Intraductal and intralobular epithelial
proliferations
Sarah E Pinder
Usual Epithelial Hyperplasia
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Architectural features
– Irregular fenestrations
– Peripheral fenestrations
– Stretched or twisted epithelial bridges
– Uneven distribution and overlapping of nuclei
Cellular features
– Multiple cell types
– Variation in appearance of epithelial cells
– Variation in appearance of nuclei
– Often oval rather than round
– Indistinct cell margins
Atypical Ductal Hyperplasia
Architectural features
• Some features of UEH & some features of low
grade DCIS
Cytological features
• Cells similar to those seen in low grade DCIS
present in a portion of the space
• Second population of cells typical of florid
hyperplasia also present
Size/extent
• Less than 2 duct spaces with complete
involvement (2mm)
NHS BSP EQA Scheme
Kappa’s for overall diagnosis (all participants)
Benign
Atypical
hyperplasia
In situ /
Invasive
Micro-invasive
Overall
902, 911, 912
0.72
0.19
0.71
0.81
0.68
921, 922, 931
0.75
0.16
0.71
0.86
0.72
932, 941, 942
0.81
0.15
0.75
0.88
0.77
951, 952, 961
0.75
0.17
0.77
0.86
0.77
962, 971, 972
0.79
0.26
0.81
0.91
0.82
981, 982, 991
0.84
0.13
0.69
0.90
0.79
0.79
0.18
0.75
0.88
0.77
All
Common adult stem cells in the breast biological concept
Ck5/Ck8/18/19+
Ck5+
Ck5/SMA+
Ck8/18/19+
SMA+
“cells differentiate toward glandular or myoepithelial cells,
passing through either Ck5/Ck8/18/19 or Ck5/SMA-positive
intermediates” Bocker et al. Lab Invest 2002;82; 737-745
Cytokeratins in Intraductal Hyperplasia
Luminal epithelial cytokeratins (CK 8, 18, 19) & basal
intermediate epithelial cytokeratins (CK 5, 6, 14) may
be helpful in difficult intraductal proliferations identify a mixed cell population in UEH
Bocker W. Pathologe 1997;18:3-18
Gynaecomastoid Hyperplasia
• Small, papillary-like clusters of epithelial cells
• No fibrovascular stalks
• 2 - 3 cells above basement membrane
• Papillary clusters taper towards lumen
• Small, pyknotic nuclei arranged around outer
•
edge of papillary structures
Variable nuclear features - not regular, evenly
spaced, c.f. DCIS
Tham KT et al. Prog in Surg Pathol. 1989; 10; 101-9
ER in Diagnosis of Intraductal Epithelial
Proliferations
• % of ER +ve cells slightly increased in UEH
• ER +ve surrounded by ER -ve cells or
•
contiguous groups of +ve cells (sometimes
>90% cells)
In ADH, LCIS & low grade DCIS contiguous +ve
cells
Shoker BS et al. J Pathol 1999;188;237-244
Side of Biopsy vs
Side of Breast Cancer
% Ipsilateral
% Contralateral
Low Grade DCIS
~100
~0
ADH
(NHS, Dupont & Page)
~50%
~50%
AIDH
(Tavassoli & Norris)
~75%
~25%
ADH - hints
1. If you have not considered low grade
DCIS as diagnosis, then is NOT ADH
2. ADH is small, microfocal lesion - if
lesion more than a few mm, then not
ADH
3. ADH is clonal, luminal (CK5 negative,
CK15 negative), uniformly ER positive
DCIS - Frequency
5% symptomatic breast carcinoma
Over 20% screen-detected breast cancer
General Population?
Autopsy studies
0-15%
Welch Ann Int Med
1997
Excision of DCIS
3D Mapping Egans Technique
82 cases
1 quadrant
>1 quadrant
Central
66%
23%
11%
81 cases
1 duct system
1 case
Multiple ducts systems
= a unicentric process
Holland. Lancet 1990; 335; 519
Recurrent DCIS Genetic Studies
• 18 pure DCIS with ipsilateral DCIS recurrence
• 17 cases high concordance with CGH (median
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81%)
In only 1 case, no agreement
Mean no. CGH changes higher in recurrence
Commonest were gain of 17q, loss of 8p, 17p
i.e. recurrent DCIS = residual DCIS
Waldman et al. JNCI 2000; 92; 313
Diagnosis of DCIS - NHS BSP EQA Scheme
Kappa - Overall Diagnosis
Circulation
Benign
902,911,912
0.72
921,922,931
Inv.
