10/26/2016
Objectives
• Review the changes to lung cancer in the
2015 WHO classification
What is new in the new WHO
Classification of lung cancer
• Focus on the interpretation in small biopsies
And the impact on small biopsy diagnosis
Marie-Christine Aubry, M.D.
Mayo Clinic
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Adenocarcinoma
2004 WHO
2015 WHO
• Bronchioloalveolar ca
• AIS
• MIA
2015 WHO Classification
of Lung Cancer 4th Ed.
• Lepidic predominant
• Acinar
• Acinar predominant
• Papillar
• Papillary predominant
• Solid
• Solid predominant
• Micropapillary predominant
• Mixed
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Adenocarcinoma
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Adenocarcinoma, mucinous
2004 WHO
2015 WHO
• Variants
• Mucinous (colloid)
• Variants
• Mucinous
• Colloid
• Fetal
• Fetal
• Signet ring
• Clear cell
Travis et al JTO 2011
• AD with globlet or
columnar cells with
abundant mucin
• All histologic patterns
• Lepidic most
common
• Immunostains
• CK7+
• CK20+
• TTF1• Napsin-
• Enteric
Travis et al JTO 2011
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2015 WHO recommendation
Adenocarcinoma, enteric subtype
• Grading scheme
• Grade 1= lepidic
• Grade 2= papillary
and acinar
• Grade 3= solid and
micropapillary
• Issues
• Still could be 1ary GI,
pancreaticobiliary
• Prognostic value
Figure 3a. Overall survival by observer 1 predominant score (mucinous in group 3).
Figure 4a. Overall survival by observer 2 predominant score (mucinous in group 3).
100
100
80
80
60
60
Percent survival
• Immunostains
• Should retain CK7
• CK20+
• CDX2+
• Reproducibilty?
• 534 cases – 2 observers
• Exact match 51.7%
• 27.3% in same
prognostic score
• 21% with different
prognostic score
Percent survival
• For non mucinous AD,
assign most
predominant growth
pattern
• Resembles morphology
of colorectal carcinomas
40
20
40
20
Score 1 (n=124)
Score 2 (n=263)
Score 3 (n=147)
0
0
1
Score 1 (n=117)
Score 2 (n=284)
Score 3 (n=133)
0
2
3
4
Years
5
0
1
2
3
4
5
Years
Boland et al
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AIS/MIA
• 3 cm and less
• No vascular, pleural invasion
• No airspace spread
• No necrosis
• Stromal invasion:
• Absent in AIS
• ≤ 5mm in MIA
• Predicts for 5-yr DFS of, or near 100%
AIS
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Lepidic predominant
• 3 cm and less
• >5mm of stromal invasion
• Pleural or vascular invasion
• Airspace spread
• Necrosis
Invasion 2mm
• > 3cm
• Even if ≤ 5mm or no invasion
MIA
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Features of invasion
Invasion > 5mm
Papillary
Micropapillary
LPA
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Active fibroblasts/ Desmoplasia = Invasion
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Interobserver variation
Rater 2
AIS
Rater
1
MIA
More than one area of invasion
IA
AIS
11 (3.7%)
3 (1.0%)
0 ( 0.0%)
MIA
6 (2.0%)
71 (24.2%)
12 ( 4.1%)
IA
0 (0.0%)
36 (12.2%)
155 (52.7%)
• Several recommendations
• Measure the largest
• In the WHO section on MIA and LPA
• Estimate the % of invasive
components
• X by the overall tumor diameter
Boland et al
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Squamous cell carcinoma
2004 WHO
2015 WHO
• Squamous cell ca
• Keratinizing
Basaloid SQCC
• Nested architecture with • Differential diagnosis
palisading
• LCNEC/SCLC
• NUT carcinoma
• >50-100%
• Adenoid cystic ca
• Immunostains
• Non-keratinizing
•
•
•
•
• Basaloid
p63 and p40+
CK5/6 +
TTF-1NE markers
• <10% cases
• Focal
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Adenosquamous cell carcinoma
2004 WHO
2015 WHO
• Adenosquamous cell
carcinoma
• Adenosquamous cell
carcinoma
“…components of
both SQCC and AD
with each component
constituting at least
10% of the tumor.
