ca., '''L'''CIS, '''C'''olumnar cell lesions.
 
===Microscopic===
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>
*Well-formed tubules.
*Myoepithelial cells absent.
*+/- Cribriform spaces.
*Apocrine snouts typical.
*+/- Calcification.
*Angled ducts common: "prows" - important feature (low power).
*Looks benign to the uninitiated -- '''IMPORTANT'''.
 
Notes:
*Prow = front of a ship.
 
DDx:
*[[Sclerosing adenosis]].
 
Image:
*[http://radiology.uchc.edu/eAtlas/Breast/1714.htm Tubular carcinoma - (uchc.edu)].
 
===IHC===
*ER +ve.
*PR +ve.
*HER2 -ve.
**HER2 positivity should prompt consideration of another diagnosis!


==Metaplastic breast carcinoma==
==Metaplastic breast carcinoma==
*[[AKA]] ''metaplastic carcinoma''.
*[[AKA]] ''metaplastic carcinoma''.
===General===
{{Main|Metaplastic breast carcinoma}}
*May be difficult to diagnose.
*Prognosis - poor.
 
===Microscopic===
Features - one of the following:<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><ref name=pmid15868445>{{Cite journal  | last1 = Barnes | first1 = PJ. | last2 = Boutilier | first2 = R. | last3 = Chiasson | first3 = D. | last4 = Rayson | first4 = D. | title = Metaplastic breast carcinoma: clinical-pathologic characteristics and HER2/neu expression. | journal = Breast Cancer Res Treat | volume = 91 | issue = 2 | pages = 173-8 | month = May | year = 2005 | doi = 10.1007/s10549-004-7260-y | PMID = 15868445 }}</ref>
#Malignant mesenchymal elements - either:
##Spindle cells.
##Osseous, chondroid or rhabdoid differentiation.
#Squamous component.
#*Non-skin [[squamous cell carcinoma]] of the breast = metaplastic breast carcinoma.
 
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>
*[http://path.upmc.edu/cases/case116.html Metaplastic carcinoma - case 1 - several images (upmc.edu)].
*[http://path.upmc.edu/cases/case294.html Metaplastic carcinoma - case 2 - several images (upmc.edu)].
 
====Subclassification====
*There are various way to subclassify this subtype of breast cancer. This a consequence of physician automomy.
**There is a series of articles on the topic by ''Wargotz & Norris'' that is quite old... yet it is mentioned in ''Sterberg'':<ref>{{Ref Sternberg5|328}}</ref>
*#Matrix-producing carcinoma:<ref>{{Cite journal  | last1 = Wargotz | first1 = ES. | last2 = Norris | first2 = HJ. | title = Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma. | journal = Hum Pathol | volume = 20 | issue = 7 | pages = 628-35 | month = Jul | year = 1989 | doi =  | PMID = 2544506 }}</ref>
*#*Features: cartilaginous and/or osseous stromal matrix; '''no''' osteoclastic giant cells.
*#Spindle cell carcinoma:<ref>{{Cite journal  | last1 = Wargotz | first1 = ES. | last2 = Deos | first2 = PH. | last3 = Norris | first3 = HJ. | title = Metaplastic carcinomas of the breast. II. Spindle cell carcinoma. | journal = Hum Pathol | volume = 20 | issue = 8 | pages = 732-40 | month = Aug | year = 1989 | doi =  | PMID = 2473024 }}</ref>
*#*Features: (non-malignant) spindle cells.
*#*Prognosis: better prognosis than other metaplastic carcinomas.
*#Carcinosarcoma:<ref>{{Cite journal  | last1 = Wargotz | first1 = ES. | last2 = Norris | first2 = HJ. | title = Metaplastic carcinomas of the breast. III. Carcinosarcoma. | journal = Cancer | volume = 64 | issue = 7 | pages = 1490-9 | month = Oct | year = 1989 | doi =  | PMID = 2776108 }}</ref>
*#*Features: malignant mesenchymal element.
*#*Prognosis: survival worse when compared to other metaplastic carcinomas.
*#Squamous cell carcinoma of ductal origin:<ref>{{Cite journal  | last1 = Wargotz | first1 = ES. | last2 = Norris | first2 = HJ. | title = Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin. | journal = Cancer | volume = 65 | issue = 2 | pages = 272-6 | month = Jan | year = 1990 | doi =  | PMID = 2153044 }}</ref>
*#*Features: purely squamous; metastases are squamous cell carcinoma.
*#Metaplastic carcinoma with osteoclastic giant cells:<ref>{{Cite journal  | last1 = Wargotz | first1 = ES. | last2 = Norris | first2 = HJ. | title = Metaplastic carcinomas of the breast: V. Metaplastic carcinoma with osteoclastic giant cells. | journal = Hum Pathol | volume = 21 | issue = 11 | pages = 1142-50 | month = Nov | year = 1990 | doi =  | PMID = 2227922 }}</ref>
*#*Features: osteoclastic [[giant cells]].
**The WHO subclassifies as follows:<ref>{{Ref BP|214}}</ref>
*#Epithelial - includes: squamous cell carcinoma, adenocarcinoma with spindle cell differentiation, adenosquamous carcinoma.
*#Mixed epithelial and mesenchymal - includes: carcinosarcoma, carcinoma with metaplasia (chondroid, osseous).
 