Overall
0.71
0.81
0.68
0.75
0.71
0.86
0.72
932,941,942
0.81
0.75
0.88
0.77
951,952,961
0.75
0.77
0.86
0.77
962,971,972
0.79
0.81
0.91
0.82
981,982,991
0.84
0.69
0.90
0.79
All
0.79
0.75
0.88
0.77
0.00 – 0.20
0.21 – 0.40
0.41 – 0.60
0.61 – 0.80
0.81 – 1.00
In situ / MI
Slight
Fair
Moderate
Substantial
Almost perfect
Classification of DCIS
Extent of DCIS - Relation to Architecture
Comedo
Solid
Single
quadrant
24
19
20
4
67
Multiple
quadrant
2
(8%)
4
(17%)
5
(20%)
10
(71%)
21
26
23
25
14
88
Total
Cribriform Micropapillary
Total
Bellamy. Hum Pathol 1993; 24;16
DCIS - “Nottingham” Classification
• Comedo DCIS
• DCIS with necrosis (non-pure comedo)
• DCIS without necrosis
Poller et al. Modern Pathol 1994;7:257-262
DCIS - Van Nuys Classification
DCIS
Non-high grade
Without necrosis
High grade
With necrosis
Silverstein et al. Lancet 1995;345;1154-57
DCIS Differentiation
• Well differentiated
• Poorly differentiated
• Moderately differentiated
Holland et al. Sem Diag Pathol 1994; 11; 167-180
DCIS - NHS BSP Grade
• High grade
• Intermediate grade
• Low grade
(Nuclear size, pleomorphism, nucleoli, mitoses)
(Growth pattern, necrosis & polarisation)
Pathology Reporting of Breast Disease. NHS BSP
Publication 58, 2005
Grade & Number of Calcifications
Invasion in Screen Detected
Microcalcification
•Grade of DCIS in core biopsy & increasing
numbers of calcifications in lesion are predictive of
invasion
High grade & > 40 calcifications
High grade & < 40
Not high grade
48%
15%
0%
Bagnall MJC, Evans AJ, Wilson ARM et al. Clin Rad 2001
UK DCIS I Trial
Univariate analysis for ipsilateral recurrence
Grading System
n
N of events
H.R.
95 % C.I.
Nuclear Grade
1
2
3
86
225
913
6 (7.0%)
13 (5.8%)
135 (14.8%)
0.51
0.41
1.00*
0.22 - 1.15
0.23 – 0.72
Van Nuys Grade
1
2
3
99
212
913
5
14
135
0.39
0.45
1.00*
0.16 - 0.94
0.26 - 0.78
Differentiation
1
2
3
90
248
886
6
14
134
0.38
0.47
1.00*
0.22 - 0.66
0.21 - 1.07
Unpublished data
Evidence for Progression of DCIS
Type
Treatment
Outcome
High grade
Biopsy alone
Progression 50% in 5 yrs
Low grade
Biopsy alone
Progression 30% in 15 yrs
Low grade DCIS
40% of 28 patients with ‘missed’ lesions on biopsy
developed invasion at same site at 30 year follow-up
Page et al, Cancer 1995; 76; 1196-1200
Progression of DCIS to Invasive Carcinoma
Supported by Morphology
• In tumours with both DCIS and invasion there is a
significant correlation between grade of the DCIS
and of invasive carcinoma
Lampejo et al, Sem Diag Pathol 1994; 11:215-222
Gupta et al, Cancer 1997; 80 : 1740-1745
• No progression in grade between the in-situ,
invasive, locally recurrent and metastatic phases
Millis et al, Eur J Cancer 1998; 34:548-553
Progression of DCIS to Invasive Carcinoma
Supported by Genetic studies
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LOH common in DCIS (70 - 79%)
80% of DCIS shares LOH with associated invasive cancer
O’Connell et al. JNCI; 1998; 90; 697
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CGH studies show a high degree of genetic homology
between DCIS and invasive carcinoma
Buerger et al, J Pathol 1999; 189:521-526;
Bocker et al, J Pathol 2001; 195:415-421
DCIS Genetic studies
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Allelic imbalance analysis suggests that low
grade & high grade carcinomas follow different
genetic pathways
Roylance et al. J Pathol. 2002; 196:32-36
Normal cell
Hyperplasia
“In situ neoplasia”
-16q
-16p
-17p
-22q
+6q
-16q
-17p
+11q13
+1q
Lobular in
situ neoplasia
Low Grade DCIS
+17q12
+17q12
Intermediate Grade DCIS
High Grade DCIS
Heterogeneity?
