Download Thurs_Boardroom_0832 Breast Pathology Zena Slim

Pathology of Breast Cancer
Zena Slim
Senior Registrar in Anatomical Pathology
Aims
1. Current concepts in breast cancer evolution
2. In-situ carcinoma
3. Classification of invasive breast carcinoma
4. Reporting of breast cancer
5. Genomic profiling
Terminal Duct Lobular Unit (TDLU)
Breast cancer evolution
Breast cancer is biologically heterogeneous disease
Lopez-Garcia M A, Geyer F C, Lacroix-Triki M, et al Breast cancer precursors
revisited: molecular features and progression pathways (2010) Histopathology
57, 171–192
LOW GRADE
NEOPLASIA PATHWAY
HIGH GRADE
NEOPLASIA PATHWAY
IN-SITU CARCINOMAS
(PRE-INVASIVE LESIONS - INTRADUCTAL CANCER - NON-INVASIVE CARCINOMA
PRECURSORS TO INVASIVE MALIGNANCY
Approximately 20-25% of screen-detected cancer is in-situ disease
(NHS Breast Screening Programme Audit 2010 and BreastScreen Aotearoa Annual Report 2012)
Ductal Carcinoma In-Situ
Lobular Carcinoma In-Situ
Ductal Carcinoma In situ (DCIS)
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Average age of presentation 50-59 years
Most unilateral
Segmental disease
Palpable mass, discharge or Paget disease –
80% detected on mammography alone
• Incidence rising in most countries with
screening programmes
• Risk factors: Family history, nulliparity, late
age at first birth, late menopause, raised BMI
and increased mammographic breast density.
Ductal Carcinoma In situ
• Precursor (non-obligate) to invasive breast cancer
• Highly heterogenous group of lesions with variable risk of progression to invasive
cancer
• Overall relative risk of developing invasive breast cancer 8-10%
• Low-grade and high-grade DCIS appear to represent genetically distinct disorders
leading to distinct types of invasive cancer
• Breast cancer specific mortality is extremely low (approximately 1-2.6%) dying
from invasive breast cancer 8-10 years after a diagnosis.
Ductal Carcinoma In situ (DCIS)
Low-grade
Interval to
progression to
invasive cancer
>15 years
Intermediate grade
High-grade
Interval to
progression to
invasive cancer is
on average 5 years
Ductal Carcinoma In situ (DCIS)
• 15 - 20 % of cases diagnosed on biopsy will turn out to be invasive
carcinoma on surgical excision
• Diagnostic difficulty
• Distinguishing low-grade DCIS from ADH
• Missed small foci of invasive carcinoma
Management
• Requires excision
• Managed as high-risk lesion with complete margin resection
• Radiotherapy
• Monitoring with aim of detecting recurrences and new carcinoma
Lobular Carcinoma In-situ (LCIS)
• Atypical non-cohesive cells filling TDLU +/- spread into the ductal system
• LCIS and Atypical lobular hyperplasia = lobular neoplasia.
• Detected in 0.5 – 4% of otherwise benign breast biopsies (often incidental)
• Multi-centric in 85% and bilateral in 30-67%
• Some diagnostic challenges on biopsy
• Types
• Classic LCIS
• Classic type with necrosis
• Pleomorphic LCIS (more aggressive)
• Bulky/mass forming LCIS
LCIS ‘variants’
• Can progress to any type of invasive breast cancer but most common is
invasive lobular and ‘special type’ carcinoma (low-grade pathway)
• Insufficient evidence on time course for progression to invasive carcinoma
Lobular Carcinoma In-situ (LCIS)
• Careful clinical and radiological
correlation to decide if surgical
excision is warranted
• Variant LCIS diagnosed on core
needs diagnostic excision.
