Breast pathology

The breast is an important organ for the continuance of the species and one that pathologists see quite often because it is often afflicted by cancer. Before women started smoking in large numbers, it was the number one cause of cancer death in women (in Canada).

Fortunately, breast cancer, these days, has a relatively good prognosis if it is detected early... and this is why there are week-ends to end breast cancer -- there are large numbers of breast cancer survivors that are well, wealthy and can advocate for better care and research into breast cancer.

Clinical

Classic presentation:

• Nipple discharge.
• Pain.
• Breast lump/mass.
• New nipple inversion.
• Skin changes, e.g. peau d'orange.

Most common presentation:

• Abnormal/suspicious screening mammogram - suspicious microcalcifications and/or suspicious mass.

Breast cancer screening

Breast cancer screening, for normal risk individuals, starts at age 50 in Canada. In the USA, breast screening starts at age 40.

Radiologic screening is less effective in younger individual as:

1. The breast is more dense and thus radiologically more difficult to interpret, and
2. The incidence of breast cancer is lower.

Breast radiology

BI-RADS = Breast Imaging Reporting And Data System:

• 0: Incomplete - come back for more imaging (radiologist cha-ching).
• 1: Negative.
• 2: Benign finding(s).
• 3: Probably benign -- often short follow-up.
• 4: Suspicious abnormality -- needs biopsy.
• 5: Highly suggestive of malignancy.
• 6: Pathologist says there is a malignancy.

Specimens

Breast comes in three main flavours:

1. Core needle biopsy (CNB).
2. Lumpectomy.
3. Modified radical mastectomy.

Note:

• Breast cytopathology is dealt with in the breast cytopathology article. It is almost dead, as it is not as sensitive and specific as CNB.

Core needle biopsy

Work-up of CNBs is dependent on the clinical abnormality:

1. Mass lesion - usu. obvious what is going on; typically 3 levels.
2. Calcifications - abnormality may be very small; typically 10 levels.

Lumpectomy

Lumpectomies are usually oriented with short and long suture; short is typically superior (aspect) and long is typically lateral (aspect).

Modified radical mastectomy

• Usually done with sentinel lymph node biopsy - as one cannot go back later to do this.

Normal

Resting

• Glands -- normally has two cell layers (like the prostate).
  • Myoepithelial cells
    • Frequently spindle-like, often hard to see.
  • Secretory cells.
• Stroma:
  • Not cellular.
  • Not myxoid.

May be present:

• Calcification:
  • Purple globs (with concentric rings) on H&E = calcium phosphate.
    • Q. How to remember? A. Purple = Phosphate.
  • Calcium oxalate visible with (light) polarization - not assoc. with malignancy.
  • Often in the lumen of a gland, may be in the stroma.
  • Calcific material typically has a well-demarcated border +/- "sharp corners".
  • Radiologists can pick-up calcs (calcifications) that are approximately 100 micrometers; if "calcs" is on the requisition one needs to find calcs this size.
    • The large calcs seen on radiology are approximately 1/5 - 1/6 the size of a HPF, if the field of view (FOV) is ~0.55 mm (as is the case with 22 mm-10x eye pieces and a 40x objective).

Image:

• Breast with calcifications (breastpathology.info).

Notes:

• The architecture is more important than the cytologic features in the diagnosis of malignancy in the breast; low grade tumours have distorted architecture but normal/near normal cytology.

Lactational changes

• AKA secretory change, AKA lactational adenoma.

General

• May be present focally in non-pregnant females.

ASIDE:

• Some believe lactational change and secretory change aren't the same...
  • Lactational change = only in lactation.
  • Secretory change = other times.
• This hair splitting is clinically irrelevant-- both are benign. Also, experts use the terms interchangeably.

Microscopic

Features:

• Glands dilated.
• Increased number of lobules.
  • Relative decrease in intralobular and extralobular stroma.
• Luminal cells enlarged.
  • Vacuolated cytoplasm.
  • Hobnail morphology - hang into the lumen.
• Myoepithelial cells indistinct - after second trimester.

DDx:

• Secretory carcinoma of the breast.

Images

• 

  Lactational change - low mag. (WC/Nephron)

• 

  Lactational change - high mag. (WC/Nephron)

www:

• Lactational changes (gfmer.ch).
• Lactational changes in an angiosarcoma of the breast (webpathology.com).
• Lactating breast (uwa.edu.au).

