1. No category

Morphological and Molecular Typing of
breast Cancer
Ian Ellis
Molecular Medical Sciences, University of Nottingham
Department of Histopathology, Nottingham University Hospitals NHS Trust
Nottingham Tenovus Primary Breast
Cancer Study
Histological Type
Survival (%)
Histological
type
Tubular
Tubular variant
Lobular
Cribriform
Papillary
Mucinous
Medullary
Ductal NST
Histological type
Long term
survivors
n = 119
Consecutive
series
n = 1050
Short term
survivors
n = 200
8
7
16
13
5
2
9
30
3
5
10
3
1
2
5
67
0
0
5
0
0
0
4
83
Dixon et al, Br J Surg 1985; 72: 445-448
Excellent (>80% 10 year survival)
Tubular, tubulo-lobular, invasive cribriform, mucinous
Good (60-80% 10 year survival)
Tubular mixed, alveolar lobular, mixed ductal NST
& special type
Moderate (50-60% 10 year survival)
Medullary, atypical medullary, classical lobular, invasive
papillary
Poor (<50% 10 year survival)
Ductal NST, solid lobular, lobular mixed, mixed ductal
NST & lobular
1
NHS BSP EQA Scheme
Infiltrating Lobular Carcinoma
Morphological features
Subtype of invasive carcinoma
Composed of small regular cells identical to those seen
in LCIS
• The cells are usually dissociated from each other and
form single files and ‘targetoid’ patterns around normal
ducts and acini
• The following sub-types are recognised: classical,
alveolar, solid, tubulo-lobular, mixed, pleomorphic
NB 90% of the tumour must be of lobular pattern to
be so classified
902,911,912
0.18
0.09
0.24
-
-
0.03
0.03
0.15
921,922,931
0.22
0.26
0.36
0.30
-
0.01
0.03
0.22
932,941,942
0.50
0.68
0.68
0.49
0.98
0.02
0.15
0.60
951,952,961
0.53
0.65
0.64
0.50
0.79
0.19
0.82
0.58
962,971,972
0.64
0.81
0.71
0.54
0.99
0.04
0.16
0.68
981.982,991
0.43
0.74
0.30
0.31
0.59
0.09
0.80
0.49
0.50
0.70
0.55
0.48
0.89
0.10
0.56
0.56
All
NHS BSP EQA Scheme
Medullary Carcinoma
Morphological features
Subtype of invasive carcinoma
Circulation NST Lobular Tubular Medullary Mucinous Mix Other Overall
(No. cases) (66)
(12)
(9)
(4)
(9)
(1)
(2)
(103)
902,911,912
0.18
0.09
0.24
-
921,922,931
0.22
0.26
0.36
932,941,942
0.50
0.68
0.68
951,952,961
0.53
0.65
962,971,972
0.64
981.982,991
All
Circulation NST Lobular Tubular Medullary Mucinous Mix Other Overall
(No. cases) (66)
(12)
(9)
(4)
(9)
(1)
(2)
(103)
-
0.03
0.03
0.15
0.30
-
0.01
0.03
0.22
0.49
0.98
0.02
0.15
0.60
0.64
0.50
0.79
0.19
0.82
0.58
0.81
0.71
0.54
0.99
0.04
0.16
0.68
0.43
0.74
0.30
0.31
0.59
0.09
0.80
0.49
0.50
0.70
0.55
0.48
0.89
0.10
0.56
0.56
Sharply circumscribed soft, rounded tumour mass with
pushing rather than infiltrating margin
• Interconnecting sheets of large, bizarre and
pleomorphic carcinoma cells forming a syncytial
network
• Stroma contains moderate to large numbers of
lympho-plasmacytoid cells which do not intervene
extensively between individual tumour cells
• In situ component insignificant
Biological Importance of Tumour Type Hereditary and Familial Breast Cancer
Histopathological and genetic characteristics
Invasive carcinomas of medullary type or with
medullary features occur more frequently in
familial and early-onset (< 35 years) cases - Rosen
et al, 1992; Kollias et al, 1997
Medullary-like carcinomas are found significantly
more frequently in BRCA-1 carriers than in BRCA-2
carriers and control populations - Marcus et al,
1996; Breast Cancer Linkage Consortium, 1997;
Lakhani et al, 1998; Lakhani et al, 1999
2
Hereditary and Familial Breast Cancer
Round 2002 2
Histopathological, immunohistochemical
and genetic characteristics
Breast cancers in patients with BRCA1 germline
mutations are more often negative for ER, PgR
and HER-2 and positive for p53 protein
The combined morphologic and
immunohistochemical data can be used to
predict the risk of a young patient harbouring a
germline mutation in BRCA1
Updated Guidelines
Case
Lobular
NST
Tubular
Mucinous
16 ST
MIX
429
22
22
22
0
0
0
0
17 ST
MIX
21
18
0
9
0
0
425
27
20 ST
MIX
6
207
0
0
287
207
0
0
Updated Guidelines
Pure Special Type:
Classification of Histological Type
Revised system with emphasis on
concordance of recognition
• A classical example showing the hall mark
histological features
• You would be confident that other
pathologists would recognise this case as a
pure special type
• The definitions used are as in the UK
Guidelines and require 90% purity.
