Transcript Slide 1

Ming Tsao, MD, FRCPC
Professor of Laboratory Medicine and Pathobiology, University of Toronto
Consultant Pathologist and Senior Scientist, University Health Network
Disclaimer
• The information in this presentation is not a substitute for clinical
judgement in the care of a particular patient. CAP is not liable for
any damages arising from the use or misuse of any information
contained in or implied by the information in this presentation.
Made possible through an educational grant from Eli Lilly Canada.
Copyright © 2010
Disclosure Related to this Lecture
• I have been a Consultant for and received
Honoraria from:
– Lilly Canada (Lung cancer histopathology)
– AstraZeneca Canada (EGFR mutation testing)
– Roche Oncology (EGFR TKI biomarkers)
– Pfizer (Targeted therapy and ALK testing)
• I will not discuss off label use and/or
investigational use in my presentation.
•
Learning Objectives
Participation at this Royal College MOC (Maintenance of Certification)
Section 1 Accredited Group Learning event will enable participants to:
– Learn about the latest advances in lung cancer targeted
therapy and recognize the importance of histology in
targeted therapy for NSCLC
– Recognize predictive biomarkers currently used in clinical
practice in patients with lung cancer
– Learn about the accuracy and reliability of NSCLC
subclassification in small tissue samples
– Know the commonly used immunohistochemical stains in
the diagnosis and sub-classification of NSCLC
– Appreciate the value of prioritizing the use of small
tissue samples from patients with advanced lung cancer
– Understand the increasingly important role of the
Anatomical Pathologist in targeted therapy for lung
cancer
Leading Causes of Deaths (WHO)
In 2002:
1. Ischaemic heart disease
2. Cerebrovascular disease
3. Lower respiratory infection
4. HIV/AIDS
5. COPD
6. Perinatal conditions
7. Diarrheal diseases
8. Tuberculosis
9. Lung cancer
10.Road traffic accidents
In 2030:
1. Ischemic heart disease
2. Cerebrovascular disease
3. HIV/AIDS
4. COPD
5. Lower respiratory infection
6. Lung cancer
7. Diabetes Mellitus
8. Road traffic accidents
9. Perinatal conditions
10. Stomach cancer
Mathers CD, Loncar D, PLosMed 2006;3:e442
5-year survival rate (%)
Cancer Survival Rates (1975 – 2003)
Cancer Facts & Figures 2008
Canadian Cancer Statistics 2009
Estimated
New cases
Est.
Deaths
Death/
Case R
5-yr
survival
Lung
23400
20500
0.876
15%
Breast
22900
0.246
87%
Prostate
25500
0.172
95%
Colorectal
22000
0.414
62%
18900
Canadian Cancer Statistics 2009: www.cancer.ca
HIGH DEATH RATES: 70% of Lung
Cancer Patients are Diagnosed at
Advanced Stage
NSCLC
Lung cancer survival
local
SCLC
regional
distant
SEER STATISTICS
(US NCI Surveillance Epidemiology
and End Results)
2004 WHO Classification of Malignant
Lung Cancer
•
Squamous cell carcinoma
•
Small cell carcinoma
–
•
•
Combined
Adenocarcinoma
–
Mixed type (>80%)
–
Acinar type
–
Papillary type
–
Bronchioloalveolar carcinoma
–
Solid type
Large cell carcinoma
–
LCNEC (neuroendocrine)
–
Etc.
•
Adenosquamous carcinoma
•
Sarcomatoid carcinoma
• Carcinoid tumour
– Typical
– Atypical
• Salivary gland tumors
– Mucoepidermoid
– Adenoid cystic
– Epithelial-myoepithelial
• Mesenchymal tumours
– Epithelioid
hemangioendothelioma
– Etc.
Practical Classification for Treatment
Decision
Small cell lung cancer: 20%
“Non-small cell lung cancer” (NSCLC):
80%
Adeno
(~ 50%)
Squamous
(~ 25%)
Others (15%)
Before 2004
• Histological classification underwent minor
revisions
(1982, 91, 97, 2004)
• Most important to distinguish small cell from
non-small cell carcinoma
• Distinction between major subtypes of NSCLC, i.e.
adeno, squamous, large cell are not crucial
• Use of non-specific term such as “Non-small cell
NOS” has been acceptable
Standard Therapy for NSCLC
• EARLY STAGE NSCLC – surgical resection
• Adjuvant chemotherapy
• LOCALLY ADVANCED NSCLC – combined radiation and
chemotherapy
– Sometimes surgery
• ADVANCED STAGE NSCLC – palliative chemotherapy
and/or radiation
– Combinations of chemotherapy agents
60-70%
Landmark Discoveries or Studies Pacing for
Paradigm Shift in Lung Cancer Diagnosis
Activating (oncogenic) mutations in the EGFR
gene in NSCLC, mainly adenocarcinoma
2. Mutations may confer “oncogene addiction” to
tumor cells, which sensitize them to drugs
targeting protein encoded by the gene
3. New targeted anti-cancer drugs may have tumor
specific efficacy or toxicity, necessitating more
accurate markers to select patients for therapy
1.
