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What Do Breast Pathologists Find Difficult?

Learning from My Referral Practice

Sarah E Pinder

• Approximately 2300 cases

• Epithelial proliferations (237)• Sub-typing invasive carcinoma (236)• Fibroepithelial lesions (206)• Papillary lesions (203)• Sclerosing lesions (166)

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Commonest lesions referred = epithelial proliferations

• FEA vs ADH vs DCIS; UEH vs DCIS; DCIS vs LCIS (PLCIS)

• Invasion vs DCIS vs seeding

• Apocrine lesions• Atypia in papillary lesions• Etc• Etc

CCC

FEA

FEA

FEA

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ADH LG DCIS

Features of UEH & of low gradeDCIS

Punched-out spaces, rigid bars, micropapillae

Cells as in low grade DCIS.Microfocal; < 2 duct spaces with complete involvement (mixed with UEH) (or < 2mm)

Evenly-spaced.Small, regular cells.Round nuclei.

Intraductal Epithelial Proliferations

Low grade DCIS

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Epithelial proliferation

CK5 (5/6), CK14, ER

Ck5 +ve Ck5 -ve, Ck14 -ve, ER +ve

(Intermediate or) high grade

morphology

UEH DCIS ADH, LG DCIS, LISN, FEA,

Ck5, Ck14 & ER

mosaicism

CK5

CK14

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CK5

CK14

Learning from my referral practice =

Confusion and variation in use of term ‘basal’ in the breast- Basal position;- Myoepithelial;- Cells expressing 'basal'

cytokeratins

Flat high grade DCIS Nuclear Grade of DCIS

Arch Pathol Lab Med 2009;133:15-25; UK Guidelines 2016

Feature Low grade Intermediate High

Pleomorphism Monotonous Intermediate Markedly pleomorphic

Size 1.5x to 2x RBCs or normal duct

epithelial nucleus

Intermediate >2.5 RBCs or normal epithelial

nucleusChromatin Usually diffuse,

finely dispersedIntermediate Usually vesicular,

regular chromatin distribution

Nucleoli Only occasional Intermediate Prominent, often multiple

Mitoses Only occasional Intermediate May be frequent

Orientation Polarized Intermediate Usually not polarized

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Atypical pregnancy-like hyperplasia Learning from my referral practice = HER2 can be helpful

Inter-observer variability in diagnosis• Retrospective study of original diagnostic reports vs

later review by specialist in breast pathology • 610 specimens sent for consultation and/or 2nd opinion • Poor agreement for diagnoses of pleomorphic LCIS

(κ=0.22)• Weak correlations for diagnoses of columnar cell

change (κ=0.38) & columnar cell hyperplasia (κ=0.32)• Moderate agreement (κ=0.47) for FEA; ADH (κ=0.44),

low-grade DCIS (κ=0.47), intermediate-grade DCIS (κ=0.45) and DCIS with microinvasion (κ=0.56)

• Good agreement for ALH (κ=0.62) & LCIS (κ=0.66) and high-grade DCIS (κ=0.68)Gomes DS et al. Diagn Pathol. 2014;9:121

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LCIS – classical type

Learning from my referral practice =Some cases are just very difficult……..

• All of 25 ILCs harboured an in-frame deletion in exon 7 (867del24) of E-cadherin gene & loss of wild type allele

• Even when E-cadherin is expressed, cadherin-catenin complex maybe nonfunctional

Learning from my referral practice =Don’t overinterpret E-cadherin

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Referral PracticeFibroepithelial lesions

• Classification of phyllodes tumour• Fibroadenoma vs benign phyllodes tumour• Phyllodes tumour with another element –

liposarcoma, carcinoma, melanoma

• 76 cases of benign or borderline PT • Mean age 37.9 years & median follow-up 58 months• 75 patients (99%), mean tumour size 27 mm, had BCS• Margins considered positive (tumour at ink) in 7 of 76

cases (9%) & negative in 65 of 76 (86%)• Small negative margins (<10mm) in 89%; <1mm in 71%;

no re-excision• No increase in local recurrence (4%) compared literature • “Systematic revision surgery for close or positive

surgical margins for benign PT should not be systematically performed”Moutte A et al. 2016. DOI: 10.1111/tbj.12623

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Phyllodes TumoursBenign Borderline Malignant

Mitoses 0-2/10HPF 2-5 >5, usually >10

Margins Circumscribed

(>90%)

Focally

infiltrative

Infiltrative (>50%)

Stromal

overgrowth

Mild Moderate Marked

Stromal atypia/

pleomorphism

Mild Moderate Marked

Heterologous

elements

No No Yes - Sometimes

Necrosis No No Yes - Sometimes

Tumour ?type• Metaplastic?• Metastasis or primary• Neuroendocrine• Salivary gland-like

(adenoid cystic; collagenous spherulosis; cylindroma; acinic cell)

• Histiocytoid/signet ring• Secretory• Thyroid-like• Mucinous

cystadenocarcinoma

Learning from my referral practice =Pathologists love to pigeon-hole Always remember clinical relevance

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MNF116

CAM5.2

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Learning from my referral practice =

All spindled cell lesions are metaplastic carcinomas, until proven

otherwise……

• Papillary lesions +/- invasion• Adenomyoepithelioma – diagnosis and classification• Granular cell tumour - classification• Classification of nodal disease – micromet vs ITCs• Squamous metaplasia, squamous cysts

Other referral cases - miscellany

Summary • Epithelial proliferations are lesions most commonly

referred & cause most major diagnostic discrepancies• We sometimes over-rely on IHC (E-cadherin) and

sometimes do not request the best markers• Difficulties include:

• Entities where reliance for diagnosis is heavily on one feature alone (e.g. flat high grade DCIS, PLCIS)

• Lesions with poorly described cut-points for classfication or difficulty in predicting clinical behaviour (e.g. PT classification, adenomyoepithelioma, some granular cell tumour)

• Rare lesions we see uncommonly, or have never seen before, or don’t know exist………

Cases for opinionPlease provide

• Background – patient & clinical details• Local opinion (+ provisional report)• Relevant slides – not necessarily all• IHC performed (avoids repeat)• Representative block (or unstained slides) for any

additional IHC• Level of urgency - but allow time for case to arrive

and be booked in ……• Any specific questions – diagnosis, clinical

management etc.• Be prepared for delay if IHC, additional

‘molecular’ tests, third opinion, needed

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