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DCIS (n = 120)
Distribution of grades, & biomarkers by IHC, ranging
from well to poorly differentiated [“nearly identical to
IBCs”]
Multiple grades, biomarker phenotypes often coexist
Supports hypothesis that poorly differentiated DCIS
evolves from well-differentiated DCIS by randomly
acquiring genetic defects
Allred DC et al. Clin Cancer Res. 2008;14:370-8
Classification of DCIS by Nuclear Grade
NHS BSP EQA Scheme
Circulation
No. of cases
952,961
962,971,972
981,982,991
992,001,002
High
11
0.47
0.34
0.09
0.64
0.51
Intermediate
13
0.19
0.25
0.06
0.29
0.23
Low
4
0.41
0.09
0.19
0.30
0.31
Overall
28
0.35
0.28
0.11
0.44
0.36
College of American Pathologists’
Guidelines for DCIS Grading
Nuclear Grade
Grade 1
Monotonous nuclei, 1.5 to 2.0 RBC diameters,
with finely dispersed chromatin & only occasional
nucleoli
Grade 2
Neither nuclear grade 1 nor nuclear grade 3
Grade 3
Markedly pleomorphic nuclei, usually greater than 2.5
RBC diameters, with coarse chromatin & prominent or
multiple nucleoli
Molecular markers in DCIS
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Gene expression patterns in DCIS & invasive &
metastatic tumours
Serial analysis of gene expression (SAGE)
mRNA ISH to examine gene expression & IHC on
TMAs
Most dramatic change at normal to DCIS transition
No clear universal "in situ" or "invasive" tumour
signature
16,430 transcripts analyzed
Identified only 5 preferentially up-regulated in DCIS
Porter D et al.Mol Cancer Res. 2003;1:362-75
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Basal-epithelial-like group
ERBB2-overexpressing group
Normal breast-like group
Luminal epithelial/ER positive group - subdivided
into at least 2 sub-groups
Robust - both by clustering using set selected for
intrinsic properties and by outcome
Equivalent Subclasses of DCIS?
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Population-based series of 245 cases DCIS
Histological characteristics & ER, HER2, EGFR, CK5/6,
p53 & Ki-67
Luminal A (ER+, HER2-); n = 149 (61%)
Luminal B (ER+, HER2+); n = 23 (9%)
HER2 positive (ER-, HER2+); n = 38 (16%)
Basal-like (ER-, HER2-, EGFR+ and/or CK5/6+); n = 19
[8%]
16 (6%) unclassified (-ve for all 4 markers)
Livasy CA et al. Hum Pathol. 2007;38:197-204
Classification of DCIS by gene
expression profiling
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Supervised cluster analysis of 14 poorly differentiated
DCIS & 24 grade 3 invasive carcinomas
80 genes differentially expressed, 13 up-regulated in
DCIS & 67 down-regulated
Mostly involved in cell growth & metabolism, protein
binding
Hannemann et al. Breast Cancer Res 2006; 8; R61
Normal cell
Hyperplasia
“In situ neoplasia”
-16q
-16p
-17p
-16q
-17p
LCIS & subgroup of
DCIS may be different
phenotypic forms of a
common genotype
+11q13
+1q
Lobular in
situ neoplasia
Low Grade DCIS
+17q12
+17q12
Intermediate Grade DCIS
High Grade DCIS
Distinguishing LCIS from DCIS
LCIS Vs. Low Grade Solid DCIS
• Both processes - filling of membrane-bound
spaces by uniform, regularly-placed cells with
clear cytoplasm
• DCIS - sharply defined cell membranes
• LCIS - discohesion
• Intracytoplasmic lumina more often in LCIS
• Low power view - lobulo-centricity of LCIS,
more haphazard lobular & duct distortion in
DCIS
• If features of both then classify as LCIS &
DCIS because of bilateral & precursor risk
E-Cadherin
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17 of 28 cases of indeterminate CIS (61%)
E-cadherin heterogeneous
Jacobs TW. Am J Surg Pathol 2001;25:229-36
23 of 50 indeterminate CIS = ductal or lobular on
immunoprofile
In 27 IHC not typical of DIN or classic LIN
Bratthauer GL et al. Hum Pathol. 2002;33:620-7
Group of lesions with overlapping morphological &
IHC profile
At present, regard as combined LCIS & DCIS because
of the ?bilateral risk & precursor risk? respectively
Lobular in Situ Neoplasia
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Follow-up of 39 of 48 patients
0.5% of 10,542 benign breast biopsies
Higher risk with LCIS (9x)
Lower risk with ALH (4-5x)
Page DL. Human Pathol. 1991; 22; 1232-1239
Genetics of Lobular Neoplasia
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CGH of 31 LCIS, 14 ALH
Loss from 16p, 16q, 17p & 22q & gain from 6q found at similar high
frequency in LCIS & ALH
Lu YJ. Cancer Res. 1998. 15;58:4721-7
Low average rate of copy no. changes
High rate gains & losses of material at 1q & 16q
Buerger H et al. Mol Pathol. 2000;53:118-21
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ALH and LCIS are at similar genetic stage
High degree of genetic homology with low grade DCIS
LCIS
• Marker of adjacent malignancy (?precursor)
as well as of increased risk of subsequent
carcinoma in either breast?
