Difference between revisions of "Invasive breast cancer"

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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%.
*Lobular 10%.
*[[invasive lobular carcinoma|Lobular]] - 10%.
*Cribriform (tubular) 6%.
*[[Tubular carcinoma of the breast|Cribriform / tubular]] - 6%.
*Mucinous (colloid) 2%.
*[[mucinous breast carcinoma|Mucinous]] (colloid) - 2%.
*Medullary 2%.  
*[[medullary breast carcinoma|Medullary]] - 2%.  
*Papillary 1%.
*Papillary - 1%.
*Metaplastic <1%.
*[[Metaplastic breast carcinoma|Metaplastic]] - <1%.


===Common stromal types===
===Common stromal types===
*Malignant [[phyllodes tumour]].
*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==
==Comprehensive list of invasive breast cancer subtypes==
====Epithelial====  
====Epithelial====  
Counterparts of in situ lesions:
Counterparts of in situ lesions:
*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.
*[[Invasive papillary carcinoma of the breast|Invasive papillary carcinoma]].
*Invasive micropapillary carcinoma.
*[[Invasive micropapillary carcinoma of the breast|Invasive micropapillary carcinoma]].


Other epithelial tumours:
Other epithelial tumours:
*Tubular carcinoma.
*[[Tubular carcinoma of the breast|Tubular carcinoma]].
*Medullary carcinoma.
*[[Medullary breast carcinoma|Medullary carcinoma]].
*Mucinous carinoma.
*[[Mucinous breast carcinoma|Mucinous carinoma]].
*[[Metaplastic carcinoma]].
*[[Metaplastic breast carcinoma|Metaplastic carcinoma]].
*[[Neuroendocrine tumour]].
*[[Neuroendocrine tumour]].
*Apocrine carcinoma.
*[[Apocrine carcinoma of the breast|Apocrine carcinoma]].
*Lipid-rich carcinoma.
*Lipid-rich carcinoma.
*Secretory carcinoma.
*[[Secretory breast carcinoma|Secretory carcinoma]].
*Oncocytic carcinoma.
*Oncocytic carcinoma.
*Glycogen-rich clear cell carcinoma.
*[[Glycogen-rich clear cell carcinoma of the breast|Glycogen-rich clear cell carcinoma]].


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]].


Seen in the skin:
Seen in the skin:
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Papillary:
Papillary:
*Papilloma.
*[[Intraductal papilloma of the breast|Papilloma]].
*Atypical papilloma.
*Atypical papilloma.
*Intraductal papillary carcinoma.
*Intraductal papillary carcinoma.
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Adenomas:
Adenomas:
*Ductal adenoma.
*Ductal adenoma.
*Tubular adenoma.
*[[Tubular adenoma of the breast|Tubular adenoma]].
*Lactating adenoma.
*[[Lactating adenoma]].
*Apocrine adenoma.
*Apocrine adenoma.
*Pleomorphic adenoma.
*[[Pleomorphic adenoma]].


====Myoepithelial====  
====Myoepithelial====  
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*[[Phyllodes tumour]].
*[[Phyllodes tumour]].
*Periductal stromal sarcoma, low grade.
*Periductal stromal sarcoma, low grade.
*Mammary hamartoma.
*[[Mammary hamartoma]].


====Nipple lesions====  
====Nipple lesions====  
*Nipple adenoma.
*[[Nipple adenoma]].
*Syringomatous adenoma.
*Syringomatous adenoma.
*[[Paget disease of the breast]].
*[[Paget disease of the breast]].
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====Other====  
====Other====  
*[[Lymphoma]].
*[[Lymphoma]].
*Metastasis.
*[[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=
Line 144: Line 139:
| ER- PR- HER2-
| ER- PR- HER2-
| poorly differentiated
| poorly differentiated
| aggressive, may have good chemo response
| aggressive, may have good chemo response, classic for [[BRCA1]] mutation
|-
|-
| HER2 positive
| HER2 positive
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|}
|}


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>


==Subtyping breast cancer==
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>


*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>
== Basal-like breast carcinoma==
**E-cadherin (+ve DCIS, -ve LCIS).
 
