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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!
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