===IHC===
*S100 -ve (r/o [[melanoma]]).
*AE1/AE3 +ve (epithelial elements only).
*CK7 +ve (epithelial elements only).
*p63 +ve (epithelial elements only).
*Vimentin +ve.
*Desmin -ve.
*EMA -ve. (???)


==Invasive micropapillary carcinoma of the breast==
==Invasive micropapillary carcinoma of the breast==
*[[AKA]] ''micropapillary carcinoma''.
*[[AKA]] ''micropapillary carcinoma''.
===General===
{{Main|Invasive micropapillary carcinoma of the breast}}
*Poor prognosis.
*LVI common.<ref name=pmid20304650>{{Cite journal  | last1 = Yu | first1 = JI. | last2 = Choi | first2 = DH. | last3 = Park | first3 = W. | last4 = Huh | first4 = SJ. | last5 = Cho | first5 = EY. | last6 = Lim | first6 = YH. | last7 = Ahn | first7 = JS. | last8 = Yang | first8 = JH. | last9 = Nam | first9 = SJ. | title = Differences in prognostic factors and patterns of failure between invasive micropapillary carcinoma and invasive ductal carcinoma of the breast: matched case-control study. | journal = Breast | volume = 19 | issue = 3 | pages = 231-7 | month = Jun | year = 2010 | doi = 10.1016/j.breast.2010.01.020 | PMID = 20304650 }}</ref>
 
===Microscopic===
Features:
*Clear spaces/clefting around (small) nests of tumour - '''diffuse/through-out the tumour''' - '''key feature'''.
**Described as "small clusters of tumour lying within dilated vascular channel-like spaces".<ref name=pmid20444748>{{Cite journal  | last1 = Yamaguchi | first1 = R. | last2 = Tanaka | first2 = M. | last3 = Kondo | first3 = K. | last4 = Yokoyama | first4 = T. | last5 = Kaneko | first5 = Y. | last6 = Yamaguchi | first6 = M. | last7 = Ogata | first7 = Y. | last8 = Nakashima | first8 = O. | last9 = Kage | first9 = M. | title = Characteristic morphology of invasive micropapillary carcinoma of the breast: an immunohistochemical analysis. | journal = Jpn J Clin Oncol | volume = 40 | issue = 8 | pages = 781-7 | month = Aug | year = 2010 | doi = 10.1093/jjco/hyq056 | PMID = 20444748 | URL = http://jjco.oxfordjournals.org/content/40/8/781.long }}</ref>
 
Note:
*Ductal carcinoma commonly has clefting... but it isn't diffuse.
 