Updated Guidelines
Medullary Carcinoma:
• Worse concordance in EQA scheme
• BRCA 1 emerging data
Updated Guidelines
Medullary Like Carcinoma:
Syncytial interconnecting masses
Grade III
Large vescicular nuclei, prominent nucleoli
Lymphoid cell rich stroma
Pushing/well defined margins
In situ uncommon
3
Updated Guidelines
Updated Guidelines
NST with special type features (mixed):
A tumour heterogeneous in morphology with some
special type characteristics (>50%, <90%) e.g.
tubular differentiation. The special type should be
identified as an additional feature
No Special Type:
A tumour showing no or less than 50% special type
characteristics
Or have one or more characteristics of a special type
but lack the full combination of features required for
pure special type designation, for example a
distinctive lobular infiltrative growth pattern with
pleomorphic non lobular cell morphology.
Updated Guidelines
Rare Tumour Type:
A tumour showing the features (Pure
>90%) of a recognised but unusual
tumour type
Apocrine
Invasive micropapillary
Adenoid cystic
Metaplastic
Tubular carcinoma is known to have a favourable
prognosis, but does this subtype represents a distinct
type of breast carcinoma and does it behave like other
low-grade luminal A–type breast carcinomas?
Rakha et al. J Clin Oncol 28:99-104
Assessed the clinicopathologic and molecular features and
prognostic value of TC compared with grade 1 ductal
carcinomas of the breast.
TC more likely to be detected on mammographic
screening, had smaller median size, and less frequently
showed lymphovascular invasion.
Large well-characterized series of breast cancers
Compared with grade 1 ductal carcinoma, TC was
associated with longer disease-free survival (213.25, P
0.001) and breast cancer–specific survival (28.8, P 0.003).
2,608 invasive carcinoma, unselected consecutive cases
212 Grade 1 ductal carcinomas
102 Tubular carcinomas
Rakha et al. J Clin Oncol 28:99-104
None of the patients with TC developed distant
metastasis or died from the disease without an
intervening recurrence as invasive carcinoma of different
histologic type
Rakha et al. J Clin Oncol 28:99-104
4
Conclusion
The biologic behaviour of TC is excellent and is more
favourable than that of grade 1 ductal carcinoma.
Allele Loss in Breast
Carcinoma
Patients with TC may be at risk of developing second
primary carcinomas in the contralateral breast, which
may be of higher grade and poorer potential prognostic
outcome.
•11p
•11q
•13q
•16q
•17p
•17q
•18q
•1p
•1q
•3p
•6q
•7q
•8p
Patients with TC have a close to normal life expectancy,
and as a consequence, adjuvant systemic therapy may
not be justified in their routine management.
Rakha et al. J Clin Oncol 28:99-104
Allele Loss in Tubular
Carcinoma
High LOH:
•3p
•11q
•13q
•16q
E Cadherin
?Common
Precursor
C-erbB-2
& p53
Other candidates:
?Common
Precursor
Lobular Carcinoma
C-erbB-2
& p53
Low Grade Carcinoma
High Grade Carcinoma
High Grade Carcinoma
BRCA 1 17q
BRCA 2 13q
1q 3p 11q 13q 17q
E Cadherin
Lobular
Ductal
LOH 16q
Low Grade Carcinoma
FHIT
ATM?
