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]

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

Syndromes associated with breast cancer

Gene Syndrome Other cancers Notes
BRCA1 Familial breast and ovarian cancer[4] male breast, ovarian, prostate, pancreas, fallopian tube younger individuals vis-à-vis BRCA2
BRCA2 Familial breast and ovarian cancer 2[5] 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) sarcomas, 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 hamartomas, mucocutaneous pigmentation
PTEN Cowden syndrome breast, thyroid (PTC), endometrial, renal, colorectal -
CDH1 Familial diffuse gastric cancer[6] invasive lobular carcinoma, gastric signet ring cell carcinoma -

BRCA1 and BRCA2

BRCA1 vs. BRCA2:[7]

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, ovarian, prostate, pancreas.

How to remember types of cancer associated with BRCA2 - PUM:

  • Pharynx, upper GI (stomach, gallbladder, biliary), melanoma.

Breast IHC

Molecular classification of invasive carcinoma

A molecular classification:[8]

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.[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

Main article: 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]

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:[16][19][20]

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

ISH based testing:[19]

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

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.

General

  • Most common type of invasive breast cancer.

Microscopic

Features:

  • Atypical cells:
    • Usually >2x RBC diameter.
    • Nucleoli common.
    • Forming ducts or sheets.
    • +/-Mitoses.
    • +/-Necrosis.
  • Evidence of invasion:
    • Atypical nucleus adjacent to adipocyte - diagnostic.
    • "Infiltrative" pattern:
      • Small glands of variable size within desmoplastic stroma.
      • Glands lined by a single layer of cells.

DDx:

IHC

Myoepithelial markers - diagnostic for invasion:

  • SMMS -ve.
  • p63 -ve.

Prognostic markers - may be useful for metastates:

  • ER +ve (diffuse).
  • PR +ve (diffuse).
  • HER2 -ve.

Invasive lobular carcinoma

  • Abbreviated ILC.
  • AKA lobular carcinoma.

General

  • May be associated with a CDH1 mutation - seen in diffuse type gastric cancer.[21][6]

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."[22]

Medullary breast carcinoma

  • AKA medullary carcinoma of the breast.

General

  • Uncommon breast cancer subtype.
  • Some pathologists don't believe this exists.

Epidemiology:

  • Thought to have a better prognosis that no special type (NST).
  • May be associated with a BRCA1 mutation.

Gross

  • Well-circumscribed border.[23]

Aside - malignant well-circumscribed breast masses - radiologic DDx:[23]

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.

IHC

Features - typical:[24]

  • ER -ve.
  • PR -ve.
  • HER2 -ve.

Tubular carcinoma of the breast

  • AKA tubular carcinoma.

General

Epidemiology:

  • Typically excellent prognosis.
  • Hormone receptors commonly present (ER +ve, PR +ve).
  • Usually HER2 -ve.
  • Classically seen in post-menopausal women.

Note:

  • May be seen in association with lobular carcinoma in situ and columnar cell lesions - known as Rosen triad.[25]
    • Memory device TLC = Tubular ca., LCIS, Columnar cell lesions.

Microscopic

Features:[26][27][28]

  • Well-formed tubules.
    • Typically have angled ducts - "prows" - important feature (low power).
    • Myoepithelial cells absent - diagnostic - may be have to appreciated without IHC.
    • >70% of the tumour cells should be adjacent to lumen.[29]
  • +/- Cribriform spaces.
  • Apocrine snouts typical.
  • +/-Calcification.

Notes:

  • Prow = front of a ship.
  • Looks benign to the uninitiated -- important.

DDx:

Image:

IHC

  • ER +ve.
  • PR +ve.
  • HER2 -ve.
    • HER2 positivity should prompt consideration of another diagnosis!

Metaplastic breast carcinoma

  • AKA metaplastic carcinoma.

General

  • May be difficult to diagnose.
  • Prognosis - poor.
  • Top of the differential diagnosis for spindle cell lesions of the breast.

Microscopic

Features - one of the following:[30][31]

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

Notes:

  • Calcifications are uncommon.
  • Cytology may be very bland, i.e. it may look very benign.
  • May have minimal mitotic activity.

