Invasive breast cancer

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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]

  • Ductal - AKA no special type (NST) - 79%.
  • Lobular 10%.
  • Cribriform (tubular) 6%.
  • Mucinous (colloid) 2%.
  • Medullary 2%.
  • Papillary 1%.
  • Metaplastic <1%.

Common stromal types

Comprehensive list of invasive breast cancer subtypes

Epithelial

Counterparts of in situ lesions:

  • Invasive ductal carinoma, not otherwise specified.
  • Invasive lobular carcinoma.
  • Invasive cribriform carcinoma.
  • Invasive papillary carcinoma.
  • Invasive micropapillary carcinoma.

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:

  • Ductal adenoma.
  • Tubular adenoma.
  • Lactating adenoma.
  • Apocrine adenoma.
  • Pleomorphic adenoma.

Myoepithelial

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

Mesenchymal tumours

See: Soft tissue lesions.

Fibroepithelial tumours

Nipple lesions

Other

Familial breast cancer

BRCA1 vs. BRCA2:[3]

  • BRCA1:
    • Younger.
    • Ovarian cancer.
    • Worse types of breast cancer (e.g. triple negative breast cancer: PR-, ER-, HER2/neu-).
  • BRCA2:
  • BOTH are associated with increased risk of (memory device CPP):

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
HER2 positive ~10% ER- PR- (?) HER2+ poorly differentiated poor

The above is not applied clinically. IHC (ER, PR, HER2, EGFR, CK5/6) can reproduce the molecular groupings and has been proposed as a way to applied the classification.[5]

Subtyping breast cancer

  • DCIS vs LCIS:[6]
    • E-cadherin (+ve DCIS, -ve LCIS).
    • antibody 34betaE12 (+ve perinuclear LCIS, -ve DCIS).
    • CAM5.2 (peripheral stain = DCIS, perinuclear stain = LCIS).
      • CAM5.2 is against CK8.
    • Beta-catenin (-LCIS, +DCIS).
  • D2-40:[7][8]
    • Monoclonal antibody to podoplanin.
    • Useful to assess lymphovascular invasion.
  • ADH and DCIS:[9]
    • E-cadherin.
      • Present in most epithelial cells.
      • Lost in LCIS & invasive lobular carcinoma.
    • SMMHC (smooth muscle cell myosin heavy chain).
      • Marks myoepithelial cells.

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%.[10]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[10]
  • HER2/neu.
    • Usually negative; -ve in 70-80%.[10]
    • Positivity association with a worse prognosis.

ER & PR scoring[10]

  • 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:[10][11][12]

Score Staining intensity Cells stained (%) Membrane staining Management Percentage of cases
0 nil <10% incomplete No HER2 blocker ~60%
1+ minimum >10% incomplete No HER2 blocker ~10%
2+ weak >10% complete Needs SISH or FISH ~10%
3+ uniform staining (used to be strong) >30% (used to >10%) complete HER2 blocker ~20%

Notes 1:

  • Normal breast epithelial cells do not stain with HER2.
  • Evaluated on the invasive component.
  • SISH = silver in situ hybridization.
  • FISH = fluorescence in situ hybridization.

ISH based testing:[11]

Result Ratio criteria Gene copy number criteria
Positive >2.2 HER2/CEP17 >6.0 copies of HER2/cell
Equivocal 1.8-2.2 HER2/CEP17 4.0-6.0 copies of HER2/cell
Negative <1.8 HER2/CEP17 <4.0 copies of HER2/cell

Notes 2:

  • 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

Ductal carcinoma

  • AKA "NST" = No Specific Type.

Microscopic

Features:

  • Cohesive cells - forming ducts or in sheets.
  • Nuclear pleomorphism.

Clinical

  • Typically: ER+, PR+, HER2-.