===IHC===
*EMA +ve (periphery of nests); described as inside-out pattern.<ref name=pmid20444748>{{Cite journal  | last1 = Yamaguchi | first1 = R. | last2 = Tanaka | first2 = M. | last3 = Kondo | first3 = K. | last4 = Yokoyama | first4 = T. | last5 = Kaneko | first5 = Y. | last6 = Yamaguchi | first6 = M. | last7 = Ogata | first7 = Y. | last8 = Nakashima | first8 = O. | last9 = Kage | first9 = M. | title = Characteristic morphology of invasive micropapillary carcinoma of the breast: an immunohistochemical analysis. | journal = Jpn J Clin Oncol | volume = 40 | issue = 8 | pages = 781-7 | month = Aug | year = 2010 | doi = 10.1093/jjco/hyq056 | PMID = 20444748 | URL = http://jjco.oxfordjournals.org/content/40/8/781.long }}</ref>
*E-cadherin +ve (centre of nests). (???)
*p63 +ve/-ve.


==Apocrine carcinoma of the breast==
==Apocrine carcinoma of the breast==
===General===
{{Main|Apocrine carcinoma of the breast}}
*Need >=90% apocrine morphology.<ref name=Ref_BP217>{{Ref BP|217}}</ref>
 
===Microscopic===
Features:<ref name=Ref_BP217>{{Ref BP|217}}</ref>
*Prominent [[nucleoli]].
**Often multiple.<ref>{{Cite journal  | last1 = O'Malley | first1 = FP. | last2 = Bane | first2 = A. | title = An update on apocrine lesions of the breast. | journal = Histopathology | volume = 52 | issue = 1 | pages = 3-10 | month = Jan | year = 2008 | doi = 10.1111/j.1365-2559.2007.02888.x | PMID = 18171412 }}</ref>
*Abundant granular eosinophilic cytoplasm.
*Architecture like invasive ductal carcinomas ''no special type''.
 
Images:
*[http://path.upmc.edu/cases/case209/micro.html Apocrine carcinoma (upmc.edu)].
 
===IHC===
Smaller tumours classically:<ref name=pmid16045781>{{Cite journal  | last1 = Honma | first1 = N. | last2 = Takubo | first2 = K. | last3 = Akiyama | first3 = F. | last4 = Sawabe | first4 = M. | last5 = Arai | first5 = T. | last6 = Younes | first6 = M. | last7 = Kasumi | first7 = F. | last8 = Sakamoto | first8 = G. | title = Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast. | journal = Histopathology | volume = 47 | issue = 2 | pages = 195-201 | month = Aug | year = 2005 | doi = 10.1111/j.1365-2559.2005.02181.x | PMID = 16045781 }}</ref>
*AR +ve.
*GCDFP-15 +ve.
Usually:<ref name=Ref_BP217>{{Ref BP|217}}</ref>
*ER -ve.
*PR -ve.


==Mucinous breast carcinoma==
==Mucinous breast carcinoma==
*[[AKA]] ''mucinous carcinoma of the breast'', [[AKA]] ''colloid carcinoma of the breast''.
*[[AKA]] ''mucinous carcinoma of the breast'', [[AKA]] ''colloid carcinoma of the breast''.
 
{{Main|Mucinous breast carcinoma}}
===General===
*Rare.
*Good prognosis.<ref name=pmid18809061>{{Cite journal  | last1 = Barkley | first1 = CR. | last2 = Ligibel | first2 = JA. | last3 = Wong | first3 = JS. | last4 = Lipsitz | first4 = S. | last5 = Smith | first5 = BL. | last6 = Golshan | first6 = M. | title = Mucinous breast carcinoma: a large contemporary series. | journal = Am J Surg | volume = 196 | issue = 4 | pages = 549-51 | month = Oct | year = 2008 | doi = 10.1016/j.amjsurg.2008.06.013 | PMID = 18809061 }}</ref>
 