**antibody 34betaE12 (+ve perinuclear LCIS, -ve DCIS).
 
**CAM5.2 (peripheral stain = DCIS, perinuclear stain = LCIS).
*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 }}
***CAM5.2 is against CK8.
</ref>
**Beta-catenin (-LCIS, +DCIS).
**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
|}
 
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
|}


*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>
===Lymphovascular invasion===
**Monoclonal antibody to podoplanin.
{{Main|Lymphovascular invasion}}
**Useful to assess 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.


*ADH and DCIS:<ref name=Ref_Lester122>{{Ref Lester|122}}</ref>
===Lymph node metastases===
**E-cadherin.
Immunostaining of sentinel lymph nodes to look for [[isolated tumour cells]] and small [[lymph node metastases]] may be done.
***Present in most epithelial cells.
*CAM5.2 may be used.
***Lost in LCIS & invasive lobular carcinoma.
*'''Not''' done routinely.
**SMMHC (smooth muscle cell myosin heavy chain).
***Marks myoepithelial cells.


==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 196: 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]]
| Needs [[SISH]] or [[FISH]]
| ~10%
| ~10% †
|-
| '''2+'''
| intense
| '''≤10%'''
| '''complete'''
| Needs [[SISH]] or [[FISH]]
| ~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 266: 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
==Medullary breast carcinoma==
*Typically: ER+, PR+, HER2-.
*[[AKA]] ''medullary carcinoma of the breast''.
{{Main|Medullary breast carcinoma}}


==Lobular carcinoma==
==Tubular carcinoma of the breast==
===General===
*[[AKA]] ''tubular 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>
{{Main|Tubular carcinoma of the breast}}


===Microscopic===
==Metaplastic breast carcinoma==
Features:
*[[AKA]] ''metaplastic carcinoma''.
*"Single file" - cell line-up in a row.
{{Main|Metaplastic breast carcinoma}}
**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:
==Invasive micropapillary carcinoma of the breast==
*commonly have low grade nuclear features
*[[AKA]] ''micropapillary carcinoma''.
{{Main|Invasive micropapillary carcinoma of the breast}}


Images:
==Apocrine carcinoma of the breast==
*[http://commons.wikimedia.org/wiki/File:Lobular_carcinoma_-_low_mag.jpg Lobular carcinoma - low mag. (WC)].
{{Main|Apocrine carcinoma of the breast}}
*[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:
==Mucinous breast carcinoma==
*Classic lobular carcinoma.
*[[AKA]] ''mucinous carcinoma of the breast'', [[AKA]] ''colloid carcinoma of the breast''.
**Low nuclear grade - NO significant variation of nucleus size.
{{Main|Mucinous breast carcinoma}}
*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==
===General===
*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==
==Adenoid cystic carcinoma of the breast==
===General===
*[[AKA]] ''breast adenoid cystic carcinoma''.
Epidemiology:
{{Main|Adenoid cystic carcinoma of the breast}}
*Typically excellent prognosis.
*Hormone receptors commonly present.


Note:
==Intracystic papillary breast carcinoma==
*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>
*[[AKA]] ''encapsulated or encysted papillary carcinoma of the breast'', abbreviated ''EPC''.
**Memory device ''TLC'' = '''T'''ubular ca., '''L'''CIS, '''C'''olumnar cell lesions.
{{Main|Intracystic papillary breast carcinoma}}


===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'''.


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


DDx:
==Invasive cribriform carcinoma of the breast==
*[[Sclerosing adenosis]].
{{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>
*Malignant mesenchymal elements:
**Spindle cells
*+/-Adenocarcinoma.
*+/-Squamous carcinoma.
 
Notes:
*If it looks like squamous cell carcinoma... in the breast it is metaplastic 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>
 
====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. (???)
 
==Micropapillary carcinoma==
===General===
*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==
===General===
*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==
*[[AKA]] ''mucinous carcinoma of the breast''.
 
