B3 LESIONS: What the pathologist needs to knowELENA PROVENZANOLEAD BREAST HISTOPATHOLOGISTCAMBRIDGE BREAST UNIT

What are B3 lesions? Precursor lesions

Flat Epithelial Atypia Atypical Intraductal Epithelial Proliferations (ADH) Lobular in situ neoplasia (LCIS and ALH)

Lesions with risk of associated malignancy Papillary lesions Radial scars/ complex sclerosing lesions

Cellular fibroepithelial lesions and rarer spindle cell lesions; fibromatosis, myofibroblastoma, vascular lesions

Columnar Cell Lesions

Spectrum of lesions, consisting of columnar epithelial cells lining variably dilated TDLUs

Oval nuclei orientated perpendicular to the basement membrane

No atypia Associated with other benign

changes including fibrocystic change

Flat Epithelial Atypia (FEA)

= columnar cell change with atypia Cells lack polarity Mild atypia similar to low grade

DCIS – round uniform nuclei (monotonous)

NO architectural complexity NO high grade atypia = flat DCIS

Differential diagnosis• CCC v FEA• Low power clues

– CCC often has an undulating outline compared with rigid glandular spaces in FEA

– Nuclear hyperchromasia in FEA, glands look bluer

Why are CCL important?

Diagnosis rate of CCL has increased since the introduction of digital mammography, the majority presenting with microcalcifications

5% of calcifications on screen-filmed versus 11% of calcifications on digital mammography

Verschuur-Maes et al., Modern Pathology 2011;24:1191-7

CCL in 42% of 100 consecutive bxs for microcalcifications Calcifications in CCL in 74% Fraser JL et al. Am J Surg Pathol.1998;22:1521-7

Long term follow up of FEA – low risk of invasive cancer

25 low grade “clinging carcinoma” from 80 DCIS from 9,446 biopsies originally diagnosed as benign

Mean F-U 17.5 years - No invasive recurrencesEusebi V. Semin Diagn Pathol 1994;11:223-35

EORTC 10853 DCIS trial –59 low grade ‘clinging’ carcinoma - no recurrences after median FU of 5.4 years

84 cases of FEA alone on excision followed up for 10 yrs – NO subsequent cancers. DeMascarel . Virchows Arch 2007;451:1-10.

Dutch series of 259 patients with 8 years follow up….. 9 invasive cancers (3.5%), however 3 contralateral CCL without atypia – 2% risk of progression FEA & ADH – 16% risk of progression (ipsilateral events)

Vershuur-Maes et al. Int J Cancer 2011; 129:2674-80

ADH An epithelial proliferation with some but not all

the features of low grade DCIS. Architectural atypia; bars, roman arches,

cribriform spaces and micropapillaryprojections

Monomorphic cell population that is evenly spaced with distinct cell borders

Limited size – complete involvement of ≤ 2 duct spaces or < 2 mm, or partial involvement of multiple spaces

As cannot assess extent on CB use alternative terms such as ‘atypical intraductal epithelial proliferation’

Architectural Atypia = ADH

Upgrade rates on CBLiterature R/V by Verschuur-Maes, Ann Surg 2012 CCL without atypia – upgrade rate 0-26% Pure FEA – upgrade rate 0-36% FEA with ADH – upgrade rate 11-33% ADH – upgrade rate 27-35%HOWEVER problems comparing study results Selection bias; Mode of detection important:

screening vs symptomatic, Ca++ vs mass; Type of biopsy: VAB vs 14G core

Lobular Neoplasia Proliferation of small non-cohesive cells within the terminal

duct lobular unit ALH – distension of fewer than 50% of acini within the TDLU LCIS – more than 50% of acini in the TDLU expanded by

monomorphic cells with loss of central lumina Detection increased in recent years; approximately 1%

(0.5 - 3.6%) of all breast biopsy specimens True incidence unclear as usually

asymptomatic/incidental finding Often widespread with high rate of multicentricity (up to

85%) & bilaterality (30-67%) 9x risk of cancer with LCIS Lower risk with ALH, 4-5x

Lobular In Situ Neoplasia

Upgrade rate of LN

Upgrade rate of 0-36% (18% for ALH, 22% for LCIS)