===Microscopic===
Features:
*Mucin producing glands.
**Should comprise >90% of the tumour.<ref name=pmid22006768>{{Cite journal  | last1 = Dogan | first1 = E. | last2 = Aksoy | first2 = S. | last3 = Dizdar | first3 = O. | last4 = Arslan | first4 = C. | last5 = Dede | first5 = DS. | last6 = Ozisik | first6 = Y. | last7 = Altundag | first7 = K. | title = Pure mucinous carcinoma of the breast: a single center experience. | journal = J BUON | volume = 16 | issue = 3 | pages = 565-7 | month =  | year =  | doi =  | PMID = 22006768 }}</ref>
 
Note:
*The amount of mucinous component to call ''[[mucinous carcinoma]]'' varies by anatomical site.


==Adenoid cystic carcinoma of the breast==
==Adenoid cystic carcinoma of the breast==
*[[AKA]] ''breast adenoid cystic carcinoma''.
*[[AKA]] ''breast adenoid cystic carcinoma''.
===General===
{{Main|Adenoid cystic carcinoma of the breast}}
*Like tumour of the [[salivary gland]].
*Very rare <0.1% of breast malignancies.<ref name=pmid22154460/>
*Good prognosis.<ref name=pmid22154460>{{Cite journal  | last1 = Boujelbene | first1 = N. | last2 = Khabir | first2 = A. | last3 = Boujelbene | first3 = N. | last4 = Jeanneret Sozzi | first4 = W. | last5 = Mirimanoff | first5 = RO. | last6 = Khanfir | first6 = K. | title = Clinical review - Breast adenoid cystic carcinoma. | journal = Breast | volume =  | issue =  | pages =  | month = Dec | year = 2011 | doi = 10.1016/j.breast.2011.11.006 | PMID = 22154460 }}</ref>


===Microscopic===
==Intracystic papillary breast carcinoma==
:See: ''[[Adenoid cystic carcinoma]]'' article.
*[[AKA]] ''encapsulated or encysted papillary carcinoma of the breast'', abbreviated ''EPC''.
 
{{Main|Intracystic papillary breast carcinoma}}
DDx:
*Cribriform [[DCIS]].
*[[Collagenous spherulosis]].
 
Images:
*[http://path.upmc.edu/cases/case140.html Adenoid cystic carcinoma of the breast (upmc.edu)].
 
==Invasive papillary carcinoma of the breast==
*[[AKA]] ''intracystic papillary carcinoma of the breast''.
*[[AKA]] ''encapsulated papillary carcinoma of the breast''.
===General===
*Very good prognosis.
*Classical menopausal women.
*~30% present with bloody discharge.<ref name=pmid21057133>{{Cite journal  | last1 = Rodríguez | first1 = MC. | last2 = Secades | first2 = AL. | last3 = Angulo | first3 = JM. | title = Best cases from the AFIP: intracystic papillary carcinoma of the breast. | journal = Radiographics | volume = 30 | issue = 7 | pages = 2021-7 | month = Nov | year = 2010 | doi = 10.1148/rg.307105003 | PMID = 21057133 | URL = http://radiographics.rsnajnls.org/cgi/pmidlookup?view=long&pmid=21057133 }}</ref>
 
===Microscopic===
Features:
*Lesion confined to a duct (intraductal) ''or'' cyst (intracystic).
**May have a thick fibrous capsule = ''encapsulated papillary carcinoma''.<ref name=pmid21057133/>
*Loss of myoepithelial cells - '''key feature'''.
*Neoplastic epithelial cells:
**[[Nuclear atypia]] - including: nucleoli, [[nuclear pleomorphism]].
**Abnormal architecture - including cribriform, solid, micropapillary, papillary.