===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.


=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>
*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.


==Lymphovascular invasion==
=Lymphovascular invasion=
There are famous criteria for lymphovascular invasion (LVI).
{{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>
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.
Line 526: Line 471:
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=
Line 550: 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:
*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==
Line 626: Line 550:


=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]]

Latest revision as of 17:50, 24 June 2017

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.

Introduction

Overview of invasive breast cancer subtypes

Common epithelial subtypes

Type and percentage of breast carcinomas:[1]

Common stromal types

Good prognosis subtypes

Three good prognosis subtypes:[3]

  • Tubular carcinoma.
  • Mucinous carcinoma.
  • Papillary carcinoma.

Comprehensive list of invasive breast cancer subtypes

Epithelial

Counterparts of in situ lesions:

Other epithelial tumours:

Epithelial tumours seen in the salivary gland:

Seen in the skin:

Clinically diagnosed:

  • Inflammatory carcinoma.

In situ lesions:

Proliferative lesions:

Non-specific:

  • Microinvasive carcinoma.

Papillary:

  • Papilloma.
  • Atypical papilloma.
  • Intraductal papillary carcinoma.

Adenomas:

Myoepithelial

  • Myoepitheliosis.
  • Adenomyoepithelial adenosis.
  • Adenomyoepithelioma.
  • Malignant adenomyoepithelioma.

Mesenchymal tumours

See: Soft tissue lesions.

Fibroepithelial tumours

Nipple lesions

Other

Familial breast cancer

Main article: Hereditary breast cancer

Breast IHC

Molecular classification of invasive carcinoma

A molecular classification:[4]

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[5]

A newer classification outlines 10 subtypes based on molecular drivers identified by analysis of genomic and transcriptomic data from 2,000 breast tumors.[6]

Basal-like breast carcinoma

  • Overview:[7]
    • 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.
  • 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:[8]

    • 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.[9]
        • May respond to therapies targeting the androgen receptor.
      • BCL11A overexpression recently identified as an oncogenic driver for some triple negatives [10]
        • 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:[11][12]

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:[13]

Stain Location Notes
p63 nuclear up to 10% of invasive tumours +ve[14]
Smooth muscle actin (SMA) cytoplasmic stains myofibroblasts & blood vessels
Calponin cytoplasmic stains myofibroblasts & blood vessels
Smooth muscle myosin
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. [15]

Usual ductal hyperplasia versus ductal carcinoma in situ

Markers for UDH versus DCIS:[14]

Disease CK5/6 ER
UDH diffuse +ve patchy +ve
DCIS -ve diffuse +ve

Lymphovascular invasion

Main article: Lymphovascular invasion
  • D2-40 - marks the lymphatic spaces.[16][17]
  • 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

  • ER (estrogen receptor).
    • Positive in most breast cancers; +ve in ~75-80%.[18]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[18]
  • HER2/neu (HER2).
    • Usually negative; -ve in 70-80%.[18]
    • Positivity associated with a worse prognosis.
    • In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.[19][20]

Notes:

  • Male breast cancer is usually hormone receptor positive (~97%), and HER2 positivity is quite rare (~6%).[21]
  • ASCO/CAP guidelines recommend that cold ischemia time be <1 hour.[22]

ER & PR scoring

Nuclear staining:[18]

  • Give a percentage, i.e. 0-100%.
    • Important cut points: 1% and 10%.
      • 0% = negative - not treated.
      • <10% = low positivity - treated.

Notes:

  • Normal breast epithelial cells have a patchy staining for ER and PR.
  • Evaluated on the invasive component.

