Difference between revisions of "Invasive breast cancer"

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(→‎Invasive versus non-invasive: added information from recent study on microinvasion)
 
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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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*[[Invasive ductal carcinoma of the breast|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%.  
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*[[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]].
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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]].
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Papillary:
Papillary:
*[[Intraductal papilloma|Papilloma]].
*[[Intraductal papilloma of the breast|Papilloma]].
*Atypical papilloma.
*Atypical papilloma.
*Intraductal papillary carcinoma.
*Intraductal papillary carcinoma.
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==Familial breast cancer==
==Familial breast cancer==
===Syndromes associated with breast cancer===
{{Main|Hereditary breast cancer}}
{| class="wikitable sortable"
! Gene
! Syndrome
! Other cancers
! Notes
|-
| BRCA1
| Familial breast and ovarian cancer<ref name=omim113705>{{OMIM|113705}}</ref>
| male breast, ovarian, prostate, pancreas, fallopian tube
| younger individuals vis-à-vis BRCA2
|-
| BRCA2
| Familial breast and ovarian cancer 2<ref name=omim600185>{{OMIM|600185}}</ref>
| male breast, ovarian, prostate, pancreas, stomach, melanoma, gallbladder, bile duct, pharynx
| older individuals vis-à-vis BRCA1
|-
| TP53 (p53)
| [[Li-Fraumeni syndrome]] ([[AKA]] ''SBLA syndrome'')
| [[sarcoma]]s, brain cancer, larynx, lung, leukemia, [[adrenal cortical carcinoma]]
| often present in childhood
|-
| CHEK2
| [[Li-Fraumeni syndrome]] (variant)
| see ''p53''
| -
|-
| STK11
| [[Peutz-Jeghers syndrome]]
| breast cancer, GI cancer, [[Sertoli cell tumour]], [[Granulosa cell tumour]], [[SCTAT]]
| characteristic GI [[hamartoma]]s, mucocutaneous pigmentation
|-
| PTEN
| [[Cowden syndrome]]
| breast, thyroid (PTC), endometrial, renal, colorectal
| -
|-
| CDH1
| Familial diffuse gastric cancer<ref name=omim192090>{{OMIM|192090}}</ref>
| [[invasive lobular carcinoma]], gastric [[signet ring cell carcinoma]]
| -
|-
|}
 
===BRCA1 and BRCA2===
BRCA1 vs. BRCA2:<ref name=Ref_PBoD8_1078>{{Ref PBoD8|1078}}</ref>
{| 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 associated with both BRCA1 and BRCA2 - ''male OPP'':
*'''Male''' breast, '''o'''varian, '''p'''rostate, '''p'''ancreas.
 
How to remember types of cancer associated with BRCA2 - ''PUM'':
*'''P'''harynx, '''u'''pper GI (stomach, gallbladder, biliary), '''m'''elanoma.


=Breast IHC=
=Breast IHC=
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| 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
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|}
|}


The above is not applied clinically. A panel of [[immunostains]] (ER, PR, HER2, EGFR, CK5/6) can reproduce the molecular groupings.<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]].
 
*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==
==Immunostains for typing and diagnosis==
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| stains myofibroblasts & blood vessels
| 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===
===Usual ductal hyperplasia versus ductal carcinoma in situ===
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{| class="wikitable sortable"  
{| class="wikitable sortable"  
!Disease  
!Disease  
!CK5/6
![[CK5/6]]
!ER
![[ER]]
|-
|-
|UDH
|UDH
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*CD31 - marks lymphovascular spaces.
*CD31 - marks lymphovascular spaces.
*CD34 - marks lymphovascular spaces, less specific than CD31.
*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>
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**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>  
**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>  