HOWEVER, LN rarely accounts for mammographic lesion so issue of radiological-pathological discordance

Upgrade rates lower if discordant cases excluded (3-4%)

Biology of LN Similar changes in ALH and LCIS Gains on 1q and loss on 16q similar to LG DCIS Polymorphisms and mutations in Ecadherin gene (CDH1)

identified in LCIS Ipsilateral cancer 3 x more likely than contralateral Invasive lobular carcinomas over-represented Identical truncating mutations in CDH1 identified in LCIS

and adjacent ILC ALH/ LCIS represent a true precursor lesion with low risk of

progression to invasive carcinoma

Variants of LCIS

‘Mass forming’ LCIS where there is marked distension of lobular units with formation of macroacini and associated comedo-type necrosis (B4)

Pleomorphic LCIS – marked nuclear pleomorphism similar to high grade DCIS (B5a)

= more aggressive variantsCan be ER negative or HER2 positive24-67% associated with invasive cancer75-90% of associated cancers lobular type

Historical concept of breast cancer progression

Garcia-Lopez et al., Histopathology 2010, 57, 171–192.

PROGRESSION

Normal breast

ADH DCIS IDC/NST

ALH LCIS ILC

FEA

Low and High grade lesions follow different evolutionary pathways

FEA, ADH and LN are precursor lesions on low grade ER +vepathway

Current Concept of Breast Cancer Progression

Pre-invasive Lesions – the dilemma A spectrum of lesions with blurring of boundaries of

diagnoses between ADH / low grade DCIS, lobular neoplasia and columnar cell lesions

DCIS is true precursor with high risk of progression to invasion (esp. high grade DCIS)

Other lesions have a genuine but lower risk of development to invasion

We cannot as yet identify which of these lower risk processes may progress, either histologically, immunohistochemically or genetically…

Papillary lesions A proliferative lesion characterised

by finger-like projections composed of central fibrovascular cores covered by epithelium

Classification dependent upon presence of cytological and

architectural atypia presence of an internal and/ or

external myoepithelial layer

Latest WHO Classification

Intraductal papilloma (B3)Intraductal papilloma with atypia (B3)

/ DCIS (B5a)Intraductal papillary carcinoma /

Papillary DCIS (B5a)Encapsulated papillary carcinoma

(B5a)Solid papillary carcinoma (B5a/b)

Atypical features

Papilloma with atypia/ DCIS

Background benign papilloma with focal atypia/ DCIS DCIS usually low or intermediate grade with solid or

cribriform architecture >3mm = DCIS

CB Upgrade Rates

No atypia – 0 to 25% upgrade to atypia0 to 20% upgrade to malignant

Atypia – 22-100% upgraded to DCIS (av 54%)BUT bias a problem Benign CB excision rate varies from 15-100% Many small series with huge variation in patient

populations Series with central pathology review show lower

upgrade rates – 6-11% to malignancy Main risk factor associated with malignancy is older age

Epithelial displacement

Common finding in VAE and resection specimens following CB

Nests of epithelial cells lying within the biopsy tract – fibrosis, fat necrosis, haemosiderin laden macrophages

In case of papillary carcinoma cells will be atypical

Should not be called invasion

Radial Scar/ CSL

Central fibroelastotic core with entrapped glands

Risk of associated malignancy is related to the presence of cytological atypia

Atypia present – 28-44% upgradedNo atypia – 4-6%

Malignancy is usually in the form of low grade DCIS or low grade invasive carcinoma, particularly tubular carcinomas

Associated invasive carcinoma often present at periphery of lesion

What the pathologist needs to know

Clinical and radiological findings Presence of microcalcifications Nature of calcifications

– ideally specimen xrays should be available for histological correlation = do the calcs down the microscope account for the radiological calcs

Pre cassetting cores with Ca++ very helpful Vacuum biopsies – diagnostic versus excision

Specimen Handling

VAB 3-4mm thick cf 2mm

Longer fixation required – ideally at least 6 hours

Longer processing – 13 hour processing schedule

Initially cut at 3 levels – depth 0.3 mm (ie only 10% of biopsy)

May require additional levels to identify calcifications – longer turnaround times