Definitive diagnosis
requires resection…”
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Adenosquamous cell carcinoma
AD component
SQC component
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Immunostains
Immunostains in Adenosquamous cell ca
• TTF-1
• 2 clones with different sensitivity and
specificity
• SPT24 is very sensitive not as specific
• Can be + in SQCC
• Different tumor cells with different
immunoprofile
• If the same tumor cells stain for TTF-1 and
p63
• It is NOT adenosquamous cell carcinoma
• It is AD with p63 staining
• p63
• Up to 30% of AD + p40 more specific
• CK7
• Up to 20% of SQCC +
• Up to 10% of AD –
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Sarcomatoid carcinoma
Sarcomatoid Carcinoma
2004 WHO
2015 WHO
• Pleomorphic
• Pleomorphic, spindle
and giant cell
• Spindle cell
• Giant cell
• Carcinosarcoma
• Pulmonary blastoma
• Carcinosarcoma
• Most often spindle cell
morphology
• Keratins are commonly
negative or only focally
positive
• Pulmonary blastoma
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Large cell carcinoma
Large cell carcinoma
2004 WHO
Large cell carcinoma
•
•
•
•
•
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2015 WHO
Large cell carcinoma
Large cell NE carcinoma
Basaloid
Lymphoepithelioma-like
Clear cell
Rhabdoid
• Undifferentiated NSCC
• Lacks cytological, architectural and
immunohistochemical features of AD,
SQCC, LCNEC and SCLC
• Requires resected tumor
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ADENOCARCINOMA
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SQUAMOUS CELL CARCINOMA
p40
TTF-1
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LARGE CELL CARCINOMA
AD
SQCC
LCC
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Small cell carcinoma
Neuroendocrine tumors
2004 WHO
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• Still defined by H&E
morphology
2015 WHO
• Small cell carcinoma Neuroendocrine tumors
• Small cell carcinoma
• Carcinoid tumors
• Large cell NE
• Typical
carcinoma
• Atypical
• Carcinoid tumor
• Typical
• Atypical
• About 10% of SCLC
negative or focally weakly
+ for NE markers
• Up to 30% NSCLC + for
NE markers
• IHC useful IF
• SCLC vs SQCC
• TTF-1+/p40• NOT p63 (20% +)
• SCLC vs carcinoid
• Ki-67
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Large cell neuroendocrine carcinoma
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Other unclassified
Lymphoepithelioma-like
• Neuroendocrine
morphology
• Rosettes
• Trabecula
• Peripheral palisading
NUT carcinoma
• Nucleoli prominent
• >10 mitosis/ HPF
• AND expresses IHC
markers
NUT
EBV ISH
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t(15;19)
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GOAL
• To make a diagnosis on H&E or at least with
the smallest number of immunostains
• Save tissue for molecular testing
• Most cancers in advanced stage
• If surgically resectable not as critical
Interpretation on small biopsies
Recommendations of the 2015 WHO
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Remember that…
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Tissue Processing
• Do not decalcify
• If can’t be avoided, consider making 2
blocks
• …our diagnosis dictates mostly additional
studies to be performed…
• Everything but SQCC may be tested for
EGFR, ALK, ROS etc
• 1 with the calcified tissue
• 1 with softer tissue
• …eventually SQCC with own studies
• If more than 1 core or “abundant” aggregate
of tissue
• Consider making 2 paraffin blocks
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Most useful stains in Lung 1ary
A few things about IHC
• TTF-1 and p40
• If not sure about tumor type
• Lymphoma? Melanoma? Carcinoma?
Sarcoma?
• Carcinoma by far most common
• Keratin stains with unstained slides
• Keratin, CD45, S100 prot with
unstained slides
• Use morphology to guide stains
• Best avoid many stains in 1st round
 Avoid exhausting block
• Could even argue p40 is sufficient
• SQCC versus all others
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A few things about IHC
A few things about IHC
• If considering metastasis from another site
• CDX2 can be + in Lung AD
• ER can be + in Lung AD
• STP24 clone of TTF-1 can be + in 1aries
from other sites
Use clinical/radiologic information,
compare to prior specimens, use and
interpret IHC cautiously
• Neuroendocrine markers
• Do only if tumor looks
like a carcinoid (or
LCNEC)
• SCLC can be negative –
H&E diagnosis
• Many NSCLC that are
not carcinoid or LCNEC
can be focally +
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Non small cell carcinoma
• 68 yo male
• Smoker
• Lung mass with
mediastinal
adenopathy
p40
Diagnosis
Non-small cell carcinoma, NOS
TTF-1
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Adenosquamous cell carcinoma?
• NO
• Not 2 distinct cell
morphology
• Not 2 distinct cell
population with
different immunoprofile
• The cells + for TTF-1
are also positive for p40
• p40 trumps
p40
STP24
TTF-1
8G7
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SQC component
AD component
Diagnosis
Non-small cell carcinoma, favor SQCC
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Diagnosis
Non-small cell carcinoma, NOS
Comment: AD and SQC components present,
could represent ADSQC carcinoma
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keratin
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Diagnosis
Non-small cell carcinoma with
spindle cells
Comment: Could represent a
pleomorphic, spindle cell and/or giant cell
carcinoma i.e. sarcomatoid carcinoma
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Benign versus Neoplastic
• If benign reactive pneumocyte hyperplasia,
reactive to what?
• AAH?
• Size ≤ 5mm
• Radiologic context is very helpful and knowing
that the lesion has actually been sampled
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Clinical and radiologic findings
Concluded that it is neoplastic
• Adenocarcinoma with pure lepidic growth, no
stromal invasion….
• 65 yo woman
• AIS? MIA? LPA?
• Single GGO 2.5cm
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Positive biopsy
Diagnosis?
? type
Keratins +/- others
Unstained slides
Classic AD
Other than carcinoma
Carcinoma
1ary vs metastasis
Primary lung
Clinic – Radiologic
Prior pathology
IHC
Molecular
Analysis
Adenocarcinoma with lepidic pattern
Undifferentiated
Comment: Although no invasion identified, an
invasive component which is unsampled
cannot be excluded
NSCC
favor AD
NE morphology
+ IHC
SCLC
Classic
SQCC
?LCNEC
?Carcinoid
TTF-1 +
TTF-1 and p40
NSCC, NOS
Neg ICH
P40+
NSCC favor SQCC
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Depends…
How much is too little?
Amount of tissue needed for molecular testing
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Test
Thickness
# slides
# tumor cells
H&E diagnosis
5µ
1
20-50
IHC
5µ
1 per stain
50
FISH
5µ
1 per study
100
Test
Thickness
#
slides
# tumor
cells
% tumor Amount
cells
of DNA
EGFR
5µ
5
5,000
3X6mm2
10
10ng
K-ras
5µ
5
5,000
3X6mm2
20
10ng
50 gene panel
5µ
10
5,000
5X6mm2
20
30ng
Mayo Lung Cancer
panel
5µ
10
5,000
5x6mm2
20
10ng DNA
10ng RNA
Foundation One
4µ
8-10
NOS
20
NOS
Caris
4µ
15
25mm2
20
NOS
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Questions & Discussion
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