Difference between revisions of "Invasive breast cancer"

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===IHC===
===IHC===
[Triple negative] breast cancer - ER, PR and HER2 negative<ref>{{Cite journal  | last1 = Azoulay | first1 = S. | last2 = Laé | first2 = M. | last3 = Fréneaux | first3 = P. | last4 = Merle | first4 = S. | last5 = Al Ghuzlan | first5 = A. | last6 = Chnecker | first6 = C. | last7 = Rosty | first7 = C. | last8 = Klijanienko | first8 = J. | last9 = Sigal-Zafrani | first9 = B. | title = KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. | journal = Mod Pathol | volume = 18 | issue = 12 | pages = 1623-31 | month = Dec | year = 2005 | doi = 10.1038/modpathol.3800483 | PMID = 16258515 }}</ref>
*[Triple negative] breast cancer - ER, PR and HER2 negative<ref>{{Cite journal  | last1 = Azoulay | first1 = S. | last2 = Laé | first2 = M. | last3 = Fréneaux | first3 = P. | last4 = Merle | first4 = S. | last5 = Al Ghuzlan | first5 = A. | last6 = Chnecker | first6 = C. | last7 = Rosty | first7 = C. | last8 = Klijanienko | first8 = J. | last9 = Sigal-Zafrani | first9 = B. | title = KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. | journal = Mod Pathol | volume = 18 | issue = 12 | pages = 1623-31 | month = Dec | year = 2005 | doi = 10.1038/modpathol.3800483 | PMID = 16258515 }}</ref>
[Basal-like] breast cancer - p63 and CK5/6 positive
*[Basal-like] breast cancer - p63 and CK5/6 positive<ref>{{Cite journal  | last1 = Azoulay | first1 = S. | last2 = Laé | first2 = M. | last3 = Fréneaux | first3 = P. | last4 = Merle | first4 = S. | last5 = Al Ghuzlan | first5 = A. | last6 = Chnecker | first6 = C. | last7 = Rosty | first7 = C. | last8 = Klijanienko | first8 = J. | last9 = Sigal-Zafrani | first9 = B. | title = KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. | journal = Mod Pathol | volume = 18 | issue = 12 | pages = 1623-31 | month = Dec | year = 2005 | doi = 10.1038/modpathol.3800483 | PMID = 16258515 }}</ref>
CD117 positive
CD117 positive<ref>{{Cite journal  | last1 = Azoulay | first1 = S. | last2 = Laé | first2 = M. | last3 = Fréneaux | first3 = P. | last4 = Merle | first4 = S. | last5 = Al Ghuzlan | first5 = A. | last6 = Chnecker | first6 = C. | last7 = Rosty | first7 = C. | last8 = Klijanienko | first8 = J. | last9 = Sigal-Zafrani | first9 = B. | title = KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. | journal = Mod Pathol | volume = 18 | issue = 12 | pages = 1623-31 | month = Dec | year = 2005 | doi = 10.1038/modpathol.3800483 | PMID = 16258515 }}</ref>


DDx:  
DDx:  

Revision as of 07:18, 28 March 2015

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

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==[7]

  • Overview
    • 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 carcinomas
    • Metaplastic carcinomas
    • 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 ==[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
    • 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.
    • BCL11A overexpression recently identified as an oncogenic driver in this group [9]

Immunostains for typing and diagnosis

DCIS versus LCIS

Tabular comparison for DCIS versus LCIS:[10][11]

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:[12]

Stain Location Notes
p63 nuclear up to 10% of invasive tumours +ve[13]
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

Usual ductal hyperplasia versus ductal carcinoma in situ

Markers for UDH versus DCIS:[13]

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

Lymphovascular invasion

  • D2-40 - marks the lymphatic spaces.[14][15]
  • CD31 - marks lymphovascular spaces.
  • CD34 - marks lymphovascular spaces, less specific than CD31.