Note:
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>  
*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===
===ER & PR scoring===
Nuclear staining:<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
Nuclear staining:<ref name=Ref_Lester241-2>{{Ref Lester|241-2}}</ref>
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*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 sortable"
{| class="wikitable sortable"
! Score
! Score
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|-
|-
| '''0'''
| '''0'''
| nil
| no staining/barely visible
| '''<=10%'''
| '''≤10%'''
| '''incomplete'''
| '''incomplete'''
| No HER2 blocker
| No HER2 blocker
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|-
|-
| '''1+'''
| '''1+'''
| minimal-to-weak
| minimal/barely visible
| '''>10%'''
| '''>10%'''
| '''incomplete'''
| '''incomplete'''  
| No HER2 blocker
| No HER2 blocker
| ~10%
| ~10%
|-
|-
| '''2+'''
| '''2+'''
| weak-to-moderate ''or'' intense
| weak-to-moderate
| '''>10% ''and'' <=30%'''
| '''>10%'''
| '''incomplete''' (circumferential)
| Needs [[SISH]] or [[FISH]]
| ~10% †
|-
| '''2+'''
| intense
| '''≤10%'''
| '''complete'''
| '''complete'''
| Needs [[SISH]] or [[FISH]]
| Needs [[SISH]] or [[FISH]]
| ~10%
| ~10% †
|-
|-
| '''3+'''
| '''3+'''
| intense & uniform staining (used to be ''strong'')
| intense staining  
| '''>30%''' (used to ''>10%'')
| '''>10%''' ‡
| '''complete'''
| '''complete'''
| HER2 blocker
| HER2 blocker
Line 353: Line 368:
*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 sortable"
{| class="wikitable sortable"
! Result
! Result
Line 361: Line 378:
|-
|-
| 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
|}
|}
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==Metaplastic breast carcinoma==
==Metaplastic breast carcinoma==
*[[AKA]] ''metaplastic carcinoma''.
*[[AKA]] ''metaplastic carcinoma''.
===General===
{{Main|Metaplastic breast carcinoma}}
*May be difficult to diagnose.
*Prognosis - poor.
*In the [[differential diagnosis]] for [[spindle cell lesions]] of the breast.{{fact}}
 
===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.
 
Notes:
*Calcifications are uncommon.
*Cytology may be very bland, i.e. it may look very benign.
*May have minimal mitotic activity.
 
DDx:
*[[Fibromatosis]].
*Malignant [[phyllodes tumour]].
*Primary mammary sarcoma.
*[[Mammary myofibroblastoma]].
*[[Nodular fasciitis]].
*[[Squamous cell carcinoma of the skin]].
 
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:
*[[Invasive ductal carcinoma of the breast|Ductal carcinoma]] commonly has clefting... but it isn't diffuse.
 
Images:
*[http://www.flickr.com/photos/euthman/5300126397/ Invasive micropapillary carcinoma (flickr.com/euthman)].
*[http://www.breast-cancer.ca/images/invasive-micropapillary-breast-carcinoma-cells1.jpg Invasive micropapillary carcinoma - crappy image (breast-cancer.ca)].<ref>URL: [http://www.breast-cancer.ca/type/micropapillary-breast-carcinoma.htm http://www.breast-cancer.ca/type/micropapillary-breast-carcinoma.htm]. Accessed on: 30 May 2012.</ref>
 
===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==
Line 510: Line 432:
==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===
:See: ''[[Adenoid cystic carcinoma]]'' article.
 
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'', abbreviated ''IPC''.
*[[AKA]] ''encapsulated papillary carcinoma of the breast'', abbreviated ''EPC''.
===General===
*Very good prognosis<ref name=pmid21753694>{{Cite journal  | last1 = Rakha | first1 = EA. | last2 = Gandhi | first2 = N. | last3 = Climent | first3 = F. | last4 = van Deurzen | first4 = CH. | last5 = Haider | first5 = SA. | last6 = Dunk | first6 = L. | last7 = Lee | first7 = AH. | last8 = Macmillan | first8 = D. | last9 = Ellis | first9 = IO. | title = Encapsulated papillary carcinoma of the breast: an invasive tumor with excellent prognosis. | journal = Am J Surg Pathol | volume = 35 | issue = 8 | pages = 1093-103 | month = Aug | year = 2011 | doi = 10.1097/PAS.0b013e31821b3f65 | PMID = 21753694 }}</ref> - it is similar to [[DCIS]].
*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.