Lobular carcinoma

General

  • May be associated with a CDH-1 mutation - seen in diffuse type gastric cancer.[13]

Microscopic

Features:

  • "Single file" - cell line-up in a row.
    • Cell should not be cohesive -- lymphoma should briefly come to mind.
      • primary lymphoma of the breast exists... but it is extremely rare.
  • NO gland formation.
    • If it forms glands... it is more likely NST.
  • May have signet ring morphology.
  • NO desmoplastic reaction, i.e. the stroma surrounding the tumour cells should look benign and undisturbed.

Note:

  • commonly have low grade nuclear features

Images:

Subclassification:

  • Classic lobular carcinoma.
    • Low nuclear grade - NO significant variation of nucleus size.
  • Pleomorphic lobular carcinoma.
    • Significant nuclear atypia.

Note: Some pathologist grade lobular carcinoma like other types and avoid the term "pleomorphic lobular carcinoma."[14]

Medullary breast carcinoma

  • AKA medullary carcinoma of the breast.

General

  • Some pathologists don't believe this exists.

Epidemiology:

  • Thought to have a better prognosis that no special type (NST).
  • Association with BRCA1 mutations.

Microscopic

Features:

  1. Lesion has well-circumscribed border.
  2. Syncytial growth pattern = clumps of cells with poorly defined cell borders.
  3. Lymphocytic infiltrate.
  4. High nuclear grade (as per Nottingham grading system).
  5. No tubule formation.

Tubular carcinoma

General

Epidemiology:

  • Typically excellent prognosis.
  • Hormone receptors commonly present.

Note:

  • May be seen in association with lobular carcinoma in situ and columnar cell lesions - known as Rosen triad.[15]
    • Memory device TLC = Tubular ca., LCIS, Columnar cell lesions.

Microscopic

Features:[16][17][18]

  • Well-formed tubules.
  • Myoepithelial cells absent.
  • +/- Cribriform spaces.
  • Apocrine snouts typical.
  • +/- Calcification.
  • Angled ducts common: "prows" - important feature (low power).
  • Looks benign to the uninitiated -- IMPORTANT.

Notes:

  • Prow = front of a ship.

DDx:

Metaplastic breast carcinoma

  • AKA metaplastic carcinoma.

General

  • May be difficult to diagnose.
  • Prognosis - poor.

Microscopic

Features - one of the following:[19][20]

  1. Malignant mesenchymal elements - either:
    1. Spindle cells.
    2. Osseous, chondroid or rhabdoid differentiation.
  2. Squamous component.

Images:

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:[21]
    1. Matrix-producing carcinoma:[22]
      • Features: cartilaginous and/or osseous stromal matrix; no osteoclastic giant cells.
    2. Spindle cell carcinoma:[23]
      • Features: (non-malignant) spindle cells.
      • Prognosis: better prognosis than other metaplastic carcinomas.
    3. Carcinosarcoma:[24]
      • Features: malignant mesenchymal element.
      • Prognosis: survival worse when compared to other metaplastic carcinomas.
    4. Squamous cell carcinoma of ductal origin:[25]
      • Features: purely squamous; metastases are squamous cell carcinoma.
    5. Metaplastic carcinoma with osteoclastic giant cells:[26]
    • The WHO subclassifies as follows:[27]
    1. Epithelial - includes: squamous cell carcinoma, adenocarcinoma with spindle cell differentiation, adenosquamous carcinoma.
    2. Mixed epithelial and mesenchymal - includes: carcinosarcoma, carcinoma with metaplasia (chondroid, osseous).

IHC

  • S100 -ve (r/o melanoma).
  • AE1/AE3 +ve (epithelial elements only).
  • CK7 +ve (epithelial elements only).
  • p63 +ve (epithelial elements only).
  • Vimentin +ve.
  • Desmin -ve.
  • EMA -ve. (???)

Micropapillary carcinoma

General

  • Poor prognosis.
  • LVI common.[28]

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".[29]

Note:

  • Ductal carcinoma commonly has clefting... but it isn't diffuse.

IHC

  • EMA +ve (periphery of nests); described as inside-out pattern.[29]
  • E-cadherin +ve (centre of nests). (???)
  • p63 +ve/-ve.

