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.

The world of pathology can neatly be divided into two... those that like the breast and those that don't.

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. Radical mastectomy.

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

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

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.

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 approx. 100 micrometers; if "calcs" is on the requisition one needs to find calcs this size.

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 one ought lactational change and secretory change aren't the same...
  • Lactationl 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.

Images:

• WC:
  • Lactational change - low mag. (WC).
  • Lactational change - high mag. (WC).
• www:
  • Lactational changes (gfmer.ch).
  • Lactational changes in an angiosarcoma of the breast (webpathology.com).
  • Lactating breast (uwa.edu.au).

Where to start

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. EHUT (epithelial hyperplasia of the usual type).
   • Too many cells in a duct, cells overlap & form slit-like spaces.
5. DCIS (ductal carcinoma in situ).
   • 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 classifcation

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

EHUT, 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

EHUT

Lobular lesion

Lobular carcinoma

Papillary lesions

Two cell layers

One cell layer

<50% of gl.

>50% of gl.

Ductal non-inv. neoplasm

Ductal carcinoma

LDH

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....

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

EHUT 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.
• EHUT = 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 epithelial hyperplasia of the usual type (EHUT) - instead of - benign breast tissue.

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).

Image:

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

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.

Image:

• WC:
  • FCC - intermed. mag. (WC).
  • FCC - high mag. (WC).
  • FCC - left of image - and a phyllodes tumour - very low mag. (WC).

Columnar cell change

Importance

• 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 +/-eosinophilic.

DDx:

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

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.

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 dysmoplastic 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.

Lesions with increased risk of malignancy

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.

Microscopic

Features:

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

DDx:

• Columnar cell change.
• ADH.
• Low grade DCIS.

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.

Image: Radial scar (breastpathology.info).

Notes:

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

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

General

• Very common benign finding.
• The pathology is in the stroma; so, the lesion is really a misnomer by the naming rules.
  • It ought to be called adenofibroma (as a few occasionally do), as the glandular component is benign and the stromal component lesional.

Management:

• Local excision (without a large margin).

Microscopic

Features (fibroadenoma not otherwise specified):

• Myxoid stroma -- most important feature.
  • Stroma is white/pale on H&E -- normal stroma is pink on H&E.
• Compression of glandular elements -- commonly seen.

DDx:

• Phyllodes tumour.
  • Stroma is more cellular than in fibroadenoma.
  • May have mitoses.
  • "Stromal overgrowth" large area where there is a 'loss of glands'.
  • Patients with phyllodes tumour are usually older than those with fibroadenoma.
• Sarcoma.

Notes:

1. There is stuff about intracanalicular vs. pericanalicular. It is irrelevant; there is no prognostic difference between the two.
2. Do not comment on the margin - it is irrelevant.

Phyllodes tumour vs. fibroadenoma

Histology of phyllodes:

• More cellular.
• More mitoses.
• More nuclear pleomorphism.
• Stromal overgrowth - epithelial elements absent in one low power field (x40).
• Infiltrative borders.
• Long/large slit-like spaces - key feature.
  • Small foci of long slit-like space may exist -- how much... no definition.

Epidemiology:

• Phyllodes = older patients (usually)

Tx:

• Wide excision for phyllodes vs. local excision for fibroadenoma.

Variants

Four variants are described:

1. Juvenile.
2. Complex.
3. Myxoid.
4. Cellular.

Juvenile fibroadenoma

• As the name suggests, is typically found in younger patients.
• Classic history: rapid growth.

Features (juvenile variant):

• Stromal and epithelial hyperplasia - key feature.
• Mitoses uncommon.

Myxoid fibroadenoma

• May be associated with Carney's complex.

Features:

• Myxoid stroma.

Cellular fibroadenoma

Features (cellular variant):

• Cellular.
• Mitoses.

Complex fibroadenoma

• Contain proliferative epithelium which outside and inside a fibroadenoma is associated with an increased risk of malignancy.

Features:

1. Apocrine metaplasia.
2. Cysts > 3 mm.
3. Calcification.
4. Sclerosing adenosis.

Memory devices:

• FACS: complex fibroadenoma, apocrine metaplasia, calcs & cysts, , sclerosing adenosis.
• CAMS: calcs, apocrine metaplasia, microcysts, sclerosing adenosis.

Phyllodes tumour

The name comes from the word "leaf"; with imagination or psychotropic drugs, it may look like one (the epithelial component = the veins of the leaf).

General

• Wide excision -- this differs from fibroadenoma (just local excision).
• Approximately 6% are malignant.