Where to start

Main articles: Short_power_list#Breast_pathology and Long_power_list#Breast_pathology

The following entities are a starting point for understanding routine breast pathology & some of challenges in breast pathology:

1. Apocrine change.
   • Pink benign cells.
2. Columnar cell change.
   • Columnar cells with blebs ("snouts") - often have calcifications (purple).
3. Fibroadenoma.
   • Abundant myxoid (light/blanched) stroma - very common.
4. Florid epithelial hyperplasia.
   • Too many cells in a duct, cells overlap & form slit-like spaces.
5. Ductal carcinoma in situ (DCIS).
   • Too many cells in a duct, nuclei do not touch - "cells are spaced".
   • Cells line-up around ovoid/circular spaces - "punch-out" appearance/"cookie cutter" look.
   • Myoepithelial cells present.
6. Invasive ductal carcinoma.
   • Bread & butter cancer - in sheets or glands.
7. Lobular carcinoma.
   • Dyscohesive cells - can easily be missed.
8. Tubular carcinoma.
   • Glands have one cell layer... but near normal appearance.

The key to breast pathology is... seeing the two cell layers (at low power). The myoepithelial layer is hard to see at times and that is the challenge.

Common diagnoses - overview

• Normal.
• Benign.
  • Columnar cell change.
    • Calcification often in lumen.
• Neoplastic.
  • Benign neoplastic:
    • Epithelial/myoepithelial - intraductal papilloma.
    • Stromal - fibroadenoma, benign phyllodes.
  • Malignant neoplastic:
    • Epithelial/myoepithelial - most common, e.g. ductal carcinoma, lobular carcinoma.
    • Breast stroma - malignant phyllodes tumour.
    • Stromal, e.g. angiosarcoma - quite rare.

A tree diagram (overview)

General classification

Breast pathology

Stromal pathology

Miscellaneous

Glandular pathology

Myxoid

Long slit-like spaces

Simple epithelium

Dilated

Cellular lesions

Fibroadenoma

Malignant features

Benign features

Tubular carcinoma

FEA, FCC, CCC

FEHUT, Neoplastic, Malignant

Malignant phyllodes

Benign phyllodes

Notes:

• The challenges in breast pathology are in: the Simple epithelium category and the Cellular lesions category.
• Neoplastic includes: ADH and LDH.
• Malignant includes: DCIS, LCIS, ductal carcinoma (DC) and lobular carcinoma (LC), some papillary lesions.
• Lobular carcinoma (a pitfall) may appear to be a stromal problem, i.e. the stroma looks too cellular.
• Miscellaneous includes rare tumours of the breast that do not fit into another category, i.e. metastases, lymphomas, melanoma, sarcomas. Skin-related pathology is dealt within the dermatologic neoplasms article. Paget disease of the breast, which may be seen in the context of malignant breast lesions, is discussed in its own article.

Cellular lesions

Cellular lesions (Glandular)

Equal spacing, punched-out

Streaming, periph. slit-like spaces.

Discohesive cells, expanded gl.

Single cells or single file

Fibrovascular cores

Ductal lesion

FEHUT

Lobular lesion

Lobular carcinoma

Papillary lesions

Two cell layers

One cell layer

<50% of gl.

>50% of gl.

Ductal non-inv. neoplasm

Ductal carcinoma

ALH

LCIS

Large extent

Small extent

DCIS

ADH

Notes:

• The largest challenge is: differentiating between the first two categories on level 2, i.e. equal spacing' vs. streaming.
• The fibrovascular cores must arise from a tuft, i.e. if they are arising directly from the wall of glands only it is likely papillary DCIS.

Papillary lesions

Papillary lesions

Myoepithelial cells present

Myoepithelial cells absent

Unremarkable papillae

Atypia or arch. abnorm. or cellular proliferation

Neoplastic cells present

Benign intraductal papilloma

High grade atypia

Low grade atypia or abnorm. arch.

Only cellular proliferation

Intracystic (encapsulated) papillary ca.

DCIS in papilloma

FEHUT in papilloma

>3 mm extent

<3 mm extent

DCIS in papilloma

ADH in papilloma

Notes:

• Adapted from Mulligan & O'Malley.
• The most important decision is the first one: myoepithelial cells present vs. absent.
• abnorm. arch. = abnormal architecture present.
• DCIS = ductal carcinoma in situ.
• FEHUT = florid epithelial hyperplasia of the usual type.
• extent refers to the size of the abnormal cell population within the papillary lesion.