Apocrine carcinoma

General

  • Need >=90% apocrine morphology.[30]

Microscopic

Features:[30]

  • Prominent nucleoli.
  • Abundant granular eosinophilic cytoplasm.
  • Architecture like invasive ductal carcinomas no special type.

Images:

IHC

Smaller tumours classically:[32]

  • AR +ve.
  • GCDFP-15 +ve.

Usually:[30]

  • ER -ve.
  • PR -ve.

Mucinous breast carcinoma

  • AKA mucinous carcinoma of the breast.

General

  • Rare.
  • Good prognosis.[33]

Microscopic

Features:

  • Mucin producing glands.
    • Should comprise >90% of the tumour.[34]

Note:

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.[35] They also wrote a follow-up article in 2002.[36]

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.[37]

Staging breast cancer

Definitions:[38]

  • Isolated tumour cells: <=0.2 mm and <200 cells.
  • Micrometastasis: <=0.2 cm and ( >0.2 mm or >=200 cells ).

Tumour:[39][40]

  • pT1: <= 2 cm.
    • pT1mic <= 0.1 cm.
    • pT1a > 0.1 cm and <= 0.5 cm.
    • pT1b > 0.5 cm and <= 1.0 cm.
    • pT1c > 1.0 cm and <= 2.0 cm.
  • pT2: > 2 cm and <= 5 cm
  • pT3: > 5 cm.
  • pT4: chest wall or skin involvement.

Lymph nodes:[41]

  • pN0: nil.
    • pN0(i+): <=0.2 mm and <200 cells.
  • pN1: 1-3 axillary LNs or internal mammary LNs.
    • pN1mi: <=0.2 cm and ( >0.2 mm or >=200 cells ).
    • pN1a.
    • pN1b.
    • PN1c.
  • pN2 4-9 positive LNs; internal mammary LNs or axillary LNs.
  • pN3.

Lymphovascular invasion

There are famous criteria for lymphovascular invasion (LVI).

Rosen criteria for LVI:[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.

Other

Paget's disease

Main article: Paget disease of the breast

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:

Sentinel lymph node biopsy

General

  • Used for staging, positive LNs = poorer prognosis.

Notes:

  • If there is no palpable disease, there is no mortality benefit from axillary lymph node dissection, i.e. positive axillary lymph nodes can be left in situ without affecting outcome.[45]
    • 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.[46]

IHC

Some hospitals use:

  • CAM5.2 (LMWK) - to look for isolated tumour cells and small lymph node metstases.

Trivia

Tumour size and lymph node metastases

There is a paper[47] 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.[48] The study is supported by NCI's SEER data.[49] Also, it generated many comments.[48]

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.[50]