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).
    • Positive in most breast cancers; +ve in ~75-80%.[16]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[16]
  • HER2/neu (HER2).
    • Usually negative; -ve in 70-80%.[16]
    • Positivity associated with a worse prognosis.
    • In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.[17][18]

Note:

  • Male breast cancer is usually hormone receptor positive (~97%), and HER2 positivity is quite rare (~6%).[19]

ER & PR scoring

Nuclear staining:[16]

  • 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:[20][21]

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%.[20]

ISH based testing:[22]

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.

Invasive lobular carcinoma

  • Abbreviated ILC.
  • AKA lobular carcinoma.

Medullary breast carcinoma

  • AKA medullary carcinoma of the breast.

Tubular carcinoma of the breast

  • AKA tubular carcinoma.

Metaplastic breast carcinoma

  • AKA metaplastic carcinoma.

Invasive micropapillary carcinoma of the breast

  • AKA micropapillary carcinoma.

General

  • Poor prognosis.
  • LVI common.[23]

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".[24]

Note:

Images:

IHC

  • EMA +ve (periphery of nests); described as inside-out pattern.[24]
  • E-cadherin +ve (centre of nests). (???)
  • p63 +ve/-ve.

Apocrine carcinoma of the breast

Mucinous breast carcinoma

  • AKA mucinous carcinoma of the breast, AKA colloid carcinoma of the breast.

Adenoid cystic carcinoma of the breast

  • AKA breast adenoid cystic carcinoma.

General

Microscopic

See: Adenoid cystic carcinoma article.

IHC

  • [Triple negative] breast cancer - ER, PR and HER2 negative[27]
  • [Basal-like] breast cancer - p63 and CK5/6 positive[28]

CD117 positive[29]

DDx:

Images

Other Resources

Pathology Outlines [1]

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[30] - it is similar to DCIS.
  • Classical menopausal women.
  • ~30% present with bloody discharge.[31]

Microscopic

Features:

  • Lesion confined to a duct (intraductal) or cyst (intracystic).
    • May have a thick fibrous capsule = encapsulated papillary carcinoma.[31]
  • Loss of myoepithelial cells - key feature.
  • Neoplastic epithelial cells:

DDx:

IHC

  • Loss of myoepithelial markers within the lesion.

Glycogen-rich clear cell carcinoma of the breast

  • Abbreviated GRCC.

Secretory carcinoma of the breast

  • AKA secretory breast carcinoma, abbreviated SBC.

Grading breast cancer

Most common system: Nottingham (aka Scarff-Bloom-Richardson) which is based on:

  1. Nuclear grade.
    • Small, regular (1.5-2x RBC dia.) = 1.
    • Moderated variability = 2.
    • Marked variation (>2.5x RBC dia.) = 3.
  2. Tubule formation.
    • Majority of tumour - tubules >75% = 1.
    • Moderate - 10% to 75% = 2.
    • Minimal <10% = 3.
  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.[32] They also wrote a follow-up article in 2002.[33]

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.[34]

Staging breast cancer

Sentinel lymph node sampling in breast cancer

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.[35]
    • 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.[36]

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:[37]

  • 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:[38]

  • 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".[38] 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:[39]

  • 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:[40][41]

  • 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

In the context of breast pathology, the Rosen criteria for LVI are widely excepted, and are as follows:[42][43]

  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

General

  • Associated with underlying breast carcinoma.[44]

Notes:

Microscopic

Features:[44]

  • 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[45] 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.[46] The study is supported by NCI's SEER data.[47] Also, it generated many comments.[46]

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.[48]

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. 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.
  10. 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.
  11. 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.
  12. Lester, Susan Carole (2010). Manual of Surgical Pathology (3rd ed.). Saunders. pp. 88. ISBN 978-0-323-06516-0.
  13. 13.0 13.1 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.
  14. 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.
  15. 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.
  16. 16.0 16.1 16.2 16.3 Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 241-2. ISBN 978-0443066450.
  17. 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.
  18. 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.
  19. 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.
  20. 20.0 20.1 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.
  21. URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed on: October 7, 2014.
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