Malignant lesions

Non-invasive breast cancer

Main article: Non-invasive breast cancer

This includes the in situ lesions - DCIS and LCIS.

Invasive breast cancer

Main article: Invasive breast cancer

This is includes descriptions of the usual types... and the not so common ones.

Common benign lesions

The breast has lots of benign things. Unlike the prostate, the where benign is called benign, everything has a name. It is more common among breast pathologists to sign-out things like: apocrine metaplasia (benign), columnar cell change (benign), and florid epithelial hyperplasia of the usual type (FEHUT) - instead of - benign breast tissue.

Mild epithelial hyperplasia

General

• No increased risk of malignancy.
  • Often not reported - as it has not clinical signficance.
• Has to be separated from moderate epithelial hyperplasia / florid epithelial hyperplasia.

Microscopic

Features:

• Breast glands with three or four cell layers above the basement membrane.
• Variable cells.

Note:

• No nuclear atypia.

DDx:

• Flat epithelial atypia.
• Moderate epithelial hyperplasia / florid epithelial hyperplasia.
• Atypical ductal hyperplasia.

Apocrine metaplasia

General

• Benign/not significant. Can be considered to be pretty wallpaper in the house of breast pathology.

Etiology

• Increased number of mitochondria.
  • In other body sites this has different names, e.g. Hurthle cell change (thyroid), oncocytic change (kidney - oncocytoma, thyroid).

Microscopic

Features:

• Eosinophilic cytoplasm - key feature.

Note:

• Apocrine changes, i.e. cytoplasmic eosinophilia, can appear in malignant tumours; eosinophilia doesn't make something benign.
• Apocrine snouts may be present. (???)
  • Small globules at the apical aspect of the cell (composed of cytoplasm and plasma membrane).

Images

• 

  FCC with apocrine metaplasia (right bottom of image) - high mag. (WC/Nephron).

Fibrocystic change

• Abbreviated FCC.
• AKA fibrocystic changes.

General

• Really common.
• Benign.

Microscopic

Features:

• Dilated glands - key change.
  • Glands normal: two cell layers present.
• Often seen together with apocrine metaplasia.

Images

• 

  FCC - intermed. mag. (WC/Nephron)

• 

  FCC - high mag. (WC/Nephron)

• 

  FCC - left of image - and a phyllodes tumour - very low mag. (WC/Nephron)

Columnar cell change

• Abbreviated CCC.
• AKA blunt duct adenosis.

General

• Columnar cell change is associated with (benign) calcification - key point.

Microscopic

Features:

• Secretory cells (line gland lumen) have columnar morphology.
• May have "apical snouts".
  • Blebs or round balls eosinophilic material appear to be adjacent to the cell at their luminal surface.
  • The snouts are attached to the cell-- appear as round ball only in the plane of section.
• Cytoplasm +/-eosinophilia.

DDx:

• Flat epithelial atypia (>2 cell layers).^{[citation needed]}

Image:

• Columnar cell change (webpathology.com).

Gynecomastoid hyperplasia

• AKA gynecomastia.

Main article: Gynecomastoid hyperplasia

Lesions with increased risk of malignancy

Florid epithelial hyperplasia

• AKA florid epithelial hyperplasia, abbreviated FEH.
• AKA florid epithelial hyperplasia of the usual type, abbreviated FEHUT.
• AKA epithelial hyperplasia - term should be avoid as it could lead to confusion with mild epithelial hyperplasia.

General

• Mild increased risk of malignancy ~ 1.5-2x.
• Has to be separated from mild epithelial hyperplasia.

Note:

• Moderate epithelial hyperplasia redirects to this section.
  • It is generally not separated from FEH, as the prognosis is thought to be the same.

Microscopic

Features:

• Breast glands with more than four cell layers above the basement membrane - key feature.
• Irregular cell spacing; streaming.
• Slit-like lumina, esp. at the periphery of the duct.
• No DCIS-like architecture (not cribriform, not papillary, not micropapillary, not solid).
• No nuclear atypia - usually no nucleoli.

Memory device CLEAN:

• Cell spacing is irregular, Lumina are slit-like, Extent is less than 2 mm or 2 ducts, Architecture not DCIS-like, Nuclear atypia not present.

DDx:

• Mild epithelial hyperplasia.
• Atypical ductal hyperplasia.
• Cribriform ductal carcinoma in situ

Sclerosing adenosis

General

• Can be scary... can look like ductal carcinoma.
• Derived from sclerosing (hardening) and adenosis (glandular enlargement).
  • Think scaring + lotsa glands and you're pretty close.
• Management: follow-up, no further treatment.