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. ↑ 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. 1133. ISBN 0-7216-0187-1.
  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. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 122. ISBN 978-0443066450.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 241-2. ISBN 978-0443066450.
  11. ↑ 11.0 11.1 Lester, Susan Carole (2010). Manual of Surgical Pathology (3rd ed.). Saunders. pp. 87. ISBN 978-0-323-06516-0.
  12. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 27 November 2011.
  13. ↑ URL: http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33006. Accessed on: 19 April 2011.
  14. ↑ MUA. Jan 22, 2009.
  15. ↑ Brandt, SM.; Young, GQ.; Hoda, SA. (May 2008). "The "Rosen Triad": tubular carcinoma, lobular carcinoma in situ, and columnar cell lesions.". Adv Anat Pathol 15 (3): 140-6. doi:10.1097/PAP.0b013e31816ff313. PMID 18434766.
  16. ↑ 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. 1146. ISBN 0-7216-0187-1.
  17. ↑ URL: http://www.bweems.com/nsj3mp2.jpg.
  18. ↑ URL: http://surgpathcriteria.stanford.edu/breast/tubularcabr/.
  19. ↑ 19.0 19.1 URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html. Accessed on: 28 November 2010.
  20. ↑ Barnes, PJ.; Boutilier, R.; Chiasson, D.; Rayson, D. (May 2005). "Metaplastic breast carcinoma: clinical-pathologic characteristics and HER2/neu expression.". Breast Cancer Res Treat 91 (2): 173-8. doi:10.1007/s10549-004-7260-y. PMID 15868445.
  21. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Reuter, Victor E; Stoler, Mark H (2009). Sternberg's Diagnostic Surgical Pathology (5th ed.). Lippincott Williams & Wilkins. pp. 328. ISBN 978-0781779425.
  22. ↑ Wargotz, ES.; Norris, HJ. (Jul 1989). "Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma.". Hum Pathol 20 (7): 628-35. PMID 2544506.
  23. ↑ Wargotz, ES.; Deos, PH.; Norris, HJ. (Aug 1989). "Metaplastic carcinomas of the breast. II. Spindle cell carcinoma.". Hum Pathol 20 (8): 732-40. PMID 2473024.
  24. ↑ Wargotz, ES.; Norris, HJ. (Oct 1989). "Metaplastic carcinomas of the breast. III. Carcinosarcoma.". Cancer 64 (7): 1490-9. PMID 2776108.
  25. ↑ Wargotz, ES.; Norris, HJ. (Jan 1990). "Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin.". Cancer 65 (2): 272-6. PMID 2153044.
  26. ↑ Wargotz, ES.; Norris, HJ. (Nov 1990). "Metaplastic carcinomas of the breast: V. Metaplastic carcinoma with osteoclastic giant cells.". Hum Pathol 21 (11): 1142-50. PMID 2227922.
  27. ↑ O'Malley, Frances P.; Pinder, Sarah E. (2006). Breast Pathology: A Volume in Foundations in Diagnostic Pathology series (1st ed.). Churchill Livingstone. pp. 214. ISBN 978-0443066801.
  28. ↑ 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.
  29. ↑ 29.0 29.1 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.
  30. ↑ 30.0 30.1 30.2 O'Malley, Frances P.; Pinder, Sarah E. (2006). Breast Pathology: A Volume in Foundations in Diagnostic Pathology series (1st ed.). Churchill Livingstone. pp. 217. ISBN 978-0443066801.
  31. ↑ O'Malley, FP.; Bane, A. (Jan 2008). "An update on apocrine lesions of the breast.". Histopathology 52 (1): 3-10. doi:10.1111/j.1365-2559.2007.02888.x. PMID 18171412.
  32. ↑ Honma, N.; Takubo, K.; Akiyama, F.; Sawabe, M.; Arai, T.; Younes, M.; Kasumi, F.; Sakamoto, G. (Aug 2005). "Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast.". Histopathology 47 (2): 195-201. doi:10.1111/j.1365-2559.2005.02181.x. PMID 16045781.
  33. ↑ Barkley, CR.; Ligibel, JA.; Wong, JS.; Lipsitz, S.; Smith, BL.; Golshan, M. (Oct 2008). "Mucinous breast carcinoma: a large contemporary series.". Am J Surg 196 (4): 549-51. doi:10.1016/j.amjsurg.2008.06.013. PMID 18809061.
  34. ↑ Dogan, E.; Aksoy, S.; Dizdar, O.; Arslan, C.; Dede, DS.; Ozisik, Y.; Altundag, K.. "Pure mucinous carcinoma of the breast: a single center experience.". J BUON 16 (3): 565-7. PMID 22006768.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ MUA. 20 January 2009.
  38. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  39. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  40. ↑ URL: http://www.cancerhelp.org.uk/type/breast-cancer/treatment/tnm-breast-cancer-staging. Accessed on: 9 July 2010.
  41. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  42. ↑ 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.
  43. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 5 August 2011.
  44. ↑ 44.0 44.1 URL: http://emedicine.medscape.com/article/1101235-diagnosis
  45. ↑ 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.
  46. ↑ URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_1107%20discussion.html. Accessed on: 28 November 2010.
  47. ↑ 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.
  48. ↑ 48.0 48.1 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.
  49. ↑ 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.
  50. ↑ 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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