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.

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.
• 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

Syndromes associated with breast cancer

Gene	Syndrome	Other cancers	Notes
BRCA1	Familial breast and ovarian cancer	male breast, ovarian, prostate, pancreas, fallopian tube	younger individuals vis-à-vis BRCA2
BRCA2	Familial breast and ovarian cancer 2	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	invasive lobular carcinoma, gastric signet ring cell carcinoma	-

BRCA1 and BRCA2

BRCA1 vs. BRCA2:

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:

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.

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 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 (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	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:

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.

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.

General

• May be difficult to diagnose.
• Prognosis - poor.
• Top of the differential diagnosis for spindle cell lesions of the breast.^{[citation needed]}

Microscopic

Features - one of the following:

1. Malignant mesenchymal elements - either:
   1. Spindle cells.
   2. Osseous, chondroid or rhabdoid differentiation.
2. Squamous component.
   • Non-skin squamous cell carcinoma of the breast = metaplastic breast carcinoma.

Notes:

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

DDx:

• Fibromatosis.
• Malignant phyllodes tumour.
• Primary mammary sarcoma.
• Mammary myofibroblastoma.
• Nodular fasciitis.
• Squamous cell carcinoma of the skin.

Images:

• Metaplastic carcinoma (breastpathology.info).
• Metaplastic carcinoma - case 1 - several images (upmc.edu).
• Metaplastic carcinoma - case 2 - several images (upmc.edu).

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

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".

Note:

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

Images:

• Invasive micropapillary carcinoma (flickr.com/euthman).
• Invasive micropapillary carcinoma - crappy image (breast-cancer.ca).

IHC

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

Apocrine carcinoma of the breast

General

• Need >=90% apocrine morphology.

Microscopic

Features:

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

Images:

• Apocrine carcinoma (upmc.edu).

IHC

Smaller tumours classically:

• AR +ve.
• GCDFP-15 +ve.

Usually:

• ER -ve.
• PR -ve.

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.

General

• Like tumour of the salivary gland.
• Very rare <0.1% of breast malignancies.
• Good prognosis.

Microscopic

See: Adenoid cystic carcinoma article.

DDx:

• Cribriform DCIS.
• Collagenous spherulosis.

Images:

• Adenoid cystic carcinoma of the breast (upmc.edu).

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

Microscopic

Features:

• Lesion confined to a duct (intraductal) or cyst (intracystic).
  • May have a thick fibrous capsule = encapsulated papillary carcinoma.
• Loss of myoepithelial cells - key feature.
• Neoplastic epithelial cells:
  • Nuclear atypia - including: nucleoli, nuclear pleomorphism.
  • Abnormal architecture - including cribriform, solid, micropapillary, papillary.

DDx:

• Intraductal papilloma.

IHC

• Loss of myoepithelial markers within the lesion.

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

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.

Indictionas for lymph node sampling

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).