HER2 scoring

Immunohistochemical based testing:[23][24]

Score Staining intensity Cells stained (%) Membrane staining Management Percentage of cases
0 no staining/barely visible ≤10% incomplete No HER2 blocker ~60%
1+ minimal/barely visible >10% incomplete No HER2 blocker ~10%
2+ weak-to-moderate >10% incomplete (circumferential) Needs SISH or FISH ~10% †
2+ intense ≤10% complete Needs SISH or FISH ~10% †
3+ intense staining >10% ‡ complete HER2 blocker ~20%

Note for IHC:

  • Normal breast epithelial cells do not stain with HER2.
  • Evaluated on the invasive component.
  • SISH = silver 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%.[23]

ISH based testing:[25]

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

  • ER & PR status determine whether a patient will get tamoxifen or other estrogen receptor modulators, such as raloxifene (Evista).
  • HER2 status determines whether patient will get traztuzumab (Herceptin) or other HER2/neu modulators.

Characteristics of the subtypes

Invasive ductal carcinoma of the breast

  • AKA "NST" = No Specific Type.
  • AKA invasive mammary carcinoma.
Main article: Invasive ductal carcinoma of the breast

Invasive lobular carcinoma

  • Abbreviated ILC.
  • AKA lobular carcinoma.
Main article: Invasive lobular carcinoma

Medullary breast carcinoma

  • AKA medullary carcinoma of the breast.
Main article: Medullary breast carcinoma

Tubular carcinoma of the breast

  • AKA tubular carcinoma.
Main article: Tubular carcinoma of the breast

Metaplastic breast carcinoma

  • AKA metaplastic carcinoma.
Main article: Metaplastic breast carcinoma

Invasive micropapillary carcinoma of the breast

  • AKA micropapillary carcinoma.
Main article: Invasive micropapillary carcinoma of the breast

Apocrine carcinoma of the breast

Main article: Apocrine carcinoma of the breast

Mucinous breast carcinoma

  • AKA mucinous carcinoma of the breast, AKA colloid carcinoma of the breast.
Main article: Mucinous breast carcinoma

Adenoid cystic carcinoma of the breast

  • AKA breast adenoid cystic carcinoma.
Main article: Adenoid cystic carcinoma of the breast

Intracystic papillary breast carcinoma

  • AKA encapsulated or encysted papillary carcinoma of the breast, abbreviated EPC.
Main article: Intracystic papillary breast carcinoma

Glycogen-rich clear cell carcinoma of the breast

  • Abbreviated GRCC.
Main article: Glycogen-rich clear cell carcinoma of the breast

Secretory carcinoma of the breast

  • AKA secretory breast carcinoma, abbreviated SBC.
Main article: Secretory carcinoma of the breast

Invasive cribriform carcinoma of the breast

Main article: Invasive cribriform carcinoma of the breast

Invasive papillary carcinoma of the breast

Main article: Invasive papillary carcinoma of the breast

Grading breast cancer

Main article: Breast cancer grading

Staging breast cancer

Main article: Breast cancer staging

Lymphovascular invasion

Main article: Lymphovascular invasion

In the context of breast pathology, the Rosen criteria for LVI are widely excepted, and are as follows:[26][27]

  1. Must be outside of the tumour proper.
    • LVI is usually very close -- typically within 0.1 cm.
  2. Contour of cells should differ from possible vessel wall.
    • DCIS with retraction artifact mimicing LVI has a contour that matches its surrounding fibrous tissue.
  3. Endothelium (usu. flat) should be visible.
  4. Lymphatics are found adjacent to blood vessels - vessels should be present in the vicinity.

Memory device LUBE-O:

  • LVI has a Unique contour, Blood vessels and Endothelium in the vicinity, and is Outside of the tumour.

Note:

  • LVI does not affect the stage.

Other

Paget's disease

Main article: Paget disease of the breast

General

  • Associated with underlying breast carcinoma.[28]

Notes:

Microscopic

Features:[28]

  • Cells in the epidermis:
    • Epitheliod morphology (round/ovoid).
    • Cells nested or single.
    • Clear/pale cytoplasm key feature - may also be eosinophilic.
    • Large nucleoli.

Images:

IHC & DDx:

Trivia

Tumour size and lymph node metastases

There is a paper[29] that calculates the probability of lymph node mets based on tumour size. The developed formula is:

Where:

  • = the probability of the lymph nodes being positive.
  • D = the largest dimension of the tumour in millimetres.
  • Z = 1.0041.
  • = 0.019.