Microscopic

Features:

• Acini are smaller than usual and there are more of them.
  • Acini often slit-like.
• Fibrosis (scleroses) - pink on H&E surrounds the acini.
  • Can mimic a desmoplastic reaction.

Notes:

• The acini should:
  • Be in lobular arrangements, i.e. in groups (benign appearance at low power) - key feature.
  • Have two cell layers like well-behaved breast glands do.

DDx:

• Low-grade ductal carcinoma.
• Tubular adenoma of the breast.
• Adenomyoepithelioma.

Flat epithelial atypia

General

Epidemiology:

• Associated with ADH & DCIS; may represent a non-obligate precursor lesion of ADH & DCIS.
• Low risk of progression to invasive malignancy.

Management:

• Excision.

Microscopic

Features:

• "Flat" ~ three cells thick.
• Hypercellular gland -- several layers.
• Columnar cell morphology.
• +/-Apical snouts.

DDx:

• Columnar cell change.
• Columnar cell hyperplasia.
• ADH.
• Low grade DCIS.
• Apocrine cyst - granular cytoplasm.
• Tubular carcinoma - should be considered due to the association.

Molecular

• Loss of 16q.
  • Not used for diagnosis.

Complex sclerosing lesion

• AKA radial scar.

General

• The term radial scar is a misnomer. It isn't a scar. It isn't associated with prior trauma or surgery.
• May appear malignant on imaging.
• Associated with subsequent elevated risk of breast cancer.
• Management - usu. surgical excision.

Gross

• Spiculated mass.
• Usually small - 3-7 mm.

Image

• 

  Radial scar - gross. (WC)

Microscopic

Features:

• Stellate appearance (low magnification).
• Center of lesion has "fibroelastosis" - stroma light pink (on H&E) - key feature.
  • Scar like stroma with entrapped normal breast ducts and lobules.
  • Glands appear to enlarge with distance from center of lesion.

Notes:

• Histomorphologic appearance may mimic a desmoplastic reaction of the stroma - leading to a misdiagnosis of malignancy.
• "Hyaline - pink stuff on H&E - is the key."

DDx:

• Invasive ductal carcinoma - should be considered if the lesion is asymmetrical or glands are dilated centrally.

Image:

• Radial scar (breastpathology.info).

IHC

Features:

• p63 +ve.
• Calponin +ve.

Note:

• HMWK +ve/-ve. (???)

Stromal lesions

This section (below) covers stromal lesions of the breast, which vary from benign to malignant. The most common is (the benign) fibroadenoma.

Non-breast stroma stromal lesions are covered in the soft tissue lesions article. Angiosarcoma (dealt with in the vascular tumours article) is the most common (non-breast stroma) sarcoma of the breast, and classically arises after treatment for a breast carcinoma.

Fibroadenoma

Main article: Fibroadenoma

Phyllodes tumour

• Previously cystosarcoma phyllodes.

Main article: Phyllodes tumour

Pseudoangiomatous stromal hyperplasia

• Abbreviated PASH.
• AKA nodular myofibroblastic stromal hyperplasia of the mammary gland.

Main article: Pseudoangiomatous stromal hyperplasia

Weird stuff

Like in all niches of pathology... there is weird stuff.

Mammary hamartoma

• AKA breast hamartoma.

Main article: Mammary hamartoma

Collagenous spherulosis

• AKA mucinous spherulosis, AKA spherulosis.

General

• Benign.
• Almost always an incidental finding.
• Can mimic ADH, cribriform DCIS, adenoid cystic carcinoma.
  • Epidemiologically, it may be associated with LCIS.

Microscopic

Features:

• Tubular/cribriform architecture.
• Intratubular eosinophilic material - key feature.
  • Classical: Arranged like the spokes of a wheel ("radial spikes").
  • Atypical: Granules ~ 1-2 micrometers.
• No mitotic activity.
• Two cells populations (epithelial & myoepithelial) - like a well-behaved breast gland.

Notes:

• Usually small lesions: < 50 spherules per lesion, <100 micrometers.
• May be multifocal.
• +/-Calcifications - may prompt biopsy.

DDx:

• Atypical ductal hyperplasia.
• Cribriform DCIS.
• Adenoid cystic carcinoma of the breast.

