who classification of lung cancer 2015...
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WHO Classification of Lung Cancer 2015: Immunohistochemistry and Molecular testing
Prof Keith M Kerr Department of Pathology
Aberdeen University Medical School Aberdeen Royal Infirmary
Foresterhill, Aberdeen, Scotland, UK
WHO Classification of Lung Cancer 2015: Immunohistochemistry and Molecular testing
Aalborg
Why the need for change? • Lack of relevance beyond surgical pathology
• Emerging data – Genetics
– Pathology
• Multidisciplinary diagnosis – Tumour boards / MDT
– Correlation with radiology
• Therapy Diversity – Cytotoxic agents
– Molecular targeted therapy
– Adjuvant therapy
– Surgical approaches
2015 WHO CLASSIFICATION • 1-1: Introduction 1-1A Lung cancer staging and grading
1-1B Rationale for classification in small biopsies and cytology
1-1C Terminology and criteria in non-resection specimens
1-1D Molecular testing for treatment selection in lung cancer
• 1-2: Adenocarcinoma 1-2A Invasive adenocarcinoma
1-2B Variants of invasive adenocarcinoma
1-2C Minimally invasive adenocarcinoma
• 1-2: Adenocarcinoma (continued) 1-2D Preinvasive lesions
1-2D-i: Atypical adenomatous hyperplasia
1-2D-ii: Adenocarcinoma in situ
• 1-3: Squamous cell carcinoma 1-3A: Keratinizing and nonkeratinizing squamous cell carcinoma
1-3B: Basaloid carcinoma
1-3C: Preinvasive lesion: Squamous carcinoma in situ
2015 WHO CLASSIFICATION • 1-4: Neuroendocrine Tumours 1-4A: Small cell carcinoma
1-4B: Large cell neuroendocrine carcinoma
1-4C: Carcinoid tumors
1-4D: Preinvasive lesion: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
• 1-5: Large cell carcinoma
• 1-6: Adenosquamous carcinoma
• 1-7: Sarcomatoid carcinoma 1-7A: Pleomorphic, spindle cell and giant cell carcinoma
1-7B: Carcinosarcoma
1-7C: Pulmonary blastoma
• 1-8: Other carcinomas 1-8A: Lymphoepithelioma-like carcinoma
1-8B: NUT-carcinoma
2015 WHO CLASSIFICATION
1-9: Salivary gland-type tumours
1-9A Mucoepidermoid carcinoma
1-9B Adenoid cystic carcinoma
1-9C Epithelial-myoepithelial carcinoma
1-2D Pleomorphic adenoma
1-10: Papillomas
1-10A: Squamous papilloma
1-10B: Glandular papilloma
1-10C: Mixed squamous and glandular papilloma
1-11: Adenomas
1-11A: Sclerosing pneumocytoma
1-11B: Alveolar adenoma
1-11C: Papillary adenoma
1-11D: Mucinous cystadenoma
1-11E: Mucus gland adenoma
1-12: Mesenchymal tumours
1-12A: Hamartoma
1-12B: Chondroma
1-12C: PEComatous tumours (LAM, PEComa)
1-12D: Congenital peribronchial myofibroblastic tumour
1-12E: Diffuse lymphangiomatosis
1-12F: IMT
1-12G: Epithelioid haemangioedothelioma
1-12: Mesenchymal tumours, cont’d
1-12H: Pleuropulmonary blastoma
1-12I: Synovial sarcoma
1-12J: Pulmonary artery intimal saraoma
1-12K: Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation
1-12L: Myoepithelial tumours
1-12M: Others
1-13: Lymphoproliferative disorders
1-13A: Marginal zone B-cell lymphoma of MALT origin
1-13B: Diffuse large B-cell lymphoma
1-13C: Lymphomatoid granulomatosis
1-13D: Intravascular lymphoma
1-13E: Langerhans cell histiocytosis
1-13F: Erdheim Chester disease
1-14: Tumours of ectopic origin
1-14A: Germ cell tumours
1-14B: Intrapulmonary thymoma
1-14C: Melanoma
1-14D: Meningioma
1-15: Metastases to the lung
Today’s presentation……….