• Ongoing surveillance and close
follow-up of both breasts
In-situ carcinoma pathology reports
• Lesion size
• Nuclear grade
• Architecture
• Papillary, micropapillary, comedo cribriform
• Associated micro-calcification
• Presence of necrosis (poor prognostic sign)
• Margin status (for DCIS, pleomorphic and variant LCIS)
INVASIVE CARCINOMAS
CLASSIFICATION OF INVASIVE BREAST
CANCER
HISTOLOGICAL TYPE
HISTOLOGICAL GRADE
IMMUNOHISTOCHEMICAL TYPE
(HORMONE RECEPTOR AND HER2 STATUS)
INTRINSIC MOLECULAR TYPE
CLASSIFICATION OF INVASIVE BREAST CANCER – HISTOLOGICAL TYPE
Invasive carcinoma of no special type
(NST)
Pleomorphic carcinoma
Carcinoma with osteoclast-like stromal giant cells
Carcinoma with choriocarcinomatous features
Carcinoma with melanotic features
Invasive lobular carcinoma
Classic lobular carcinoma
Solid lobular carcinoma
Alveolar lobular carcinoma
Pleomorphic lobular carcinoma
Tubulolobular carcinoma
Mixed lobular carcinoma
Tubular carcinoma
Cribiform carcinoma
Mucinous carcinoma
Carcinoma with medullary features
Medullary carcinoma
Atypical medullary carcinoma
Invasive carcinoma NST with medullary features
Carcinoma with apocrine differentiation
Carcinoma with signet-ring differentiation
Invasive micropapillary carcinoma
Metaplastic carcinoma of no special type
Low-grade adenosquamous carcinoma
Fibromatosis-like metaplastic carcinoma
Squamous cells carcinoma
Spindle cell carcinoma
Metaplastic carcinoma mesenchymal differentiation
Chondroid differentiation
Osseous differentiation
Other types of mesenchymal differentiation
Mixed metaplastic carcinoma
Myoepithelial carcinoma
Rare types
Carcinoma with neuroendocrine features
Neuroendocrine tumor, well differentiated
Neuroendocrine carcinoma, poorly differentiated
(small cell carcinoma)
Carcinoma with neuroendocrine differentiation
Secretory carcinoma
Invasive papillary carcinoma
Acinic cell carcinoma
Mucoepidermoid carcinoma
Polymorphous carcinoma
Oncocytic carcinoma
Lipid-rich carcinoma
Glycogen-rich clear cell carcinoma
Sebaceous carcinoma
Salivary gland/skin adnexal type tumors
Cylindroma
Clear cell hidradenoma
WHO Classification
of Tumours of the
Breast, Fourth
Edition 2012
Invasive
micropapillary
Invasive
lobular
Invasive
mucinous
Invasive
ductal
CLASSIFICATION OF INVASIVE BREAST CANCER – HISTOLOGICAL GRADE
GRADE IS STRONG PROGNOSTIC FACTOR
• Nottingham Grading system: semi-quantitative assessment of tumour differentiation based on
• % tubule formation
• degree of nuclear pleomorphism
• Mitotic activity
Rakha et al. Breast Cancer Research 2010 12:207
CLASSIFICATION OF INVASIVE BREAST CANCER – IMMUNOHISTOCHEMICAL TYPE
ER (oestrogen receptor) PR (progesterone receptor) and HER-2
powerful biomarkers with prognostic and predictive utility
• Hormone receptor status
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•
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•
•
•
ER and PR are nuclear transcription factors driving cell proliferation
Testing performed by immunohistochemistry
Level of expression given a score (Allred score) based on intensity and proportion of positive cells
80% of all invasive breast cancers show positivity (1-100%)
ER+ tumour is defined as > = 1%
ER status strong predictive factor for response to hormonal therapies (Tamoxifen)
PR expression correlates highly with ER expression
• Her-2 status
• Her-2/neu oncogene located in C17 encodes a growth factor receptor
• Testing performed by immunohistochemistry and ISH (in-situ hybridisation)
• Assessment of overexpression graded 0, 1+, 2+, or 3+.