==Glycogen-rich clear cell carcinoma of the breast==
==Glycogen-rich clear cell carcinoma of the breast==
*Abbreviated ''GRCC''.
*Abbreviated ''GRCC''.
===General===
{{Main|Glycogen-rich clear cell carcinoma of the breast}}
*Very rare.
*Possibly a variant of [[apocrine carcinoma]].<ref name=pmid7611537>{{Cite journal  | last1 = Hayes | first1 = MM. | last2 = Seidman | first2 = JD. | last3 = Ashton | first3 = MA. | title = Glycogen-rich clear cell carcinoma of the breast. A clinicopathologic study of 21 cases. | journal = Am J Surg Pathol | volume = 19 | issue = 8 | pages = 904-11 | month = Aug | year = 1995 | doi =  | PMID = 7611537 }}
</ref>
*Prognosis usu. poor.
 
===Microscopic===
Features:
*Groups of cells with abundant clear cytoplasm - need to comprise 90% of the tumour.<ref name=pmid20551566>{{Cite journal  | last1 = Thondavadi | first1 = SR. | last2 = Krishnamurthy | first2 = J. | last3 = Gubbanna | first3 = VM. | title = A case report of glycogen-rich clear cell carcinoma of breast. | journal = Indian J Pathol Microbiol | volume = 53 | issue = 2 | pages = 374-5 | month =  | year =  | doi = 10.4103/0377-4929.64289 | PMID = 20551566 | URL = http://www.ijpmonline.org/article.asp?issn=0377-4929;year=2010;volume=53;issue=2;spage=374;epage=375;aulast=Thondavadi }}</ref>
**Various architectural arrangements: cords, trabeculae, clusters, cribriform.
**Minimal nuclear pleomorphism.
 
Notes:
*Histologic appearance may be similar to ''[[hyalinizing clear cell carcinoma]]''.
 
DDx:
*Signet-ring carcinoma.
*Lipid-rich carcinoma.
*Apocrine carcinoma.
*Secretory carcinoma.
 
Image:
*[http://www.ijpmonline.org/viewimage.asp?img=IndianJPatholMicrobiol_2010_53_2_374_64289_f1.jpg GRCC (ijpmonline.org)].<ref name=pmid20551566/>
 
===Stains===
Features:<ref name=pmid20551566/>
*PAS +ve.
*PASD -ve.
 
Others:<ref name=pmid20551566/>
*Oil red O -ve.
**Lipid-rich carcinoma +ve.
 
===IHC===
Features:<ref name=pmid20551566/>
*BRST2 -ve.
**Apocrine carcinoma +ve.


==Secretory carcinoma of the breast==
==Secretory carcinoma of the breast==
*[[AKA]] ''secretory breast carcinoma'', abbreviated ''SBC''.
*[[AKA]] ''secretory breast carcinoma'', abbreviated ''SBC''.
===General===
{{Main|Secretory carcinoma of the breast}}
*Favourable prognosis.<ref name=pmid22129193>{{Cite journal  | last1 = Vasudev | first1 = P. | last2 = Onuma | first2 = K. | title = Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. | journal = Arch Pathol Lab Med | volume = 135 | issue = 12 | pages = 1606-10 | month = Dec | year = 2011 | doi = 10.5858/arpa.2010-0351-RS | PMID = 22129193 }}</ref>
*Children and adults.


===Microscopic===
==Invasive cribriform carcinoma of the breast==
Features:<ref name=pmid19011601>{{Cite journal  | last1 = Laé | first1 = M. | last2 = Fréneaux | first2 = P. | last3 = Sastre-Garau | first3 = X. | last4 = Chouchane | first4 = O. | last5 = Sigal-Zafrani | first5 = B. | last6 = Vincent-Salomon | first6 = A. | title = Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. | journal = Mod Pathol | volume = 22 | issue = 2 | pages = 291-8 | month = Feb | year = 2009 | doi = 10.1038/modpathol.2008.184 | PMID = 19011601 | URL = http://www.nature.com/modpathol/journal/v22/n2/full/modpathol2008184a.html }}</ref>
{{Main|Invasive cribriform carcinoma of the breast}}
*Abundant cytoplasm with fine vacuolation - clear/pale or amphophilic.
*Mitoses - uncommon.
*Nucleoli - rare.