• Large cell carcinoma – Sarcomatoid tumours
• Adenocarcinoma
• Squamous cell carcinoma
• Adenosquamous carcinoma
• Neuroendocrine tumours
• Small sample diagnosis
• Integration of Molecular data in a clinically meaningful way
Large Cell Carcinoma: 2004 definition
Definition
Large cell carcinoma is an undifferentiated
non-small cell carcinoma (NSCC)
that lacks the cytological (and architectural)
features of small cell carcinoma, adenocarcinoma,
or squamous cell carcinoma. The diagnosis requires a thoroughly sampled resected
tumour, and cannot be made on non-resection
or cytology specimens. ~10% of cases?
Large Cell Carcinomas: 2004
• Non-variant Large Cell Carcinoma, NOS
• Variant Large Cell Carcinomas – Basaloid Carcinomas
– Large Cell Neuroendocrine Carcinomas
– Lymphoepithelioma-like Carcinomas
– Clear Cell Carcinoma
– Large Cell carcinoma with Rhabdoid phenotype
2004 Large Cell Carcinoma variant: Clear Cell Carcinoma 2015 A morphological description Not a diagnosis
2004
Large Cell Carcinoma variant:
Large cell carcinoma
with rhabdoid phenotype 2015 A morphological description Not a diagnosis
2004 Large Cell Carcinoma variant: Lymphoepithelioma-like Carcinoma 2015 1.8 Other and unclassified carcinomas
2004 Large Cell Carcinoma variant: Large Cell Neuroendocrine Carcinoma 2015 1-4 Neuroendocrine Tumours 1-4B Large Cell Neuroendocrine Carcinoma
Immunohistochemical studies show consistent strong staining with markers associated with Squamous cell carcinomas: p63, p40, CK5/6
p63
2004 Large Cell Carcinoma variant: Basaloid Carcinoma 2015 1-3 Squamous Cell Carcinomas 1-3B Basaloid Carcinoma
Molecular studies in Basaloid carcinoma of lung
Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity.
Clin Cancer Res. 2014 Sep 4. pii:clincanres.0459.2014. [Epub ahead of print]
• DNA copy number aberrations
• mRNA expression pangenomic profiles
• Specific genetic profile
• ‘Squamous genes’ underexpressed
• SOX4 and IVL by IHC – 94% discrimination basaloid vs non-basaloid
• Very poor post-op survival
Large Cell Carcinoma – NOS: 2004
• Clinically and radiologically similar to other NSCLCs – Males, smoking related
– Tend to be more peripheral, large masses, but not always
– Pleural and Chest wall invasion common
– Usual metastatic sites
Large Cell Carcinoma: IHC Lineage
58%
18%
11%
13%
48%
22%
13%
17%
100%
Kerr KM et al, Lung Cancer 2012
SQC lineagep63p40CK5/6Strong/diffuse
AC lineageTTF1Napsin AAny staining
SQC
AC
Well Differentiated Squamous Cell Ca
Poorly Differentiated Squamous Cell Ca
Well Differentiated Adenocarcinoma
Poorly Differentiated Adenocarcinoma
Tumour progression and de-differentiation
Morphologically Large Cell
Carcinoma
Pathologists will differ How they call marginal cases
Large Cell Carcinomas -Mutations
N = Country EGFR KRAS ALK BRAF PIK3CA MEK
31 Italy 0 0 - - - -
6 Italy 0 50% - - - -
18 Japan 0 6% - - - -
72 Scotland 0* 8.3% 0 1 0 -
102 USA 1 29% 3 2 1 1
20 Italy 1 40% 1 - - -
57 USA 1 43% - - - -
Marchetti A et al. J Clin Oncol 2005 Sartori G et al. Am J Clin Pathol 2009
Takeuchi et al, J Clin Oncol 2006 Kerr KM et al, Lung Cancer 2012
Rekhtman N et al. Mon Pathol 2013 Rossi G et al, Virch Arch 2014
Hwang D et al, Arch Path Lab Med 2014 * EGFR c.2508C>T;p. R836R (SNP) in a Basaloid Ca
Mutations largely matched IHC lineage, where dataare available
1% 2%25%Overall prevalence
Diagnosis of Large Cell Carcinoma: 2015
Definition
Large cell carcinoma is an undifferentiated non-small cell carcinoma (NSCC) that lacks the cytological, architectural, and immunohistochemical features of small cell carcinoma, adenocarcinoma, or squamous cell carcinoma. The diagnosis requires a thoroughly sampled resected tumour, and cannot be made on non-resection or cytology specimens.
