medullary like tumours a vanishing diagnosis · burstein md et al. clin cancer...
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Ian Ellis
Division of Cancer and Stem Cells, University of Nottingham
Departments of Histopathology, Nottingham City Hospital NHS Trust
Medullary Like Tumours
A Vanishing Diagnosis
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WHO 2019
Is this the end of Medullary Carcinoma?
Carcinoma with medullary pattern, invasive
carcinoma with neuroendocrine differentiation,
carcinomas with pleomorphic and
choriocarcinomatous patterns, and tumours with
melanocytic features are currently considered to
be special morphological patterns of IBC-NST.
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WHO 2019
These tumours are considered morphological
patterns of IBCNST regardless of the extent of
differentiation/pattern, and the 90% rule for special
subtype is not applied to tumours showing any of
Medullary pattern.
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WHO 2019
Medullary pattern:
• Cancers described as
– medullary carcinoma
– atypical medullary carcinoma
– carcinoma with medullary features
previously recognized as a specific special type of
well-circumscribed carcinoma breast cancer
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WHO 2019
Medullary pattern:
• high histological grade
• pushing margins
• Syncytial architecture with no glandular structures
• regions of necrosis
• a prominent tumour-infiltrating lymphocyte (TIL)
infiltrate
• better clinical outcome than other stage-matched high-
grade cancers.
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WHO 2019
Medullary pattern:
• most often negative for hormone receptors (ER
and PR) and HER2 (triple-negative)
• variably express basal markers such as CK5/6,
CK14, EGFR (HER1), and p53.
• weak hormone receptor expression also occurs
• genomic instability is common
• they are highly proliferative.
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WHO 2019
• As a diagnostic category, “carcinoma with
medullary features” has suffered from poor
interobserver reproducibility
• overlap in features with carcinomas that have
basal-like molecular profiles and carcinomas
associated with BRCA1 mutations.
• recent discovery of the prognostic importance of
TILs in high grade breast cancers appears to
explain the good prognosis of these cancers (and
high-grade cancers not meeting strict medullary
criteria)
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WHO 2019
It is now proposed to:
• consider carcinomas with medullary pattern as
representing one end of the spectrum of the TIL-
rich IBCNSTs rather than a distinct
morphological subtype
• to use the term “IBC-NST with medullary
pattern”
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WHO 2019
“IBC-NST with medullary pattern”
• have histological features that correlate with the
basal-like molecular profiles
• quantification of the degree of TILs present if
clinically relevant
• categorized diagnostically as IBC-NST, with
inclusion of descriptive modifiers referring to
medullary pattern or basal like features.
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WHO 2019
“IBC-NST with medullary pattern”
• Cancers with these features belong to the
immunomodulatory subgroup of triple-negative
carcinomas mainly characterized by a high level
of expression of immune-related and
inflammation genes
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WHO 2012
Carcinoma with medullary features
Definition - Carcinomas with medullary features include
• medullary carcinomas (MC)
• atypical MC
• a subset of invasive ductal carcinomas of no special type
These tumours demonstrate all or some of the following features:
• a circumscribed or pushing border
• a syncytial growth pattern
• cells with high-grade nuclei
• prominent lymphoid infiltration.
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NHS BSP EQA Scheme
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 - - 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
All 0.50 0.70 0.55 0.48 0.89 0.10 0.56 0.56
Subtype of invasive carcinoma
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Medullary Carcinoma
Morphological features
• 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
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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
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Indices included in the second review
• Solid sheets
• Discernibility of cell borders
• Continuous pushing margins
• Lymphocytic infiltrate
• Total mitotic counts
• Vesicular nuclei
• Prominent eosinophilic nucleoli
Breast Cancer Linkage Consortium
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Multivariate AnalysisP value
BRCA1
BRCA2
Mitotic count 0.001
Continuous pushing margins 0.0001
Lymphocytic Infiltrate 0.002
Tubule formation 0.0002
Continuous pushing margins 0.0001
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Familial Breast Cancer
BRCA 1 & 2 Prediction
• BRCA 1 – Oestrogen receptor
– 90% negative (33% controls)
• BRCA 1 – HER 2
– 2.9% ck5/6+ve HER 2 +ve
– 10.8% ck5/6 –ve HER 2 +ve
Lakhani Clin Cancer Res 2005 11 5175
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Familial Breast Cancer
• BRCA 1 – basal phenotype
– Ck 5/6&14 +ve - 44% of all BRCA 1 carriers
– Ck 5/6&14 +ve – < 2% sporadic cancers
Lakhani Clin Cancer Res 2005 11 5175
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Sorlie, et al.