• HER-2 –positive tumours will respond favourably to Her-2 targeted therapies
Traztuzumab (Herceptin) and Lapatinib (Tykerb)
CLASSIFICATION OF INVASIVE BREAST CANCER – MOLECULAR SUBTYPE
15-20%
Perou CM, Sorlie T, Eisen MB, et al.
Molecular portraits of human breast tumours. Nature
2000;406(6797):747–752.
Basal-like breast cancers
• Most (77%) are ‘triple negative’ (ER/PR and HER2 negative)
• Account for 10-20% of all breast cancers
• More commonly identified in younger, premenopausal women (4656)
• More common in BRCA1 carriers and African-Americans
• Higher lymph node stage more frequent
• Aggressive clinical course with early metastatic spread
(independent of axillary nodal status and tumour size)
• High response rate to neo-adjuvant chemo but no targeted therapy
available
CK5/6
CK14
National Structured Pathology Reporting of Cancer Project
International Collaboration on Cancer
Reporting
Structured Pathology Reporting of Cancer
“Contributes to better cancer control through improvements in
• Clinical management and treatment planning
• Cancer notification, registration
• Research.”
Structured reporting of invasive breast
carcinoma
Prognostic features
• Tumour size
• Histological type
• Histological grade
• Lympho-vascular invasion
• Lymph node status (number
dissected and number positive)
• Changes in adjacent breast
(DCIS,LCIS,ADH,ALH)
• Hormone (ER,PR) receptor status
• HER2 receptor overexpression
(positive)
• Predictive features
• Oestrogen, Progesterone and HER2 status
• Associated with local recurrence
• Accompanying DCIS (if extensive in
breast conservation surgery)
• Margins of excision
• STAGE (AJCC TNM 7th Edition)
Breast Cancer in the age of
‘personalised medicine’
Genomics and Bioinformatics
• Cornerstone of personalised medicine
• Introduction of Next Generation Sequencing – massive parallel
sequencing in 2005
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•
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Whole genome
Exome (1-2% of total genome)
Targeted gene panels
Transcriptome (RNA)
• Cost of sequencing whole genome is 1000USD (Illumina MiSeq)
• Diagnostic, predictive, prognostic, and pharmacogenetic uses
TUMOUR GENE EXPRESSION PROFILING
‘GENE SIGNATURES’
‘Tools to estimate risk of recurrence and predict who would be
likely benefit from chemotherapy’
Oncotype DX®
• hormone receptor-positive, early-stage breast cancer and are node-negative.
• Screens activity of set of 21 genes to determine a “recurrence score
MammaPrint®
• used to help determine how likely breast cancers are to recur in a distant part of the body after initial
treatment.
• Screens activity of 70 different genes to determine if the cancer is low risk or high risk.
• Ongoing prospective trials to assess their clinical efficacy – results not available to date
TAKE HOME MESSAGES
• Breast cancer is a highly heterogeneous group of diseases
• Grade of in-situ cancer is a predictor of rate of progression to invasive disease
• Classification of breast cancer encompasses histological type and grade, hormone
receptor and HER-receptor expression and molecular subtypes.
• Most important prognostic and predictive features for invasive breast cancer are
tumour size and grade, lymph node status, hormone (ER,PR) receptor status and
Her-2 overexpression.
• Emerging role of genomic analysis and next generation sequencing in
‘individualizing’ the treatment of patients with breast cancer
References
1. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchió C & Reis-Filho JS; Breast
cancer precursors revisited: molecular features and progression pathways (2010)
Histopathology 57, 171–192
2. Lakhani S, Ellis I, Schnitt S, et al.. WHO Classification of Tumours of the Breast. 4th
Edition. Lyon: IARC Press; 2012
3. Rakha E, Reis-Filho JS, Baehner F. et al. Breast cancer prognostic classification in
the molecular era: the role of histological grade. Breast Cancer Research 2010 12:207
4. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours.
Nature 2000;406(6797):747–752.
5. https://www.rcpa.edu.au/Library/Practising-Pathology/Structured-PathologyReporting-of-Cancer/Cancer-Protocols
Thanks for your attention