The diagnosis of large cell carcinoma is only made when
additional staining (Immunohistochemistry and/or mucin stains)
is negative, unclear, or not available.
TTF1 NapsinA
p63 CK5/6
2015:Adenocarcinoma: Solid subtype
p63 TTF1
HMWCK CK5/6
2015:Non-keratinizing Squamous Cell Carcinoma
Well Differentiated Squamous Cell Ca
Poorly Differentiated Squamous Cell Ca
Well Differentiated Adenocarcinoma
Poorly Differentiated Adenocarcinoma
Tumour progression and de-differentiation
Pathologists will still differ how they call marginal cases !!!!
Morphology &
Immunohistochemistry Large Cell Carcinoma
Non-keratinising Squamous Cell Ca
Solid-pattern Adenocarcinoma
ICD-O code Large cell carcinoma 8012/3
Based on their immunohistochemical profiles, three subtypes of large cell carcinoma can be distinguished
- Large cell carcinoma with null immunohistochemical features - Large cell carcinoma with unclear immunohistochemical features - Large cell carcinoma with no additional stains
30% of former cohort remains?
Undifferentiated carcinoma which is not Small Cell (or LCNEC)
IN A RESECTION SPECIMEN
Mucin Stain > 5 vacuoles in at
least each of 2 hpf
Solid adenocarcinoma
yes
Immunohistochemistry P63/p40/CK5-6…… TTF1/Napsin A……
‘Adeno’ positive
‘Squamous’ positive
‘Both’ positive: Discrete and >10% each
Non-keratinising Squamous cell
carcinoma
Adenosquamouscarcinoma
no
Which markers and how much staining?
For Adenocarcinoma
• TTF1
• Napsin A
• Surfactant apoproteins
• CK7
• Definite staining but it can be weak and patchy. Which clone?
For Squamous Cell Carcinoma
• P63
• P40
• CK5/6
• Desmocollin
• 34betaE12
• Strong and diffuse staining ONLY
Morphologically poorly differentiated lesions do (relatively) badly.
1-7: Sarcomatoid Carcinomas
1-7A Pleomorphic, Spindle cell and Giant cell carcinomas
1-7B Carcinosarcoma
1-7C Pulmonary Blastoma
Pleomorphic, Spindle cell and Giant cell carcinomas
DefinitionPleomorphic carcinoma is a poorly differentiated non-small cell lung carcinoma that contains at least 10% spindle and/or giant cells, with the remainder of the tumour showing squamous cell carcinoma, adenocarcinoma, or undifferentiated non-small cell carcinoma.
Spindle cell carcinoma consists of an almost pure population of epithelial spindle cells, with no differentiated carcinomatous elements.
Giant cell carcinoma consists almost entirely of tumour giant cells (including multinucleated cells), with no differentiated carcinomatous elements.
