Invasive breast cancer: Difference between revisions

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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>


Basal-like breast cancer  
Basal-like breast cancer  


*Overview  
*Overview  
**A type of breast cancer that is defined by expression of basal markers (CK14, p63, calponin, SMA)
**A type of breast cancer defined by gene expression profiling
**Can be identified by expression of basal markers (CK14, p63, calponin, SMA)
**Not derived from myoepithelial cells, merely express a phenotype more in keeping with basal cells than ductal cells
**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  
**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 BRCA mutation  
**There is an association in young women between basal-like breast cancer and BRCA mutation.
**Sporadic basal-like cancers do not have a BRCA mutation but may have a dysfunctional BRCA1 pathway.


*Classic Morphological clues:
*This molecular group includes a variety of morphologic phenotypes including:
**High grade invasive ductal mammary carcinoma of no special type.
**Medullary-like mammary carcinoma (a carcinoma with some but not all the features of medullary carcinoma).
**Medullary mammary carcinomas
**Metaplastic mammary carcinomas
**Mammary adenoid cystic carcinoma
**Secretory mammary carcinoma
 
*Classic morphological clues of a basal type cancer usually refer to medullary carcinoma features:
**Relatively circumscribed  
**Relatively circumscribed  
**Geographic necrosis  
**Geographic necrosis  
**Abundant mitoses
**Abundant mitoses
 
**Pushing margins
*However, this molecular group includes a variety of phenotypes including:
**Central fibrosis or necrosis
**Medullary carcinomas
**High histological grade
**Medullary-like carcinomas - tumors with some, but not all, the histologic features of medullary carcinomas
**Exceptionally high mitotic rate
**Metaplastic carcinomas
**Pushing borders
**High grade invasive ductal carcinoma of no special type
**Conspicuous lymphocytic infiltrate


*Behaviour  
*Behaviour  
**Basal-like breast cancer is a heterogeneous group  
**Basal-like breast cancer is a heterogeneous group.
**The behaviour of basal-like breast cancer appears to fall into two groups:
**The behaviour of basal-like breast cancer appears to fall into two groups:
***The tumours that do not metastasise have a better prognosis than other grade 3 IDC
***The tumours that do not metastasise have a better prognosis than other grade 3 IDC
***Tumours with early metastasis – greater tendency to metastasise to visceral sites associated with poorer prognosis (such as lung and brain)  instead of to nodes and bone
***Tumours with early metastasis
****Hematogenous spread -greater tendency to metastasise to visceral sites associated with poorer prognosis (such as lung and brain)  instead of to nodes and bone


Triple Negative Breast Carcinomas
Triple Negative Breast Carcinomas
**Triple-negative and basal-like phenotypes are not synonymous but overlap (60–90% of triple-negative tumours are basal-like)
**About 15% of breast carcinomas.
**The classic phenotype of a triple negative tumor includes high histological grade (particularly high mitotic count), circumscribed edge, central fibrosis, necrosis, prominent lymphocytic infiltrate, syncytial growth and spindle cells.
**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 are.
**Classic morphological clues of a basal type cancer usually refer to medullary carcinoma features.


==Immunostains for typing and diagnosis==
==Immunostains for typing and diagnosis==

Revision as of 10:52, 20 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

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]

Basal-like breast cancer

  • Overview
    • A type of breast cancer defined by gene expression profiling
    • Can be identified by expression of 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 BRCA mutation.
    • Sporadic basal-like cancers do not have a BRCA mutation but may have a dysfunctional BRCA1 pathway.
  • This molecular group includes a variety of morphologic phenotypes including:
    • High grade invasive ductal mammary carcinoma of no special type.
    • Medullary-like mammary carcinoma (a carcinoma with some but not all the features of medullary carcinoma).
    • Medullary mammary carcinomas
    • Metaplastic mammary carcinomas
    • Mammary adenoid cystic carcinoma
    • Secretory mammary 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 do not metastasise have a better prognosis than other grade 3 IDC
      • Tumours with early metastasis
        • Hematogenous spread -greater tendency to metastasise to visceral sites associated with poorer prognosis (such as lung and brain) instead of to nodes and bone

Triple Negative Breast Carcinomas

    • 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 are.
    • Classic morphological clues of a basal type cancer usually refer to medullary carcinoma features.

Immunostains for typing and diagnosis

DCIS versus LCIS

Tabular comparison for DCIS versus LCIS:[6][7]

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:[8]

Stain Location Notes
p63 nuclear up to 10% of invasive tumours +ve[9]
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:[9]

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.[10][11]
  • 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%.[12]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[12]
  • HER2/neu (HER2).
    • Usually negative; -ve in 70-80%.[12]
    • Positivity associated with a worse prognosis.
    • In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.[13][14]

Note:

  • Male breast cancer is usually hormone receptor positive (~97%), and HER2 positivity is quite rare (~6%).[15]

ER & PR scoring

Nuclear staining:[12]

  • 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:[16][17]

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%.[16]

ISH based testing:[18]

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.

General

  • Poor prognosis.
  • LVI common.[19]

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".[20]

Note:

Images:

IHC

  • EMA +ve (periphery of nests); described as inside-out pattern.[20]
  • E-cadherin +ve (centre of nests). (???)
  • p63 +ve/-ve.

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.

General

Microscopic

See: Adenoid cystic carcinoma article.

