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

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.

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.

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

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.

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.

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)

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”

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.

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

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.

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

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

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

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

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

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

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

Sorlie, et al.

PNAS 2001

ER neg ER pos

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

Somatic Mutations in TNBC

(Cacer Genome Atlas)

TP53 82% PIK3CA 10%

• 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

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

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

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

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%

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?

Basal-like cancerHistological features

• 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

Basal Phenotype

Negative

- ER, PgR and AR

- LA CKs

- FHIT protein

- MUC1

- HER2

- BRCA1

Positive

- P-cadherin

- p53

- EGFR

- E-cadherin

ER

PR

HER 2

Ck 5 6

Ck 14

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

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

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

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

Sorlie PNAS 2003BRCA1 mutated

Basal Sub-Type

Overlap of BRCA1 and Basal-like

Genotypes

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

BRCA1 downregulation

• High histological grade

• Medullary histological type

• Basal-like immunophenotype

Hypothesis

• BRCA1 inactivation in Basal-Like cancers

– Gene promoter methylation

– Transcriptional inactivation

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

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

Basal-like carcinomas

Salivary gland-like

tumours

IDC

Basal-likeMedullary Metaplastic

BRCA1 methylationBRCA1

downregulation?

Triple Negative Breast Cancer

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

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