Selected values

Tumour size (mm) Probability
5 9 %
10 17 %
15 25 %
20 32 %
25 38 %
30 44 %
35 49 %
40 54 %
45 58 %
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.[30] The study is supported by NCI's SEER data.[31] Also, it generated many comments.[30]

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.[32]

See also

References

  1. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1143. ISBN 0-7216-0187-1.
  2. ↑ URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html. Accessed on: 28 November 2010.
  3. ↑ URL: http://emedicine.medscape.com/article/1947145-overview. Accessed on: 24 August 2012.
  4. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 547. ISBN 978-1416054542.
  5. ↑ Tang, P.; Skinner, KA.; Hicks, DG. (Sep 2009). "Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready?". Diagn Mol Pathol 18 (3): 125-32. doi:10.1097/PDM.0b013e31818d107b. PMID 19704256.
  6. ↑ Curtis, C.; Shah, SP.; Chin, SF.; Turashvili, G.; Rueda, OM.; Dunning, MJ.; Speed, D.; Lynch, AG. et al. (Jun 2012). "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.". Nature 486 (7403): 346-52. doi:10.1038/nature10983. PMID 22522925.
  7. ↑ Badve, S.; Dabbs, DJ.; Schnitt, SJ.; Baehner, FL.; Decker, T.; Eusebi, V.; Fox, SB.; Ichihara, S. et al. (Feb 2011). "Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists.". Mod Pathol 24 (2): 157-67. doi:10.1038/modpathol.2010.200. PMID 21076464.
  8. ↑ Badve, S.; Dabbs, DJ.; Schnitt, SJ.; Baehner, FL.; Decker, T.; Eusebi, V.; Fox, SB.; Ichihara, S. et al. (Feb 2011). "Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists.". Mod Pathol 24 (2): 157-67. doi:10.1038/modpathol.2010.200. PMID 21076464.
  9. ↑ Niemeier, LA.; Dabbs, DJ.; Beriwal, S.; Striebel, JM.; Bhargava, R. (Feb 2010). "Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation.". Mod Pathol 23 (2): 205-12. doi:10.1038/modpathol.2009.159. PMID 19898421.
  10. ↑ Khaled, WT.; Choon Lee, S.; Stingl, J.; Chen, X.; Raza Ali, H.; Rueda, OM.; Hadi, F.; Wang, J. et al. (2015). "BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells.". Nat Commun 6: 5987. doi:10.1038/ncomms6987. PMID 25574598.
  11. ↑ O'Malley, Frances P.; Pinder, Sarah E. (2006). Breast Pathology: A Volume in Foundations in Diagnostic Pathology series (1st ed.). Churchill Livingstone. pp. 275. ISBN 978-0443066801.
  12. ↑ Yeh IT, Mies C (March 2008). "Application of immunohistochemistry to breast lesions". Arch. Pathol. Lab. Med. 132 (3): 349-58. PMID 18318578. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=349.
  13. ↑ Lester, Susan Carole (2010). Manual of Surgical Pathology (3rd ed.). Saunders. pp. 88. ISBN 978-0-323-06516-0.
  14. ↑ 14.0 14.1 O'Malley, Frances P.; Pinder, Sarah E. (2006). Breast Pathology: A Volume in Foundations in Diagnostic Pathology series (1st ed.). Churchill Livingstone. pp. 276. ISBN 978-0443066801.
  15. ↑ Mori K, Takeda M, Kodama Y, Kiyokawa H, Yasojima H, Mizutani M, Otani Y, Morikawa N, Masuda N, Mano M (2017). "Tumor thickness and histological features as predictors of invasive foci within preoperatively diagnosed ductal carcinoma in situ". Human Pathology 64: 145-155. doi:10.1016/j.humpath.2017.04.004. PMID 28434924.
  16. ↑ Ordóñez NG (March 2006). "Podoplanin: a novel diagnostic immunohistochemical marker". Adv Anat Pathol 13 (2): 83-8. doi:10.1097/01.pap.0000213007.48479.94. PMID 16670463.