Sarcomatoid Carcinomas
• Many are combined with ‘standard’ NSCLC elements – Adenocarcinoma
– Squamous cell carcinoma
– Large Cell carcinoma
• Pure forms are very rare – Giant cell carcinoma
– Spindle cell carcinoma
0.3% of Lung Cancers
1-3% of Lung Cancers
Pleomorphic carcinoma with squamous cell carcinoma
Sarcomatoid carcinoma with squamous cell carcinoma
Sarcomatoid carcinoma with adenocarcinoma ‘Relatively’ Pure Spindle Cell and Giant Cell Carcinoma are extremely rare
43%
28%
43%
28%
Pleomorphic / Sarcomatoid Carcinoma Lineage
20%
9%
40%
33%
7%
20%
27%
27%
46%
67%
33%
Sarcomatoid Carcinomas -Mutations
No of Cases Country EGFR mutations KRAS mutations BRAF/ALK/PIK3CA
61 Korea
15% 89% exon19del
11% L858R exon21
10% -
17 Japan
18% 67% exon19del
33% L858R exon21
- -
13 Italy 0 37% -
27 Italy - 22% -
35 Scotland 0 28.6% 0
Lee S et al. J Can Res Clin Oncol 2010 Kaira K et al. J Thorac Oncol 2010 Sartori et al. Am J Clin Pathol 2009
Pelosi G et al. Mod Pathol 2004
24.4%
A malignant epithelial tumour with glandular differentiation
or mucous production by tumour cells
Adenocarcinoma: 2004
New IASLC/ATS/ERS Adenocarcinoma classification
• What was wrong with ‘WHO 2004’? – Mixed adenocarcinoma
– Bronchioloalveolar carcinoma
– Small diagnostic samples
• New ‘solutions’ for 2015 – Predominant pattern subtyping
– Adenocarcinoma in situ
– Minimally invasive adenocarcinoma
– Multifocal tumours
– Predictive sub-typing by IHC
Non-mucinous lepidic Acinar invasive pattern
Papillary pattern Solid with mucin pattern
Micropapillary pattern
Post operative survival vs predominant pattern in pulmonary adenocarcinoma – five patterns
Solid, MP
AIS, MIA Lepidic
Acinar Papillary
Yoshizawa A et al. Mod Pathol 2011; 24, 653-664 Stage 1 only Russell P et al. J Thorac Oncol 2011; epub June Stages 1-3 Warth A et al. J Clin Oncol 2012; Mar 5 epub Stages 1-4
Adjuvant therapy? Selection by Stage Selection by Adenocarcinoma
Predominant pattern Histology?
‘High Grade’ Solid, MP ,
Muc/colloid
Yoshizawa A et al. Mod Pathol 2011; 24, 653-664 Goldstraw P et al JTO 2007; 2, 706-714
Bronchioloalveolar carcinoma (BAC)
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WHO Classification of Lung Tumours, 1999 & 2004
What is (was) bronchioloalveolar carcinoma (BAC)?
• Localised non-invasive adenocarcinoma – Non-mucinous
– Mucinous
• Invasive adenocarcinoma with BAC components or features
• Multifocal advanced adenocarcinomas – Mucinous BAC
– Non-mucinous forms
– ‘alveolar cell carcinoma’
Bronchioloalveolar carcinoma (BAC)
An adenocarcinoma with a pure bronchioloalveolar pattern
and NO EVIDENCE of stromal, vascular or pleural invasion.
WHO Classification of Lung Tumours, 1999 & 2004
Pure Localised Non-Mucinous Bronchioloalveolar Carcinoma is...
Adenocarcinoma in situ
0 500 1000 1500 2000
Small Adenocarcinoma of the Lung Histologic Characteristics and Prognosis Noguchi M et al Cancer 1995; 75, 2844-2852
Post-operative Survival (Days)
Mixed
No BAC
Tumour Histology % Alive
% Alive
100%
80%
60%
40%
20%
226 adenocarcinomas 2cm or less in diameter
5 yrs
This IS Adenocarcinoma in situ
Pure BAC
Lepid(o)- Lepis (Gk) Scale ‘LEPIDIC pattern’
Lepidoptera Lepidotrichium
Lepidosaurian
Ann Thorac Surg 2000;69, 893-897
Adenocarcinomas3 cm or less in diameter
Features which may appear to indicate a more aggressive tumour….. ….in a lesion <3cm diameter……. …..but which DO NOT, in practice, increase metastatic risk.
Minimally Invasive Adenocarcinoma?
• Recognition of this lesion?
• How to treat this lesion?
• Have we created a ‘monster’?
Boland JM et al. Mod Pathol 2012; 25 suppl2,474A ‘Moderate to Good agreement’
In situ adenocarcinoma or invasive adenocarcinoma?
The nature of the ‘lepidic’ tumour.
Is all lepidic (BAC) pattern really
adenocarcinoma-in-situ?
Lepidicgrowth
Invasive tumourAdencarcinoma-in-situ
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
• consolidation
• air bronchograms
• multifocal subsolid nodules/masses
Adenocarcinoma - Cribriform pattern: Solid or Acinar?
