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

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:

  • 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

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:

  • Cohesive cells.
    • Forming ducts or sheets.
  • Nuclear pleomorphism.
    • Nucleoli common.

IHC

Typically:

  • ER +ve.
  • PR +ve.
  • HER2 -ve.

Invasive lobular carcinoma

  • AKA 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 of the breast

  • AKA 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:

Image:

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. (???)

Invasive micropapillary carcinoma of the breast

  • AKA 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, AKA colloid carcinoma of the breast.

General

  • Rare.
  • Good prognosis.[33]

Microscopic

Features:

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

Note:

Adenoid cystic carcinoma of the breast

  • AKA breast adenoid cystic carcinoma.

General

Microscopic

See: Adenoid cystic carcinoma article.

DDx:

Images:

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.[37]
    • Arranged in cords, trabeculae or clusters.
    • Minimal nuclear pleomorphism.
  • Hyalinized stroma.

Notes:

DDx:

  • Signet-ring carcinoma.
  • Lipid-rich carcinoma.
  • Apocrine carcinoma.
  • Secretory carcinoma.

Stains

Features:[37]

  • PAS +ve.
  • PASD -ve.

Others:[37]

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

IHC

Features:[37]

  • BRST2 -ve.
    • Apocrine carcinoma +ve.

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.[38] They also wrote a follow-up article in 2002.[39]

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.[40]

Staging breast cancer

Definitions:[41]

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

Tumour:[42][43]

  • 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:[44]

  • 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:[45][46]

  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

General

  • Associated with underlying breast carcinoma.[47]

Notes:

Microscopic

Features:[47]

  • 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.[48]
    • 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.[49]

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[50] 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.[51] The study is supported by NCI's SEER data.[52] Also, it generated many comments.[51]

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.[53]

See also

References

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