Gross

• Clefts, leaf-like structures - friable vis-a-vis a fibroadenoma.

Microscopic

Features:

• Large slit-like spaces.
• Cellular stroma that may be myxoid.
• +/-Mitoses.
• May have "malignant border" -- "pushing border" / "infiltrative border".

Image:

• Phyllodes tumour - very low mag. (WC).
• Phyllodes tumour - low mag. (WC).

Malignant phyllodes?

Features of malignancy:

• Stromal cellular atypia.
• Mitotic activity in 10 HPFs.
  • "HPF" is not adequately defined - see HPFitis. The authors should be spanked.
• Stromal overgrowth -- epithelial elements absent in one low power field (x40).
  • "LPF" is not adequately defined - see LPFitis. The authors should be spanked.

A comparison between benign and malignant phyllodes - adapted from Taira et al.

	Benign	Malignant
Stromal overgrowth	no	yes
Mitoses	>4/10 HPF	>=10/10 HPF
Atypia of stromal cells	<= moderate	marked

See also: Phyllodes tumour vs. fibroadenoma.

Pseudoangiomatous stromal hyperplasia

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

General

• Benign lesion.
• Thought to arise due to myofibroblast abnormality - though not well understood.

Gross

Features:

• May form mass: grey-white & firm, with well circumscribed borders.

Microscopic

Features:

• Abundant breast stromal.
• Small, complex, inter-anastomosing (blood vessel/capillary-like) channels - key feature.
  • Pseudoangiomatous = blood vessel-like.

Notes:

• May mimic angiosarcoma at low power; PASH may have the same architecture but lack nuclear atypia.

Images:

• PASH - low mag. (WC).
• PASH - intermed. mag. (WC).
• PASH - high mag. (WC).
• PASH (nature.com).

IHC

Findings:

• CD34 +ve.
• Vimentin +ve.
• Factor VIII -ve.

Weird stuff

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

Mammary hamartoma

General

• Benign.
• Disordered growth - see hamartoma.

Gross

• Well-circumscribed - key feature.

Microscopic

Features:

• Disordered arrangement of ductal and lobular structures.
• Normal arrangement of cells with in the ductal structures, i.e. myoepithelium and epithelium present.
• Variable features:
  1. Adipose tissue - predominant.
  2. Dense fibrosis tissue - predominant.
  3. Cystic glandular dilation.

Notes:

• If adipose tissue predominates; it may be labeled adenolipoma.

DDx:

• Fibroadenoma.
• Phyllodes tumour.
• Pseudoangiomatous stromal hyperplasia.
• Fibrocystic changes.

Image:

• Mammary hamartoma (breastpathology.info).

IHC

• None - it's a H&E diagnosis.

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.

Images:

• WC:
  • Collagenous spherulosis - intermed. mag. (WC).
  • Collagenous spherulosis - very high mag. (WC).
• www:
  • Collagenous spherulosis (stonybrook.edu).

Nipple adenoma

• AKA nipple duct adenoma, nipple adenoma of breast, adenoma of the nipple.

General

• Rare.

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.

DDx:

• Intraductal papilloma.

Images:

• Nipple adenoma - low mag. (WC).
• Nipple adenoma - very high mag. (WC).

Intraductal papilloma

General

• May cause nipple discharge.
• Similar to papillary hidradenoma of the vulva.

Microscopic

Features:

• True papillae - nipple-shaped structures with fibrovascular cores.
• Intraductal proliferation of epithelial and myoepithelial elements.

Notes:

• Lacks florid hyperplasia.
• May degeneration and hyalinize to form a sclerosing papilloma.

Images:

• WC:
  • Papillary hidradenoma - low mag. (WC).
  • Papillary hidradenoma - very high mag. (WC).

Diabetic mastopathy

General

• Diabetes mellitus.

Microscopic

Features:

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

Microglandular adenosis

General

• Controversial thingy.

Microscopic

Features:

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

DDx:

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

Image:

• Microglandular adenosis (surgical pathologyatlas.com).

IHC

Features:

• S100 +ve.
• 34BE12 +ve -- focal!

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 (on core biopsy).
• Mammary pleomorphic adenoma.
• Ductal adenoma.

Images:

• Webpathology.com:
  • Adenomyoepithelioma - low mag. (webpathology.com).
  • Adenomyoepithelioma - high mag. (webpathology.com).
• WC:
  • Adenomyoepithelioma - low mag. (WC).
  • Adenomyoepithelioma - high mag. (WC).

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).