Invasive breast cancer

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.

Types of invasive breast cancer

• Ductal also known as no specific type (NST) - 79%,  ???includes DCIS???
• Lobular 10%,
• Cribriform (tubular) 6%,
• Mucinous (colloid) 2%,
• Medullary 2%,
• Papillary 1%,
• Metaplastic <1%

Ref.:

Standard IHC work-up

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

ER & PR scoring

• 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

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+	strong	>10%	complete	HER2 blocker	~20%

Notes:

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

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

AKA "NST" = No Specific Type.

Micro.

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

Clinical

• Typically: ER+, PR+, HER2-.

Lobular

• "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

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."

Medullary carcinoma

• Some pathologists don't believe this exists.

Epidemiology:

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

Histol.

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

Epidemiology

• Typically excellent prognosis.
• Hormone receptors commonly present.

Microscopic

Features:

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

ASIDE: prow = front of a ship.

DDx:

• benign sclerosing lesion

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. They also wrote a follow-up article in 2002.

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.

• As someone that studied engineering, I have the impression many pathologists have difficulty with the concept of sampling when mathematics is involved. 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.

Staging breast cancer

Definitions:

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

Tumour:

• pT1: <= 2 cm
• pT2: < 2 cm and <= 5 cm
• pT3: > 5 cm.
• pT4: chest wall or skin involvement.

Lymph nodes:

• 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.

Breast IHC

• DCIS vs LCIS:
  • 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:
  • Monoclonal antibody to podoplanin.
  • Useful to assess lymphovascular invasion.

• ADH and DCIS:
  • E-cadherin.
    • Present in most epithelial cells.
    • Lost in LCIS & invasive lobular carcinoma.
  • SMMHC (smooth muscle cell myosin heavy chain).
    • Marks myoepithelial cells.

Paget's disease

General

• Cells in the epithelium, i.e. skin, that look like they don't belong.
• Associated with underlying breast carcinoma.

Note:

• Extra-mammary Paget's disease is not assoc. with malignancy.

Microscopic

Features:

• Epitheliod morphology (round/ovoid).
• Cells nested or single.
• Clear/pale cytoplasm key feature - may also be eosinophilic.
• Large nucleoli.

Images:

• Paget's disease - low mag. (WC).
• Paget's disease - high mag. (WC) .

DDx

• Benign Toker cell hyperplasia.
• Malignant melanoma.
• Bowen disease.

• Nipple duct adenoma (clinical DDx).

IHC

Panel:

• S-100 -ve, HMB-45 -ve (both typically +ve in melanoma).
• CK7 +ve
• CEA +ve (-ve in Bowen's disease, -ve in Toker cells).

Additional:

• HER2/neu - usually +ve.
• CK5/6 -ve.
  • Usu. +ve in squamous cell carcinoma.

Familial breast cancer

BRCA1 vs. BRCA2:

• BRCA1:
  • Younger.
  • Ovarian cancer.
  • Worse types of breast cancer (e.g. triple negative breast cancer: PR-, ER-, HER2/neu-).
• BRCA2:
  • Older.
  • Like sporatic.
  • Male breast cancer.
• BOTH associated with increased risk of:
  • Prostate.
  • Pancreas.
  • Colon cancer.

Sentinel lymph node biopsy

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

See also

• Breast.
• Non-invasive breast cancer.