Images

• 

  Collagenous spherulosis - intermed. mag. (WC/Nephron)

• 

  Collagenous spherulosis - very high mag. (WC/Nephron)

www:

• Collagenous spherulosis (stonybrook.edu).

Nipple adenoma

• AKA nipple duct adenoma.
• AKA nipple adenoma of breast.
• AKA adenoma of the nipple.
• AKA florid papillomatosis of the nipple.

General

• Rare.
• Reported in men.

Clinical DDx:

• Paget's disease of the breast.

Microscopic

Features:

• Proliferation of epithelial and myoepithelial elements that extends into the breast stroma.

Notes:

• Not encapsulated.
• Lacks true fibrovascular cores.
• Focal necrosis may be present.

DDx:

• Intraductal papilloma.
  • Found within the duct not the stroma.
  • Often deeper - one should not see skin in the histologic section.

Images

• 

  Nipple adenoma - low mag. (WC/Nephron)

• 

  Nipple adenoma - very high mag. (WC/Nephron)

www:

• Florid papillomatosis of the nipple - several images (breastpathology.info).

Intraductal papilloma

• AKA papilloma.

Main article: Intraductal papilloma

Lymphocytic mastitis

General

• If the individual has diabetes mellitus (DM) it is called diabetic mastopathy.
• Rare.

Microscopic

Features:

• Lymphocytic infiltrates - key feature:
  • Lobules.
  • Perivascular.
• Enlarged stromal fibroblasts.
• Stromal collagen with keloid-like changes.

DDx:

• Diabetic mastopathy - if individual has diabetes.
• Primary lymphoma of the breast.

Images:

• Lymphocytic mastitis - low mag. (webpathology.com).
• Lymphocytic mastitis - high mag. (webpathology.com).

IHC

• B cell predominant (CD20 > CD3).
  • B cells CD43 -ve.

Molecular

• Negative clonality studies.

Microglandular adenosis

Not to be confused with microglandular hyperplasia.

• Abbreviated MGA.

General

• Controversial thingy.

Management:

• Excision.

Microscopic

Features:

• Round glands lined by a single layer of cells.
• May extend into fat.
• Lack of desmoplastic stroma.

DDx:

• Tubular carcinoma - has apical snouts, desmoplasia among other things; see page by Collins.
• Sclerosing adenosis.

Images:

• Microglandular adenosis (surgical pathologyatlas.com).
• MGA - low mag. (webpathology.com).
• MGA - high mag. (webpathology.com).
• MGA (breastpathology.info).
• MGA - several images (breastpathology.info).

IHC

Features:

• S100 +ve.
• 34BE12 +ve -- focal!

Others:

• EMA -ve.
  • Tubular carcinoma usu. +ve.
• GCDFP-15 -ve.
• Ki-67 <3%.

Adenomyoepithelioma

General

• Rare lesion consisting of epithelial and myoepithelial elements.
  • May occur in other sites, e.g. tonsil.
• May be benign or malignant.

Note:

• Possibly the same tumour as epithelial-myoepithelial carcinoma of the salivary gland.

Microscopic

Features:

• Well-circumscribed.
• Glandular architecture with:
  • Easily identifiable myoepithelial cells - with clear cytoplasm - key feature.
  • Eosinophilic cuboidal epithelial cells.
• Eosinophilic basement membrane material between glands.

DDx:

• Invasive ductal carcinoma of the breast (on core biopsy).
• Mammary pleomorphic adenoma.
• Ductal adenoma.
• Tubular adenoma of the breast - does not have a prominent (clear) myoepithelial component.
• Sclerosing adenosis.

Images

• 

  Adenomyoepithelioma - low mag. (WC/Nephron)

• 

  Adenomyoepithelioma - high mag. (WC/Nephron)

Webpathology.com:

• Adenomyoepithelioma - low mag. (webpathology.com).
• Adenomyoepithelioma - high mag. (webpathology.com).

Mammary myofibroblastoma

Main article: Mammary myofibroblastoma

Squamous metaplasia of lactiferous ducts

• Abbreviated SMOLD.

Main article: Squamous metaplasia of lactiferous ducts

Granular cell tumour of the breast

Main article: Granular cell tumour

General

• Uncommon.

Gross

• May be a spiculated mass and thus mimic malignancy radiologically.

Microscopic

See granular cell tumour.

See also

• Breast cytopathology.
• Salivary gland.
• Invasive breast cancer.
• Non-invasive breast cancer.

External links

• A collection of breast pathology cases (breastpathology.info).
• Breast pathology (webpathology.com).