Invasive breast cancer

Breast cancer at cut-up. (WC/John Hayman)

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:

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

Common stromal types

• Malignant phyllodes tumour.
• Angiosarcoma - post-radiation ~ 10 years.

Good prognosis subtypes

Three good prognosis subtypes:

• Tubular carcinoma.
• Mucinous carcinoma.
• Papillary carcinoma.

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:

• Tubular carcinoma.
• Medullary carcinoma.
• Mucinous carinoma.
• Metaplastic carcinoma.
• Neuroendocrine tumour.
• Apocrine carcinoma.
• Lipid-rich carcinoma.
• Secretory carcinoma.
• Oncocytic carcinoma.
• Glycogen-rich clear cell carcinoma.

Epithelial tumours seen in the salivary gland:

• Adenoid cystic carcinoma of the breast.
• Acinic cell carcinoma.
• Carcinoma ex pleomorphic adenoma.

Seen in the skin:

• Sebaceous carcinoma.

Clinically diagnosed:

• Inflammatory carcinoma.

In situ lesions:

• Ductal carcinoma in situ.
• Lobular carcinoma in situ.

Proliferative lesions:

• Usual ductal hyperplasia.
• Flat epithelial atypia.
• Atypical ductal hyperplasia.

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

• Fibroadenoma.
• Phyllodes tumour.
• Periductal stromal sarcoma, low grade.
• Mammary hamartoma.

Nipple lesions

• Nipple adenoma.
• Syringomatous adenoma.
• Paget disease of the breast.

Other

• Lymphoma.
• Metastasis.

Familial breast cancer

Main article: Hereditary breast cancer

Breast IHC

Molecular classification of invasive carcinoma

A molecular classification:

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

A newer classification outlines 10 subtypes based on molecular drivers identified by analysis of genomic and transcriptomic data from 2,000 breast tumors.

Basal-like breast carcinoma

• Overview:
  • A category of breast carcinomas defined by gene expression profiling.
  • Not used in clinical practice.
  • Somewhere between 15-30% of breast carcinomas.
  • Can be roughly be identified by immunohistochemistry - 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 BRCA1 mutation.
  • Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
  • Increased incidence in some populations - African-Americans, young women
  • Sporadic basal-like cancers do not have a BRCA1 mutation but may have a dysfunctional BRCA1 pathway.
  • p53 mutations are frequent.

• This molecular group includes a variety of morphologic phenotypes including:
  • High grade invasive ductal carcinoma of no special type.
  • Medullary-like carcinoma (a carcinoma with some but not all the features of medullary carcinoma).
  • Medullary carcinoma
  • Metaplastic carcinoma.
  • Adenoid cystic carcinoma.
  • Secretory 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 are by nature low grade (ie adenoid cystic carcinoma) and/or do not metastasise have a better prognosis than other types of breast carcinoma.
    • The tumours with early metastasis that may behave more aggressively
      • Hematogenous spread -greater tendency to metastasise to visceral sites (notably lung and brain) instead of to nodes and bone.
  • Many have a complete response to chemotherapy and survival rates similar to typical breast cancer
  • Non-complete response to chemotherapy is associated with low survival at 5 years.

Other sources Minireview: Basal-Like Breast Cancer: From Molecular Profiles to Targeted Therapies <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035993/>

Triple Negative Breast Carcinoma

Features:

• • A category of breast carcinomas defined by immunohistochemical/FISH expression of ER, PR and HER2.
  • Important to identify in clinical practice.
  • About 15% of breast carcinomas.
  • Important group due to a lack of tailored therapies for this group
    • Some triple negatives also express androgen receptor and have and [apocrine carcinoma] morphology.
      • May respond to therapies targeting the androgen receptor.
    • BCL11A overexpression recently identified as an oncogenic driver for some triple negatives
      • Targeted therapies may include inhibitors of BCL11A.
  • 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.
  • Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
  • Classic 'morphological clues' to a triple negative cancer usually refer to medullary carcinoma features.

Immunostains for typing and diagnosis

DCIS versus LCIS

Tabular comparison for DCIS versus LCIS:

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:

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

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.
• CD31 - marks lymphovascular spaces.
• CD34 - marks lymphovascular spaces, less specific than CD31.

Treatment-related markers - overview

• Immunostaining of sentinel lymph nodes to look for isolated tumour cells and small lymph node mets.
  • CAM5.2 may be used.
  • Not done routinely.
• 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 (HER2).
  • Usually negative; -ve in 70-80%.
  • Positivity associated with a worse prognosis.
  • In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.

Note:

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

ER & PR scoring

Nuclear staining:

• 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:

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%.

ISH based testing:

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.

Main article: Invasive micropapillary carcinoma of the breast

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.

Main article: Adenoid cystic carcinoma of the breast

Intracystic papillary breast carcinoma

• AKA encapsulated or encysted papillary carcinoma of the breast, abbreviated EPC.

Main article: Intracystic papillary breast carcinoma

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

Invasive cribriform carcinoma of the breast

Main article: Invasive cribriform carcinoma of the breast

Invasive papillary carcinoma of the breast

Main article: Invasive papillary carcinoma of the breast

• Should not be confused with the indolent behaving intracystic papillary carcinoma of the breast, also known as encapsulated papillary 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. 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.
  • 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.

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.
  • 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.

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. ===Indications for lymph node sampling===

• 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:

• 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". 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:

• 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:

• 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:

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.

Notes:

• Unrelated to Paget disease of the bone.

Microscopic

Features:

• Cells in the epidermis:
  • 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).

IHC & DDx:

• See Paget disease.

Trivia

Tumour size and lymph node metastases

There is a paper that calculates the probability of lymph node mets based on tumour size. The developed formula is:

$L_{To-Nodes}=1-exp(-Q_{n}D^{Z})$

Where:

• $L_{To-Nodes}$ = the probability of the lymph nodes being positive.
• D = the largest dimension of the tumour in millimetres.
• Z = 1.0041.
• $Q_{n}$ = 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. The study is supported by NCI's SEER data. Also, it generated many comments.

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.

See also

• Breast.
• Non-invasive breast cancer.

External links

• CAP protocols/checklists (cap.org).
  • Invasive breast cancer - checklist (cap.org).
• About breast cancer - molecular subtypes (komen.org).