Spread Through Alveolar Spaces: STAS
TTF1 (clone 8G7G3/1) TRU and lesions arising from it
AAH AIS
Invasive Adenocarcinoma
TTF1 (8G7G3/1) TTF1 (SP141)
P63/CK7 combined TTF1 (8G7G3/1) / CK5-6 combined
TTF1 (SP141)
Bronchial biopsy
The bronchial epithelium derives from a different stem cell compartment than the peripheral Terminal Respiratory Unit
Adenocarcinoma 2015……. • Definition
• Invasive adenocarcinoma is a malignant epithelial tumour with glandular differentiation, mucin production, or pneumocyte marker expression. The tumours show an acinar, papillary, micropapillary, lepidic, or solid growth pattern, with either mucin or pneumocyte marker expression. After comprehensive histological subtyping in 5–10% increments, the tumours are classified according to their predominant pattern.
• ICD-O codes
• Adenocarcinoma 8140/3
• Lepidic adenocarcinoma 8250/3
• Acinar adenocarcinoma 8551/3
• Papillary adenocarcinoma 8260/3
• Micropapillary adenocarcinoma 8265/3
• Solid adenocarcinoma 8230/3
• 1-2: Adenocarcinoma
1-2A Invasive adenocarcinoma
1-2B Variants of invasive adenocarcinoma
1-2C Minimally invasive adenocarcinoma
1-2D Preinvasive lesions
1-2D-i: Atypical adenomatous hyperplasia
1-2D-ii: Adenocarcinoma in situ
Squamous cell carcinoma
Only TWO defining features•Keratinisation•Inter-cellular bridges
‘Squamoid features’• Sheets and islands• Palisading• Stratification• Irregular nuclei• Clumped chromatin• Eosinophilic glassy
cytoplasm• Intercellular gaps
Squamous Cell Carcinoma: Variants • Basaloid
– Keep. Genuine evidence of poorer prognosis
• Papillary – Not sure. Just a growth pattern? HPV associated?
• Small Cell – What is it? No publications since 2004
• Clear Cell – No. Cytological change common in lung cancer
• Microcystic Weissferdt A, Moran CA Am J Clin Pathol 2011;136,436
• ‘Creeping carcinoma’ – Early disease. Less aggresssive
• Peripheral squamous cell carcinoma – Rise in prevalence. Better prognosis.
Squamous Cell Carcinoma: Variants • Basaloid
– Keep. Genuine evidence of poorer prognosis
• Papillary – Not sure. Just a growth pattern? HPV associated?
• Small Cell – What is it? No publications since 2004
• Clear Cell – No. Cytological change common in lung cancer
• Microcystic Weissferdt A, Moran CA Am J Clin Pathol 2011;136,436
• ‘Creeping carcinoma’ – Early disease. Less aggresssive
• Peripheral squamous cell carcinoma – Rise in prevalence. Better prognosis.
Squamous Cell Carcinoma
1-3A Keratinizing and Non-keratinizing SCC Squamous cell carcinoma is a malignant epithelial tumour that either shows keratinization and/or intercellular bridges, or is a morphologically undifferentiated non-small cell carcinoma that expresses immunohistochemical markers of squamous differentiation.
1-3B Basaloid Carcinoma Basaloid carcinoma is a poorly differentiated malignant epithelial tumour that presents in its pure form as a proliferation of small cells with lobular architecture and peripheral palisading. These cells lack squamous morphology, but show immunohistochemical expression of squamous markers. Tumours with a keratinizing or non-keratinizing squamous cell component, but a basaloid component of > 50%, are also classified as basaloid carcinoma.
1-3C Pre-invasive disease – Squamous dysplasia and Carcinoma in situ
Adenosquamous Carcinoma
Definition
A carcinoma showing components of both squamous cell carcinoma and adenocarcinoma, each component comprising at least 10% of the tumour.
IHC-defined solid adenocarcinoma and non-keratinising squamous cell carcinoma are accepted for this diagnosis, provided the IHC is unequivocal and the respective zones are discrete and >10% each
p63 TTF1
CK7-p63
LCC-NOS: adenosquamous carcinoma by IHC
• 22% showed possible adenocarcinoma lineage
• 48% showed possible squamous cell carcinoma lineage
• 1.6% showed a possible adenosquamous lineage
Which are the Neuroendocrine tumours?
Tumours of the Lung: WHO 2004
• Squamous cell carcinoma
• Small cell carcinoma
• Adenocarcinoma
• Large cell carcinoma
• Adenosquamous carcinoma
• Sarcomatoid carcinoma
• Carcinoid tumour
• Salivary-type carcinomas
Primitive NeuroectodermalTumoursPNETParaganglioma etc
Which are the Neuroendocrine tumours?