DDx:
==Invasive papillary carcinoma of the breast==
*[[Lactational change]].<ref name=pmid9684599>{{Cite journal  | last1 = Vesoulis | first1 = Z. | last2 = Kashkari | first2 = S. | title = Fine needle aspiration of secretory breast carcinoma resembling lactational changes. A case report. | journal = Acta Cytol | volume = 42 | issue = 4 | pages = 1032-6 | month =  | year =  | doi =  | PMID = 9684599 }}</ref>
{{Main|Invasive papillary carcinoma of the breast}}
 
*Should '''not''' be confused with the indolent behaving [[intracystic papillary carcinoma of the breast]], also known as ''encapsulated papillary carcinoma of the breast''.
Images:
*[http://www.webpathology.com/image.asp?n=1&Case=300 Secretory breast carcinoma - low mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=2&Case=300 Secretory breast carcinoma - high mag. (webpathology.com)].
*[http://www.nature.com/modpathol/journal/v22/n2/fig_tab/modpathol2008184f1.html#figure-title Secretory breast carcinoma (nature.com)].
 
===IHC===
Triple negative (ER -ve, PR -ve, HER2 -ve).<ref name=pmid22129193>{{Cite journal  | last1 = Vasudev | first1 = P. | last2 = Onuma | first2 = K. | title = Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. | journal = Arch Pathol Lab Med | volume = 135 | issue = 12 | pages = 1606-10 | month = Dec | year = 2011 | doi = 10.5858/arpa.2010-0351-RS | PMID = 22129193 }}</ref>
 
Others:
*Alpha-lactalbumin +ve.
*S-100 protein +ve.
*Polyclonal CEA +ve.
 
===Molecular pathology===
Characteristic translocation:<ref name=pmid22129193/>
*t(12;15).
**ETV6-NTRK3.


=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:
*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>
 
==Note about mitosis counting==
*One MUST adjust for the size of the field of view.
 
*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.
**Thus, on a resident scope (with a FOV of 0.2376 mm^2) one should sample 6 or 7 fields of view (FsOV).
***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.
 
==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=
=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>
{{Main|Breast cancer staging}}
*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>
=Lymphovascular invasion=
*pT1: <= 2 cm.
{{Main|Lymphovascular invasion}}
**pT1mic <= 0.1 cm.
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>
**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.
 
==Lymphovascular invasion==
There are famous criteria for lymphovascular invasion (LVI).
 
Rosen criteria for LVI:<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.
#Must be outside of the tumour proper.
#*LVI is usually very close -- typically within 0.1 cm.
#*LVI is usually very close -- typically within 0.1 cm.
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Memory device ''LUBE-O'':  
Memory device ''LUBE-O'':  
*'''L'''VI has a '''U'''nique contour, '''B'''lood vessels and '''E'''ndothelium in the vicinity, and is '''O'''utside of the tumour.
*'''L'''VI has a '''U'''nique contour, '''B'''lood vessels and '''E'''ndothelium in the vicinity, and is '''O'''utside of the tumour.
Note:
*LVI does not affect the stage.


=Other=
=Other=
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IHC & DDx:  
IHC & DDx:  
*See ''[[Paget disease]]''.
*See ''[[Paget disease]]''.
==Sentinel lymph node biopsy==
===General===
*Used for staging, positive LNs = poorer prognosis.
Notes:
*If there is no palpable disease, 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==
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=External links=
=External links=
*[http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=committees%2Fcancer%2Fcancer_protocols%2Fprotocols_index.html&_state=maximized&_pageLabel=cntvwr CAP protocols/checklists (cap.org)].
*[http://ww5.komen.org/BreastCancer/SubtypesofBreastCancer.html About breast cancer - molecular subtypes (komen.org)].
**[http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf Invasive breast cancer - checklist (cap.org)].


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