DDx:
==Intracystic papillary breast carcinoma==
*[[Intraductal papilloma]].
*[[AKA]] ''encapsulated or encysted papillary carcinoma of the breast'', abbreviated ''EPC''.
 
{{Main|Intracystic papillary breast carcinoma}}
===IHC===
*Loss of myoepithelial markers within the lesion.


==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 of the breast|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 of the breast|Apocrine carcinoma]].
*[[Secretory carcinoma of the breast|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==
Line 592: Line 446:
{{Main|Secretory carcinoma of the breast}}
{{Main|Secretory carcinoma of the breast}}


=Grading breast cancer=
==Invasive cribriform carcinoma of the breast==
Most common system: ''Nottingham'' (aka Scarff-Bloom-Richardson) which is based on:
{{Main|Invasive cribriform carcinoma of the breast}}
#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:
==Invasive papillary carcinoma of the breast==
*Elston & Ellis devised the system that is used.<ref name=pmid12405945>{{cite journal |author=Elston CW, Ellis IO |title=Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403-410 |journal=Histopathology |volume=41 |issue=3A |pages=151–2, discussion 152–3 |year=2002 |month=September |pmid=12405945 |doi= |url=}}</ref> They also wrote a follow-up article in 2002.<ref name=pmid1757079>{{cite journal |author=Elston CW, Ellis IO |title=Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up |journal=Histopathology |volume=19 |issue=5 |pages=403–10 |year=1991 |month=November |pmid=1757079 |doi= |url=}}</ref>
{{Main|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''.


==Note about mitosis counting==
=Grading breast cancer=
*One MUST adjust for the size of the field of view.
{{Main|Breast cancer grading}}
 
*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=
==Sentinel lymph node sampling in breast cancer==
{{Main|Breast cancer staging}}
{{Main|Sentinel lymph node|Lymph node metastasis}}
===General===
*Selective sampling of lymph nodes.
*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.
 
==N stage==
Sampling usually selective, i.e. [[sentinel lymph nodes]] only.
===Indictionas for lymph node sampling===
Indications for lymph node sampling:<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: 2 April 2012.</ref>
*Extensive [[DCIS]].
*Biopsy suspicious for invasion ''or'' with microinvasion.
*Clinical findings (large palable mass) or radiology findings (irregular features) suggestive of invasion.
*Planned mastectomy.
 
===Definitions===
Definitions:<ref name=acs_website>URL: [http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging]. Accessed on: 8 July 2010.</ref>
*Isolated tumour cells: <=0.2 mm ''or'' <=200 cells -- in a single cross-section. †
*Micrometastasis: <=0.2 cm ''and'' ( >0.2 mm ''or'' >200 cells ).
*Macrometastasis: >0.2 cm.
 
Notes:
* † The ''American Cancer Society'' web site says "or".<ref name=acs_website/>  The CAP protocol says "and/or" and notes it is all subjective.
*Isolated tumour cells are essentially ignored if the there is at least one macrometastasis.
 
===Details===
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.
 
==T stage==
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: <= 20 mm.
**pT1mic <= 1 mm.
**pT1a > 1 mm ''and'' <= 5 mm.
**pT1b > 5 mm ''and'' <= 10 mm.
**pT1c > 10 mm ''and'' <= 20 mm.
*pT2: > 20 mm and <= 50 mm
*pT3: > 50 mm.
*pT4: chest wall or skin involvement.
 
Notes:
*Values should be rounded to the nearest millimetre.
**Therefore:
***1.4 mm would be ''pT1mic''.
***1.5 mm would be ''pT1a''.
 
==M stage==
Distant metastasis:
*cM0(i+) <=0.2 mm focus of tumour cells, without clinical signs and symptoms.
*pM1 focus of tumour cells > 0.2 mm.


=Lymphovascular invasion=
=Lymphovascular invasion=
Line 802: 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://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf Invasive breast cancer - checklist (cap.org)].
*[http://ww5.komen.org/BreastCancer/SubtypesofBreastCancer.html About breast cancer - molecular subtypes (komen.org)].
*[http://ww5.komen.org/BreastCancer/SubtypesofBreastCancer.html About breast cancer - molecular subtypes (komen.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.

External links

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