DDx:

Images:

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[23] - it is similar to DCIS.
  • Classical menopausal women.
  • ~30% present with bloody discharge.[24]

Microscopic

Features:

  • Lesion confined to a duct (intraductal) or cyst (intracystic).
    • May have a thick fibrous capsule = encapsulated papillary carcinoma.[24]
  • 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.
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

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.[25] They also wrote a follow-up article in 2002.[26]

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.[27]

Staging breast cancer

Sentinel lymph node sampling in breast cancer

Main articles: Sentinel lymph node and 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.[28]
    • 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.[29]

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:[30]

  • 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:[31]

  • 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".[31] 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:[32]

  • 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:[33][34]

  • 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

Main article: Lymphovascular invasion

In the context of breast pathology, the Rosen criteria for LVI are widely excepted, and are as follows:[35][36]

  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.[37]

Notes:

Microscopic

Features:[37]

  • 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[38] that calculates the probability of lymph node mets based on tumour size. The developed formula is:

LTo−Nodes=1−exp(−QnDZ)

Where:

  • LTo−Nodes = the probability of the lymph nodes being positive.
  • D = the largest dimension of the tumour in millimetres.
  • Z = 1.0041.
  • Qn = 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.[39] The study is supported by NCI's SEER data.[40] Also, it generated many comments.[39]

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.[41]

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. ↑ 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.
  7. ↑ 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.
  8. ↑ Lester, Susan Carole (2010). Manual of Surgical Pathology (3rd ed.). Saunders. pp. 88. ISBN 978-0-323-06516-0.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 12.2 12.3 Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 241-2. ISBN 978-0443066450.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed on: October 7, 2014.
  18. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/breast_biomarker_template.pdf. Accessed on: October 7, 2014.
  19. ↑ Yu, JI.; Choi, DH.; Park, W.; Huh, SJ.; Cho, EY.; Lim, YH.; Ahn, JS.; Yang, JH. et al. (Jun 2010). "Differences in prognostic factors and patterns of failure between invasive micropapillary carcinoma and invasive ductal carcinoma of the breast: matched case-control study.". Breast 19 (3): 231-7. doi:10.1016/j.breast.2010.01.020. PMID 20304650.
  20. ↑ 20.0 20.1 Yamaguchi, R.; Tanaka, M.; Kondo, K.; Yokoyama, T.; Kaneko, Y.; Yamaguchi, M.; Ogata, Y.; Nakashima, O. et al. (Aug 2010). "Characteristic morphology of invasive micropapillary carcinoma of the breast: an immunohistochemical analysis.". Jpn J Clin Oncol 40 (8): 781-7. doi:10.1093/jjco/hyq056. PMID 20444748.
  21. ↑ URL: http://www.breast-cancer.ca/type/micropapillary-breast-carcinoma.htm. Accessed on: 30 May 2012.
  22. ↑ 22.0 22.1 Boujelbene, N.; Khabir, A.; Boujelbene, N.; Jeanneret Sozzi, W.; Mirimanoff, RO.; Khanfir, K. (Dec 2011). "Clinical review - Breast adenoid cystic carcinoma.". Breast. doi:10.1016/j.breast.2011.11.006. PMID 22154460.
  23. ↑ Rakha, EA.; Gandhi, N.; Climent, F.; van Deurzen, CH.; Haider, SA.; Dunk, L.; Lee, AH.; Macmillan, D. et al. (Aug 2011). "Encapsulated papillary carcinoma of the breast: an invasive tumor with excellent prognosis.". Am J Surg Pathol 35 (8): 1093-103. doi:10.1097/PAS.0b013e31821b3f65. PMID 21753694.
  24. ↑ 24.0 24.1 Rodríguez, MC.; Secades, AL.; Angulo, JM. (Nov 2010). "Best cases from the AFIP: intracystic papillary carcinoma of the breast.". Radiographics 30 (7): 2021-7. doi:10.1148/rg.307105003. PMID 21057133.
  25. ↑ Elston CW, Ellis IO (September 2002). "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". Histopathology 41 (3A): 151–2, discussion 152–3. PMID 12405945.
  26. ↑ Elston CW, Ellis IO (November 1991). "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". Histopathology 19 (5): 403–10. PMID 1757079.
  27. ↑ MUA. 20 January 2009.
  28. ↑ Giuliano AE, Hunt KK, Ballman KV, et al. (February 2011). "Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial". JAMA 305 (6): 569–75. doi:10.1001/jama.2011.90. PMID 21304082.
  29. ↑ URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_1107%20discussion.html. Accessed on: 28 November 2010.
  30. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 2 April 2012.
  31. ↑ 31.0 31.1 URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  32. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  33. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  34. ↑ URL: http://www.cancerhelp.org.uk/type/breast-cancer/treatment/tnm-breast-cancer-staging. Accessed on: 9 July 2010.
  35. ↑ 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.
  36. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 5 August 2011.
  37. ↑ 37.0 37.1 URL: http://emedicine.medscape.com/article/1101235-diagnosis
  38. ↑ 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.
  39. ↑ 39.0 39.1 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.
  40. ↑ 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.
  41. ↑ Weaver, DL.; Ashikaga, T.; Krag, DN.; Skelly, JM.; Anderson, SJ.; Harlow, SP.; Julian, TB.; Mamounas, EP. et al. (Feb 2011). "Effect of occult metastases on survival in node-negative breast cancer.". N Engl J Med 364 (5): 412-21. doi:10.1056/NEJMoa1008108. PMID 21247310.

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