Tumours of the Lung: WHO 2004
• Squamous cell carcinoma
• Small cell carcinoma
• Adenocarcinoma
• Large cell carcinoma – Large cell neuroendocrine subtype (LCNEC)
• Adenosquamous carcinoma
• Sarcomatoid carcinoma
• Carcinoid tumour
• Salivary-type carcinomas
1-4: Neuroendocrine tumours
High Grade Neuroendocrine tumours
• 1-4A: Small cell carcinoma
• 1-4B: Large cell neuroendocrine carcinoma (LCNEC)
Low Grade Neuroendocrine tumours
• 1-4C: Carcinoid tumours – Typical Carcinoid
– Atypical Carcinoid
Precursor lesion
• 1-4D: Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH)
Small Cell Carcinoma
Large Cell Neuroendocrine Carcinoma
Chromogranin
CD56
Synaptophysin
TTF1
Pulmonary Carcinoid tumours
• Clearly different from High Grade NE tumours – Aetiology
– Morphology
– Biology
– Genetics
• Proliferative activity important in definition – Can ‘cell cycle’ IHC assist in this distinction?
• ‘Peripheral’ spindle cell carcinoids are different?
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia
TTF1 8G7G3/1
SCLC
Peripheral spindle cell carcinoid
LCNEC
Central insular/trabecular cell carcinoid
Carcinoid, Large Cell Carcinoma and Adenocarcinoma all distinct
SCLC and LCNECcould not be distinguished at a molecular level
510 AFIP Cases: TC-92; AC-127, LCNEC – 152, SCLC – 139; p<0.0001. Data courtesy of WD Travis.
LUNG NE TUMORS: SURVIVAL
TC
AC
SCLC & LCNEC
Surgically resected
Clinical requirements of diagnosis: Advanced Disease
Non-surgical cases – Most patients (85-90%)
– Hierarchy of diagnosis
– Refine as much as possible
– Sample limitations
Now a critical determinant of Therapy Choice
Identify malignancy as
carcinoma
Metastatic disease
Primary Lung Cancer
Small Cell Lung
Cancer
NOT Small Cell Lung Cancer
Subtype NSCLC?
Therapy Choice
NSCLC subtyping in small samples
• Prevalence depends on sample type & origin
• Morphological diagnostic accuracy relatively low – Lack of reliable cellular features in adenocarcinoma
– Overinterpretation of ‘squamoid’ appearances
– Undifferentiated areas
– Tumour heterogeneity
• NSCLC-NOS – Majority (66%) are adenocarcinoma
Edwards S et al, J Clin Pathol 2000; 53, 537-540
Small biopsy/Cytology: Thresholds of ‘certainty’
Sure Cannot say Hmmm........
NSCLC-NOS
NSCLC – probably adenocarcinoma
TTF1 positive in tumour cell nuclei
Tumour cells express Nuclear p63
NSCLC- probably squamous cell
Subtyping NSCLC: How good?
Predictive IHC has ‘levelled the playing field’ Better diagnosis possible on poorer specimens
25%
40%
6%
Predictive IHC in NSCLC-NOS
• Utilise sparingly, interpret with care
• Does not ‘confirm’ diagnosis
• Reduces ‘NOS rate’ to under 10%, but cannot abolish it
• Essentially ‘qualifies’ NSCLC-NOS – NSCLC-NOS
– NSCLC, ‘favour squamous’ (p63, p40, CK5/6)
– NSCLC, ‘favour adenocarcinoma’ (TTF1)
Kerr KM. J Clin Pathol 2013;66:832–838 ROS1 fusion genes 1.1-2.6% Adenocarcinomas Fusion correlates with protein (IHC) Sensitive to crizotinib
NTRK1 fusion MPRIP-NTRK1 and CD74-NTRK1 3.3% of ‘onco-negative’ adenocarcinomas Trk inhibitors exist Vaishnavi A et al. Nat Med 2013; 19, 1469-72
CD74-NRG1 fusion Search in ‘onco-negative’ adenocarcinomas ERBB3 and PI3K-AKT pathway activation Mucinous adenocarcinomas Potential therapeutic target Fernandez-Cuesta L et al. Can Disc 2014; jan30 epub
BRAF mutations 2.5-4% Adenocarcinomas Incl V600E & other V600 Smoking vs non-smoking Vemurafenib
HER2 mutations 1-2% Adenocarcinomas Mutually exclusive of EGFR, KRAS Traztuzamab?
