LOBULAR NEOPLASIA

Jean F. Simpson, M.D.

Breast Pathology Consultants, Inc.

Nashville, TN

Lobular Neoplasia

• Atypical lobular hyperplasia

• Lobular carcinoma in situ

Relative Risk for Developing

Cancer After Benign Biopsy

• No increased risk

– cysts

– duct ectasia

– adenosis

– hyperplasia, mild

• Slightly increased

risk

– hyperplasia, moderate

or florid, no atypia

– sclerosing adenosis

– solitary papilloma

• Moderately increased risk

– Atypical ductal hyperplasia

– Atypical lobular hyperplasia

LCIS NormalALH

Lobular Neoplasia

Epidemiology of LCIS

Study- Dx term # pts* Incidence

(%)

Relative

risk

%IBC/yrs

follow-up

Rosen (1978) LCIS 99 1.3 9.0 1.52

Page (1991) LCIS 44 0.5 9.0 1.27

Wheeler (1974) LCIS 32 0.8 -- 0.7

Andersen (1974 ) LCIS 47 1.5 12.0 1.4

Haagensen (1978) LN 211 3.8 7.2 1.21

Page (1985) ALH 126 1.6 4.2 0.75

*average age for all series 45 years old

Epidemiology of LCIS

Study- Dx term # pts* incidence Relative

risk

%IBC/yrs

follow-up

Rosen (1978) LCIS 99 1.3 9.0 1.52

Page (1991) LCIS 44 0.5 9.0 1.27

Wheeler (1974) LCIS 32 0.8 -- 0.7

Andersen (1974 ) LCIS 47 1.5 12.0 1.4

Haagensen (1978) LN 211 3.8 7.2 1.21

Page (1985) ALH 126 1.6 4.2 0.75

*average age for all series 45 years old

Nashville Breast Cohort

Risk of Subsequent Carcinoma after

Diagnosis of Lobular Neoplasia

Minimal ALH

ALH

ALH and DIALH

LCIS

1.2-1.5X

4-5X

7X

10X

1.6 %

0.6 %

0.5 %

% BiopsiesRelative RiskCategory

Risk of subsequent carcinoma after

diagnosis of lobular neoplasia may

vary with menopausal status

Premenopausal 9.6 3.3-27.8

Postmenopausal 3.7 1.3-10.2

95% CIRelative Risk

Marshall et al.

Cancer Epidemiol Biomarkers Prev 1997; 6:297-301

Page et. al. Lancet 2003: 361:125-29

“Atypical lobular hyperplasia as a unilateral predictor of

breast cancer risk: a retrospective cohort study”

Biopsy only

20% (50/252) IBC

14.8 yrs Ave F/U

Relative Risk 3.1 (95% CI, 2.3-4.3; P<0.0001)

252 Women with ALH

Laterality of subsequent IMC in relation to

biopsy side for 50 women having ALH

68%

24%

4% 4%

Ipsilateral (34)

Contralateral (12)

Bilateral (2)

Unknown side (2)

Page et. al. Lancet 2003: 361:125-29

Risk of Invasive Breast Cancer Associated with ALH

Prospective Case-Control

1976-1988

10 yrs ave F/U

Relative Risk 5.2 (2.5-10.9)

121, 700 female nurses

Nurses Health Study

Harvard

Nashville Breast Cohort

Vanderbilt

1952-1968

Retrospective

Relative Risk 4.2 (2.6-6.9)

17.5 yrs ave F/U>10,000 biopsies (1.6% ALH)

w/Fam Hx 8.4 (3.5-20)

15 yr

Absolute risk31-45 yrs 8%

46-55 yrs 12%CA: 62% Ipsi, 39% Contra

CA: 69% Ipsi, 31%Contra

Non-Obligate Precursor

Intermediate between

Local Precursor

and

Generalized Risk Factor for

Both Breasts

Page et. al. Lancet 2003: 361:125-29

ALH

Current Considerations

• How do we define lobular

neoplasia?

• Differential diagnosis

• LN on core biopsy

Lobular Neoplasia

1970 2019

detection incidentalcalcification

Incidental ALH

Lobular Neoplasia

1970 2019

detection incidental calcification

diagnosis H & E E-cadherin?

Loss of 16q in both ILC and LN

Ubiquitous loss of 16q includes the locus for

E-cadherin

TERMINOLOGY FOR LN• In the Nashville Cohort and Nurse’s

Health follow up studies, ALH is majority of

cases

• Extensive disease with lobular unit

distortion overlaps with DCIS - as in

NSABP 17, over 100 cases of ‘LCIS’ in

the study of DCIS

CLASSIC LCIS (AND ALH)

• age of diagnosis is 49 years

• incidental histologic finding

• often multifocal and bilateral

• invasive carcinomas can occur in either

breast, and show a variety of histologic

subtypes

CLASSIC LCIS (AND ALH)

• Margins are not assessed

• Classic LCIS and atypical lobular

hyperplasia lack E-cadherin expression,

and show a dyshesive growth pattern

• Classic LCIS and atypical lobular

hyperplasia generally express estrogen

receptor

VARIANT LCIS (PLEOMORPHIC)

• Affects older women, 55-60 years of age

• Presents as an imaging abnormality:

pleomorphic calcifications with or without a

mass.

• Frequently associated with an invasive

component showing similar cytologic

features, strongly supporting its role as a

precursor lesion

VARIANT LCIS (PLEOMORPHIC)

• Lacks E-cadherin expression, and shows

a dyshesive growth pattern

• Surgeons attempt to obtain clear margins

• May be HER2 over-expressed/amplified

• Some cases do not express estrogen

receptor.

• Pleomorphic ALH does not exist.

DCIS AND VARIANT LCIS

• Same age at diagnosis (i.e. 55-60 years)

• Both present as an imaging abnormality:

calcifications or mass

• Excision to negative margins is attempted

for both

• The invasive carcinomas that occur

following DCIS affect the same quadrant,

supporting a precursor role

DCIS AND VARIANT LCIS

• The invasive carcinomas that occur

following pleomorphic LCIS affect the

ipsilateral breast, supporting a precursor

role

• HER2 may be over-expressed/amplified in

both pleomorphic LCIS and DCIS.

Use of IHCReliably separates well-developed examples

of Disease A from Disease B

•Borderline cases, overlaps

•Often unresolvable in simple “yes/no” terms

•Requires integration of therapeutic

modalities in making clinical decisions

Diagnosing LCIS

• Consider clinical context

• Incidental versus targeted lesion

• Current state is different from incidental

findings of pre-mammographic era

Rules for LCIS

Rule #1. Clinical context is everything

Rule #2. Ancillary studies (E-cadherin) may

be helpful

Rule # 3. if E-Cadherin gives mixed

messages, see Rule #1.

Sample Diagnoses

• In situ carcinoma with mixed ductal and lobular featues– Recommend treating as DCIS

• Ductal carcinoma in situ with lobular cytology– Expected biologic behavior that of DCIS

• Pleomorphic lobular carcinoma in situ

• Indeterminate carcinoma in situ

Differential Diagnosis

ALH admixed with florid hyperplasia

ALH involving collagenous spherulosis

Lobular neoplasia

• Incidental finding, multicentric (60%), bilateral (30%)

• No evidence that amount of involvement (within the breast) influences subsequent cancer risk in long term follow up series

• Risk of cancer development is about 10% over 10-15 years, drops after menopause

• Bilateral risk, but ipsilateral breast more likely to develop cancer

• Most women don’t develop cancer

Thank You!