Update - Risk with LISN
Meta-analysis 9 studies of 228 patients
15% ipsilateral, 9% contralateral carcinoma
Ipsilateral 3x more likely than contralateral
• A “model of premalignancy for ALH
intermediate between a local precursor and a
generalised risk for both breasts”
Page DL. Lancet. 2003;361:125-9
Pleomorphic LCIS
(& Pleomorphic Apocrine LCIS (PALCIS))
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Lack E-cadherin & beta-catenin
Gain of 1q & loss of 16q - typical of lobular carcinoma
Amplification of c-myc and HER2
Same precursor or same genetic pathway as classic lobular
carcinomas
Reis-Filho J et al. J Pathol. 2005.
Lobular immunohistochemical profile & genetics
More “aggressive” re proliferation, HER2 etc
Very limited data on clinical behaviour
Columnar alteration with prominent
snouts & secretions (CAPSS)
• CAPSS in 42% of 100 consecutive bxs for
microcalcifications
• Calcifications in CAPSS in 74%
Fraser JL et al. Am J Surg Pathol.1998;22:1521-7
Columnar cell lesions
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Blunt duct adenosis
Atypical cystic lobules
Cancerization of small ectatic ducts of the breast by ductal
carcinoma in situ cells with apocrine snouts
Hypersecretory hyperplasia
Columnar alteration with prominent apical snouts and secretions
(CAPPS)
Mammary ductal intraepithelial neoplasia-flat type
“Clinging ductal carcinoma in situ"
Hyperplastic Unfolded Lobules (HULs)
Enlarged lobular units with columnar alteration (ELUCA)
Columnar cell lesions
Terminology
Schnitt and Vincent-Salomon, 2003
• Columnar cell change
• Columnar cell hyperplasia
• Columnar cell change with atypia
• Columnar cell hyperplasia with atypia
Terminology
• Columnar cell change
• Columnar cell hyperplasia
• Columnar cell change with cytological atypia
• Columnar cell change with architectural atypia
Present Terminology
• Columnar cell change
• Columnar cell hyperplasia
• Flat epithelial atypia
Columnar Cell Change
• Columnar epithelial cells (1 or 2 cell depth) line
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TDLU, often mildly dilated
Uniform, ovoid nuclei
Perpendicular to basement membrane
Cytologically bland
Mitotic figures rare
Apical snouts often present
Secretions may be present in lumen with Ca2+
Columnar Cell Hyperplasia
• Similar to CCC, but stratification > 2 cells depth
• Nuclei morphology as in CCC
• May be more crowding & overlapping of nuclei
• Tufts or hummocks mimicking micropapillae
• Exaggerated apical snouts - hobnail appearance
• Intraluminal secretions often with Ca2+
N.B. If true micropapillae, bridges, cribriform
pattern etc = consider as ADH/DCIS
Flat Epithelial Atypia
• TDLUs often darker than normal at low power
• 1 or more layers of monotonous, cuboidal to
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columnar cells, resembling LG DCIS
Round nuclei
Mild increase in nuclear/cytoplasmic ratio
Dispersed or marginated chromatin
Nucleoli sometimes more prominent
Mitotic figures rare
May be scattered lymphoid cells
Not
necessarily
flat
Columnar Cell Lesions
• Cells of columnar cell lesions show luminal
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cytokeratin (e.g. CK19) positivity
No expression with cytokeratins 5 or 14
Strong homogeneous nuclear oestrogen &
progesterone receptor & bcl-2 positivity
IHC not helpful in distinguishing FEA from
CCC or CCH
May be helpful if apocrine change or
microcysts are differential diagnoses