Gefitinib or carboplatin-paclitaxel in
pulmonary adenocarcinoma.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P,
No. at Risk
Placebo
Carboplatin
+paclitaxel
EGFR-Mutation: Positive
1.0
P<0.001
Hazard ratio, 0.48 (95% CI, 0.360.64)
Events: gefitinib, 97 (73.5%);
carboplatin + paclitaxel, 111
(86.0%)
0.8
0.6
Gefitinib
0.4
0.2
0.0
Carboplatin
+ paclitaxel
0
4
8
12
16
20
Months Since Randomization
132
129
108
103
71
37
31
7
11
2
3
1
24
Probability of Progression-free Survival
Probability of Progression-free Survival
Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B,
Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M.
N Engl J Med. 2009 Sep 3;361(10):947.
No. at Risk
0 Placebo
0 Carboplatin
+paclitaxel
EGFR-Mutation: Negative
1.0
P<0.001
Hazard ratio, 2.85 (95% CI, 0.360.64)
Events: gefitinib, 97 (73.5%);
carboplatin + paclitaxel, 111
(86.0%)
0.8
0.6
0.4
Carboplatin
+ paclitaxel
0.2
Gefitinib
0.0
0
4
8
12
16
20
24
Months Since Randomization
91
85
21
58
4
14
2
1
1
0
0
0
N Engl J Med 2009;361:947-57.
0
0
Gefitinib Labelling in Canada
(also in Europe)
Phase III studies of EGFR-TKI vs.
Platinum doublet
in EGFR Mutant Patients
Group
EGFR mutation
Primary
endpoint
WJOG 3405
EX19, L858R
PFS
NEJ 002
EX19, L858R, G719X,
L861Q
PFS
EURTARC
EX19, L858R
PFS
Optimal
EX19, L858R
PFS
N
(TKI vs. CT)
172
(HR=0.49)
320
(HR=0.69)
174
(HR=0.37)
165
(HR=0.16)
Adapted from Mitsudomi, 2011
TKI
Control
G
CDDP+DOC
G
CBDCA+PAC
E
Pt doublet
E
CBDCA+GEM
Epidermal Growth Factor Receptor
(EGFR/HER/ErbB)
Burgess, A et al (2003)
Mol Cell 12(3): 541.
Roskoski, R (2004)
Biochem Biophys Res Commun 319(1): 1.
Activation Follows Dimerization Induced by
Ligand Binding
Phosphorylated tyrosine
Kumar A, et al. J Clin Oncol 26:1742-1751
EGFR Signaling
GPR
EGFR
ras
raf
PI3K
rac
SURVIVAL
mek
akt
erk
Ral-GDS
PROLIFERATION
INVASION
DIFFERENTIATION
ANGIOGENESIS
Reported EGFR TK Domain
Mutations
Sharma, S et al (2007) Nat Rev Cancer 7(3): 169.
Standard Testing Method:
PCR/Direct Sequencing
EXON Deletion (E746_A750)
Exon
18
19
EXON 21 (L858R)
20
Santos, G and Tsao, MS (2010)
21
22
23
24
Limitations of Standard Direct
Sequencing Method
• Contamination of mutant sequences (from
tumour cells) with wild type sequences (from
normal cells) may decrease sensitivity of
assay
Minimum requirement 25-40% tumour cells, but usually over-estimated
Direct Sequencing
25%
Known and new
PCR-SSCP
10%
Known and new
TaqMan PCR
10%
Known only
Loop-hybrid mobility shift assay
7.5%
Known only
Cycleave PCR
5%
Known only
PCR-RLFP (fragment length analysis)
5%
Known only
MassARRAY genotyping
5%
Known only
LNA -PCR clamp
1%
Known only
Scorpion ARMS (DxS)
1%
Known only
dHPLC
1%
Known and new
0.05%
Known only
COLD-TaqMan PCR
All assays—other than direct sequencing—claim to be able to
detect mutations in samples containing ≤10% mutant alleles
Adapted from: Pao, W and Ladanyi , M (2007) Clin Cancer Res 13(17): 4954.