MET upregulation 4% amplification, ~50% overexpression Biomarker issues Failed trials
KRAS mutations 25-35% Adenocarcinomas MEK inhibition?
RET fusion genes ~1% Adenocarcinomas Vandetanib & others
Patterns of adenocarcinoma and ‘mutation’
EGFR Tyrosine kinase domain Exon18-21 TRU adenocarcinomas AIS, lepidic, papillary and micropapillary TTF1 positive Non-smoking, female, Asian But …………
KRAS Codon12,13,61 Solid or poorly differentiated Invasive Mucinous CD74-NRG1 fusion Smokers
ALK rearrangements Several partners recognised Solid or poorly differentiated Mucinous signet ring cells TTF1 positive Non-smoking
Cell type EGFR mutation
KRAS mutation
BRAF mutation
ALK fusion
Adeno- Carcinoma
15% 30.9% 2.5% 12.5%
Probable Adenoca (by IHC)
5.9% 41.8% 0 0
Squamous Carcinoma
0 0 0 0
Probable Squamous ca (by IHC)
0 0 0 0
NSCLC-NOS 7.3% 31% 2.7% 0
Small cell carcinoma
0 0 0 1 case*
TTF-1 positive
TTF-1 negative
Mutations missed if
only TTF-1 +ve cases
tested
EGFR mutation
15% 2.5% P<0.0001 5%
KRAS mutation
33% 36% NS 24.8%
BRAF mutation
2.5% 2.1% NS 20%
ALK fusion
4.2% 1.3% NS 8.3%
Histology vs Mutation
TTF 1 vs Mutation
Kret A et al. Lung Cancer Jan, 2015; suppl 1
Histology, IHC and mutation
Clin Can Res 2012;18, 2443-51
FGFR1 amplification Biomarker issues Definition of amplification 20% may be overestimate? Ponatinib – FGFR1 inhibitor Wynes MW et al. Clin Cancer Res 2014;20:3299-3309
Discoid Domain Receptor 2 mutation Prevalence 3.8% Good in vitro target – miRNA & Dasatinib Limited clinical evidence Hammerman PS et al. Cancer Discov 2011
PI3Kinase ~30% amplification ~6% mutations – addictive?? Inhibitors exist
IGFR1 Figitumumab Some effect in squamous Toxicity
EGFR TKI vs MoAb Mutations – rarity (vIII – 8%) Targeting the receptor
MET Inhibitors exist So far no success
IHC and Predictive testing
ALK translocation ALK tyrosine kinase inhibitors (TKIs)
Screening tool but potentially a primary response predictor
EGFR mutation EGFR TKIs
L858R well detected. Anti-ex19del lack sensitivity
EGFR wild type Anti-EGFR MoAb (Cetuximab) EGFR IHC
ROS1 translocation Crizotinib Lower specificity
MET upregulation Anti-MET agents Poor success so far
BRAF mutation BRAF TKIs Limited experience
RET translocation Cabozantinib Not so effective
PD-L1 expression Anti-PD1 and PD-L1 MoAbs Appear predictive in some circumstances
A word of caution………
‘There is nothing more dangerous (or expensive) than ………..making diagnoses on the basis of immunohistochemical profiles in disregard of the cytoarchitectural features of the lesion.’
Rosai J 2010; in Dabbs, DJ. Diagnostic Immunohistochemistry. Theranostic and genomic
applications
A word of caution………
‘....... ‘Alas, this is true for any other special technique applied for diagnostic purposes to human tissue, molecular biology being the latest and most blatant example’
Rosai J 2010; in Dabbs, DJ. Diagnostic Immunohistochemistry. Theranostic and genomic
applications
WHO Classification of Lung Cancer: New look?
• Some changes in definition
• New category – NE tumours
• Re-distribution based on molecular data leading to a MUCH greater importance of immunohistochemistry