DDx:

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:[32]
    1. Matrix-producing carcinoma:[33]
      • Features: cartilaginous and/or osseous stromal matrix; no osteoclastic giant cells.
    2. Spindle cell carcinoma:[34]
      • Features: (non-malignant) spindle cells.
      • Prognosis: better prognosis than other metaplastic carcinomas.
    3. Carcinosarcoma:[35]
      • Features: malignant mesenchymal element.
      • Prognosis: survival worse when compared to other metaplastic carcinomas.
    4. Squamous cell carcinoma of ductal origin:[36]
      • Features: purely squamous; metastases are squamous cell carcinoma.
    5. Metaplastic carcinoma with osteoclastic giant cells:[37]
    • The WHO subclassifies as follows:[38]
    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. (???)

Invasive micropapillary carcinoma of the breast

  • AKA micropapillary carcinoma.

General

  • Poor prognosis.
  • LVI common.[39]

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".[40]

Note:

Images:

IHC

  • EMA +ve (periphery of nests); described as inside-out pattern.[40]
  • E-cadherin +ve (centre of nests). (???)
  • p63 +ve/-ve.

Apocrine carcinoma of the breast

General

  • Need >=90% apocrine morphology.[42]

Microscopic

Features:[42]

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

Images:

IHC

Smaller tumours classically:[44]

  • AR +ve.
  • GCDFP-15 +ve.

Usually:[42]

  • ER -ve.
  • PR -ve.

Mucinous breast carcinoma

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

General

  • Rare.
  • Good prognosis.[45]
  • Usually older women.

Gross

  • Pale, glistening, jelly-like appearance.
  • Well-circumscribed.

Image:

Microscopic

Features:

  • Malignant mucin producing glands.
    • Mucinous component must comprise >90% of the tumour - required for diagnosis.[46]
    • Cells should float in the mucin - key feature.
    • Glands typically have irregular edges.
    • +/-Vessels within the mucin pools.

DDx:

  • DCIS with a mucinous component.
    • Mucin has a homogenous appearance, mucin lacks vascularization, mucin pools have a regular border.

Note:

  • The amount of mucinous component to call mucinous carcinoma varies by anatomical site.
  • All mucinous lesions should be excised.[47]

IHC

  • ER +ve.
  • PR +ve.
  • HER2 -ve.

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[49] - it is similar to DCIS.
  • Classical menopausal women.
  • ~30% present with bloody discharge.[50]

Microscopic

Features:

  • Lesion confined to a duct (intraductal) or cyst (intracystic).
    • May have a thick fibrous capsule = encapsulated papillary carcinoma.[50]
  • 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.

General

Microscopic

Features:

  • Groups of cells with abundant clear cytoplasm - need to comprise 90% of the tumour.[52]
    • Various architectural arrangements: cords, trabeculae, clusters, cribriform.
    • Minimal nuclear pleomorphism.

Notes:

DDx:

Image:

Stains

Features:[52]

  • PAS +ve.
  • PASD -ve.

Others:[52]

  • Oil red O -ve.
    • Lipid-rich carcinoma +ve.

IHC

Features:[52]

  • BRST2 -ve.
    • Apocrine carcinoma +ve.

Secretory carcinoma of the breast

  • AKA secretory breast carcinoma, abbreviated SBC.

General

  • Favourable prognosis.[53]
  • Children and adults.

Microscopic

Features:[54]

  • Abundant cytoplasm with fine vacuolation - clear/pale or amphophilic.
  • Mitoses - uncommon.
  • Nucleoli - rare.
  • Architecture: solid, papillary, cribriform or microcystic.

DDx:

Images:

IHC

Triple negative (ER -ve, PR -ve, HER2 -ve).[53]

Others:

  • Alpha-lactalbumin +ve.
  • S-100 protein +ve.
  • Polyclonal CEA +ve.

Molecular pathology

Characteristic translocation:[53]

  • t(12;15).
    • ETV6-NTRK3.

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.[56] They also wrote a follow-up article in 2002.[57]

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.[58]

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.[59]
    • 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.[60]

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:[61]

  • 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:[62]

  • 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".[62] 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:[63]

  • 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:[64][65]

  • 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:[66][67]

  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.[68]

Notes:

Microscopic

Features:[68]

  • 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[69] 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.[70] The study is supported by NCI's SEER data.[71] Also, it generated many comments.[70]

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.[72]

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. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 113705
  5. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600185
  6. ↑ 6.0 6.1 Online 'Mendelian Inheritance in Man' (OMIM) 192090
  7. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1078. ISBN 978-1416031215.
  8. ↑ 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.
  9. ↑ 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.
  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 16.4 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. ↑ 19.0 19.1 Lester, Susan Carole (2010). Manual of Surgical Pathology (3rd ed.). Saunders. pp. 87. ISBN 978-0-323-06516-0.
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