PNAS 2001
ER neg ER pos
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Special types of breast cancer are more
homogeneous at the transcriptome level
Luminal Basal-like Mol apocrine
Micropapillary
Mucinous A
Classic ILC/ Tubular
Mucinous B
Neuroendocrine
Adenoid cystic
Medullary
Metaplastic
Pleomorphic ILC
Apocrine
Weigelt et al. J Pathol 2008
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Somatic Mutations in TNBC
(Cacer Genome Atlas)
TP53 82% PIK3CA 10%
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• The concept of BP has been known for some
time
• First described using electron microscopy >30
years age
• Its potential poor survival first reported by
Dairkee et al in 1987
• High frequency of BRCA 1 gene carriers
Basal Breast Cancer
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Proliferation cluster: cyclin E1,budding uninhibited by benzimidazoles 1 homolog(BUB1) and enhancer of zeste homolog 2 (EZH2)Stem cell cluster: c-KIT, a6 integrin, CK5 and prion protein
Basal Like Genes
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Molecular Sub Types of TNBC
Transcriptomic classification of TNBCs into six subtypes:
• basal-like 1 (BL1)
• basal-like 2 (BL2)
• luminal AR (LAR)
• immunomodulatory (IM)
• mesenchymal (MES)
• mesenchymal stem-like (MES-L)
Lehmann BD et al J Clin Invest 2011;121;2750-2767
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Molecular Types of TNBCTranscriptomic classification of TNBCs revised to four subtypes:
• Basal-like/immune-suppressed (BLIS),
• Basal-like/immune activated (BLIA),
• Luminal (AR)
• Mesenchymal (MES)
Burstein MD et al. Clin Cancer Res 2015;21;1688-1698
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IHC surrogates for Basal
Phenotype
• ER–PR–HER2-negative (triple negative)
• ER–HER2-negative (double negative) status;
sensitivity of 83%; common markers
• ER and HER2 negative and positive for either
EGF receptor or CK5/CK6) that has a sensitivity
of 76% and a specificity of 100%
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WHO 2019
Issues:
Discussion of the basal molecular classes is in a
section titled Triple Negative Breast Cancer
Molecular Subclassification
NST breast cancer is found in all molecular
classes
Are there forms of basal like breast cancer not
recognised at present?
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Basal-like cancerHistological features
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• Grade III• Lymphocytic infiltrate• Pushing borders• High mitotic rate (>19/10HPF)• Central necrosis• Scant cytoplasm• (Atypical) Medullary features• Presence of metaplastic elements
– Squamous cells– Spindle cells
Basal-like cancerHistological features
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Basal Phenotype
Negative
- ER, PgR and AR
- LA CKs
- FHIT protein
- MUC1
- HER2
- BRCA1
Positive
- P-cadherin
- p53
- EGFR
- E-cadherin
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ER
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PR
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HER 2
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Ck 5 6
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Ck 14
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Basal / Classic TNBC Phenotype
• Grade 3
• Duct/NST, Medullary like carcinoma
• High mitotic count, lack of tubule formation, comedo necrosis
• Larger size, LN disease, poorer NPI, DM and recurrence
• High rate of liver, lung, and brain mets, less bone mets
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Triple negative grade 3 versus
all other grade 3 cancers
All triple negative versus
All breast cancers
n=2787
n=540
n=1033
n=497
p=0.00004 p=0.061
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Metastatic pattern
Tsuda et al. Am J Surg Pathol 2000; Hick et al. Am J Surg Pathol 2006; Fulford et al. Breast Cancer Res 2007
XX
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Breast Cancer Subtypes, Race and Age
N Basal HER2+ Luminal A
Luminal B
Unclass
Premenopausal
African-American
97 39% 9% 36% 9% 6%
Postmenopausal African-American
99 14% 7% 59% 16% 4%
Premenopausal non African-American
164 16% 6% 51% 18% 10%
Postmenopausal non African-American
136 16% 6% 58% 16% 4%
TOTAL 496 20% 7% 51% 16% 6%
P=0.0001Adapted from Carey LA et al, ASCO 04
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Sorlie PNAS 2003BRCA1 mutated
Basal Sub-Type
Overlap of BRCA1 and Basal-like
Genotypes
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Familial Breast Cancer
BRCA 1 Phenotype
• Histological features– High grade and mitotic count
– Medullary or atypical medullary type
• Molecular features – ER & PR negative
– HER2 negative
– P53 positive
– Basal ck positive
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BRCA1 downregulation
• High histological grade
• Medullary histological type
• Basal-like immunophenotype
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Hypothesis
• BRCA1 inactivation in Basal-Like cancers
– Gene promoter methylation
– Transcriptional inactivation
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BRCA1 methylation
• ER –ve
• PR –ve
• High histological grade
• Medullary histological type
Catteau et al. Oncogene, 1999; Esteller et al. JNCI 2000; Osin et al. Int J Surg Pathol, 2003
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BRCA1 methylation in metaplastic breast carcinomas
• BRCA1 gene promoter methylation
– 17/ 27 (63%)
U M U M U M U M U M U M U M U M
p<0.0005
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Basal-like carcinomas
Salivary gland-like
tumours
IDC
Basal-likeMedullary Metaplastic
BRCA1 methylationBRCA1
downregulation?
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Triple Negative Breast Cancer
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WHO 2019
What I am going to do when reporting a case of
Triple Negative Breast Cancer
Type: Consider the recognised histological types:
NST
Medullary like
Basal Like
Metaplastic
Apocrine
Salivary like
PS. Do not forget metastasis
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WHO 2019
What I am going to do when reporting a case of
Triple Negative Breast Cancer
Potential additional information:
AR
TILs
PDL1
BRCA germline mutation
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