Man et al Cancer Research 1996, 56: 5484
E Cadherin
LOH 16q
Lobular Carcinoma
Medullary
Tub & Lob
Tubular
Lobular Carcinoma
16q
?Common
Precursor
LOH 16q
Low Grade Carcinoma
C-erbB-2
& p53
High Grade Carcinoma
17q
5
Class 1
E Cadherin
Lobular Carcinoma
16q
?Common
Precursor
LOH 16q
Low Grade Carcinoma
Class 2
C-erbB-2
& p53
High Grade Carcinoma
17q
Genome plots of the previous
case
Cyclin D1
FEA
DCIS
Cyclin D1
Cyclin D1
LN
6
Conclusion
ER neg
Luminal Type A lesions
ER pos
CCLs
•Luminal ck
•ER rich
•HER2 neg
•16q del
ADH/
Low Grade DCIS
Sorlie, et
al.
PNAS 2001
ALH/
LCIS
LOW GRADE
NEOPLASIA FAMILY
Cribriform
TUBULAR
G1 IDC
TUBULOLOBULAR
ILC
Basal-like/ TN vs special types
Do special types of breast cancer
have distinct molecular subtypes?
Mucinous
Neuroendocrine
Micropapillary
Papillary
Medullary
Metaplastic
Secretory
Adenoid cystic
Apocrine
Pleomorphic lobular
Acinic
Reis-Filho et al., Histopathology 2006; Rakha E, Reis-Filho JS, Ellis IO. JCO, 2008; Lae et al. Mod Pathol 2008;
Weiget et al., J Pathol 2008; Weigelt et al., Breast Cancer Res Treat 2009; Weigelt et al. Nat Rev Clin Oncol 2009
Special types of breast cancer are more
homogeneous at the transcriptome level
Luminal
• N=113 (11 special types of breast cancer)
– Operon arrays – 24,650 genes
– TMAs – 22 markers
Basal-like Mol apocrine
Adenoid cystic
Medullary
Metaplastic
Mucinous A
Classic ILC/ Tubular
Mucinous B
Neuroendocrine
Micropapillary
Pleomorphic ILC
Apocrine
Weigelt et al. J Pathol 2008
7
Special types vs molecular subtypes
IDC Osteoclastic
Neuroendocrine
Luminal
Take home messages
• Each special type of breast cancer is more
homogeneous at the molecular level
Mucinous
Tubular
HER2
Classic ILC
• Luminal phenotype:
– Tubular, classic lobular, neuroendocrine and mucinous
Micropapillary
Apocrine
Molecular apocrine
• Basal-like phenotype:
– Medullary, metaplastic, secretory and adenoid cystic
Pleomorphic ILC
Adenoid cystic
Basal-like
• Molecular apocrine and HER2 phenotype:
– Apocrine and pleomorphic lobular carcinomas
Medullary
Claudin low?
Metaplastic
Reis-Filho et al., Histopathology 2006; Rakha, Reis-Filho & Ellis. JCO, 2008; Weiget et al., J Pathol 2008; Weigelt et al., Breast
Cancer Res Treat 2009; Weigelt et al. Mod Pathol 2009; Weigelt et al. Nat Rev Clin Oncol 2009; Weigelt et al. J Pathol 2010
The integrative subgroups have distinct copy number profiles
The integrative subgroups have distinct clinical outcomes
8
The integrative subgroups have distinct clinical outcomes
IntClust 2
• ER positive, poor prognosis
• 11q13/14 cis-acting tumours
• CCND1 (11q13.3), EMSY (11q113.5),
PAK1 (11q14.1), RSF1 (11q14.1)
• 11q13/14 amplicon(s)
Conclusions
IntClust 3
• Low genetic instability
• Luminal A predominant
• Good prognoses types (tubular, lobular)
Conclusions
Breast cancer classification system with clinical relevance
will be based on:
morphology
phenotype
molecular genetics
Next generation molecular methods are likely to provide
greater insight
Routine provision of prognostic and predictive information
Robust validated & standardised routine methods
Gene profiles can provide prognostic and predictive
information and some are validated for clinical use
Quality assurance integrated into service provision
Gene profile methods can be translated to alternative
simpler methods which appear equally effective
Translation of research techniques / methods to routine
clinical practice are to be expected
Pathology has a central role - analytical & coordination
Decision making support systems will be essential
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