  17. ↑ Kahn HJ, Marks A (September 2002). "A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors". Lab. Invest. 82 (9): 1255-7. PMID 12218087.
  18. ↑ 18.0 18.1 18.2 18.3 Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 241-2. ISBN 978-0443066450.
  19. ↑ Gallardo, A.; Lerma, E.; Escuin, D.; Tibau, A.; Muñoz, J.; Ojeda, B.; Barnadas, A.; Adrover, E. et al. (Apr 2012). "Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas.". Br J Cancer 106 (8): 1367-73. doi:10.1038/bjc.2012.85. PMID 22454081.
  20. ↑ Jensen, JD.; Knoop, A.; Laenkholm, AV.; Grauslund, M.; Jensen, MB.; Santoni-Rugiu, E.; Andersson, M.; Ewertz, M. (Dec 2011). "PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.". Ann Oncol. doi:10.1093/annonc/mdr546. PMID 22172323.
  21. ↑ Schildhaus, HU.; Schroeder, L.; Merkelbach-Bruse, S.; Binot, E.; Büttner, R.; Kuhn, W.; Rudlowski, C. (Sep 2013). "Therapeutic strategies in male breast cancer: Clinical implications of chromosome 17 gene alterations and molecular subtypes.". Breast. doi:10.1016/j.breast.2013.08.008. PMID 24080492.
  22. ↑ Yildiz-Aktas, IZ.; Dabbs, DJ.; Bhargava, R. (Aug 2012). "The effect of cold ischemic time on the immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 expression in invasive breast carcinoma.". Mod Pathol 25 (8): 1098-105. doi:10.1038/modpathol.2012.59. PMID 22460807.
  23. ↑ 23.0 23.1 Rakha, EA.; Starczynski, J.; Lee, AH.; Ellis, IO. (Apr 2014). "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.". Histopathology 64 (5): 609-15. doi:10.1111/his.12357. PMID 24382093.
  24. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed on: October 7, 2014.
  25. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed on: October 7, 2014.
  26. ↑ Rosen, PP. (1983). "Tumor emboli in intramammary lymphatics in breast carcinoma: pathologic criteria for diagnosis and clinical significance.". Pathol Annu 18 Pt 2: 215-32. PMID 6674861.
  27. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 5 August 2011.
  28. ↑ 28.0 28.1 URL: http://emedicine.medscape.com/article/1101235-diagnosis
  29. ↑ Porembka, MR.; Abraham, RL.; Sefko, JA.; Deshpande, AD.; Jeffe, DB.; Margenthaler, JA. (Oct 2008). "Factors associated with lymph node assessment in ductal carcinoma in situ: analysis of 1988-2002 seer data.". Ann Surg Oncol 15 (10): 2709-19. doi:10.1245/s10434-008-9947-5. PMID 18483831. http://onlinelibrary.wiley.com/doi/10.1002/cncr.24592/pdf.
  30. ↑ 30.0 30.1 Zahl, PH.; Maehlen, J.; Welch, HG. (Nov 2008). "The natural history of invasive breast cancers detected by screening mammography.". Arch Intern Med 168 (21): 2311-6. doi:10.1001/archinte.168.21.2311. PMID 19029493.
  31. ↑ Jatoi, I.; Anderson, WF. (May 2009). "Breast cancer overdiagnosis with screening mammography.". Arch Intern Med 169 (10): 999-1000, author reply 1000-1. doi:10.1001/archinternmed.2009.95. PMID 19468099.
  32. ↑ Weaver, DL.; Ashikaga, T.; Krag, DN.; Skelly, JM.; Anderson, SJ.; Harlow, SP.; Julian, TB.; Mamounas, EP. et al. (Feb 2011). "Effect of occult metastases on survival in node-negative breast cancer.". N Engl J Med 364 (5): 412-21. doi:10.1056/NEJMoa1008108. PMID 21247310.

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