Assays used in Canadian Laboratories
Assay Methods with Increased
Sensitivity
Method
Sensitivity
Mutations identified
Potential Laboratory Generated
Errors
• False Positive
– Specimen contamination
– “Formalin mutation”
– PCR artifacts
• False Negative
– Poor quality specimen
– Lack of sensitivity of assay
IMPORTANT THAT TESTING BE DONE IN ACCREDITED CLINICAL DIAGNOSTIC
LABORATORIES
Effect of Various Fixatives on
Quality of Nucleic Acids
Fixative
DNA
Quality
RNA
Quality
Unbuffered
formalin
Poor
Poor
Buffered formalin
Fair
Fair
Methacarn
Good
Ethanol
CytoLyt
Fixative
DNA
Quality
RNA
Quality
Carnoy
Good
Good
UMFIX (universal
molecular fixative)
Good
Good
Good
Prefer
Poor
Poor
Good
Good
Decalcifying acids
Poor
Poor
Fair
Unknown
Poor
Poor
Glutaraldehyde
(Karnovsky)
Good
Unknown
Mercury-containing
solutions (B-5)
Bouin
Poor
Poor
Histochoice
Good
Unknown
Hollande
Fair
Fair
HOPE
Good
Good
Good
Good
Zenker
Poor
Poor
Zinc buffered
formalin
Reprinted from Hunt (2008) Arch Pathol Lab Med 132(2): 248-260. Copyright 2008. College of American
Pathologists; Boldrini et al (2007). J Thorac Oncol 2(12): 1086.
EGFR Mutation Testing Samples
• Testing may be attempted on any tumour
samples in paraffin block (or freshly
obtained)
– Cytology (BW, BB, EBUS, FNA)
– Biopsies (core or open)
– Effusions
– Resections
• Testing should start with histologic
evaluation of the samples
by a
pathologist to determine adequacy of
Scant samples: May be extrachallenging but doable
Macro-dissection to Enrich for
Tumour Cells
Fine Needle Aspiration (FNA) Cell
Blocks
• Potentially inadequate or excellent materials
• Need the pathologist to evaluate section
Reference
EGFR Mutation Analysis on
FNA/Fluid Materials
Sample
Fixative
NSCLC
(N)
Analysis
Method
Mutant
(N, %)
WT /Negative
(N, %)
FNA/BW/BB/Eff
Ethanol
29
HRMA/DSeq
17 (59%)
12 (41)
Smith et al (2008)
FNA
Air-dried
11
HRMA/BiSeq
3 (27%)
8 (73%)
Lim et al (2009)
BrB/FNA/CB
RNAlater
88
DSeq/WGA
21 (24%)
67 (76%)
FNA
FineFix
77
HRMA/DSeq
2 (3%)
75 (%)
Wu et al (2008)
Effusion
-80oC
136
DSeq
93 (68%)
43 (32%)
Kimura et al (2006)
Effusion
-80oC
43
DSeq
11 (26%)
32 (74%)
Kimura et al (2006)
Effusion
-80oC
24
DxS/DSeq*
8 (33%)
16 (67%)
Boldrini et al (2007)
FNA/SP/BW/BB
Cytolyt
23
CSeq
3 (13%)
20 (87%)
Horiike et al (2007)
TBNA
-80oC
94
DxS/DSeq*
27 (29%)
67 (71%)
Smouse et al (2009)
FNA, Eff/BW/BL
Formalin
18
BiSeq
7 (39%)
4 (22%)**
Wash Fluid
None†
34
DSeq
17 (50%)
17 (50%)
Nomoto et al (2006)
Fassina et al (2009)
Otani et al (2008)
BB: Bronchial Brushing; BL: Bronchial Lavage; BiSeq: Bidirectionally sequencing; BrB: Bronchoscopic Biopsy, BW: Bronchial
Washing; CB: Core Biopsy; Cseq: Cyclic Sequencing; DSeq: direct sequencing; DxS: Scorpion ARMS; Ebx: endobronchial
biopsy; Eff: Effusion; FNA: fine needle aspiration ; HRMA: high resolution melting analysis; SP: Sputum; WGA: whole genome
amplification.
*Results reported for Scorpions test; ** Other samples were either not
analyzed or results were inconclusive; †Tissue processed immediately
EGFR Mutation Analysis on EBUSTBNA
and CT-guided Biopsy Samples
Reference
Sample
Fixative
NSCLC
(N)
Analysis
EGFR
Mutant
Wild-type/
Negative
Garcia-Olive´et al . (2010)
Eur Respir J 35:391.
EBUS-TBNA
Other biopsy/cytology
Ethanol
26
25
Seq
2 (8%)
3 (12%)
24 (92%)
22 (88%)
Nicholson et al. (2010)
J Thorac Oncol 5:436.
Blind-,EBUS-, EUS-TBNA
Endobronchial biopsy
Effusion
Formalin
6
2
2
DxS
0
0
0
6 (100%)
2 (100%)
2 (100%)
Nakajima et al. (2007)
Chest132:597.
EBUS-TBNA
FFPE
43
DSeq
11 (26%)
32 (74%)
Chen et al. (2008)
Acta Radiol 49:991.
CT-guided biopsy
Frozen
17
Not
specified
12 (71%)
5 (29%)
Shih et al. (2006)
Int. J. Cancer 118:963.
CT-guided core biopsy
USG-guided core biopsy
Endoscopic biopsy
Effusion cell blocks
FFPE
20
18
16
9
DSeq
12 (60%)
8 (44%)
5 (31%)
4 (44%)
Not
reported
CT: computed tomography ; DSeq: direct sequencing; DxS: EGFR29 Mutation Kit; EBUS-TBNA:
endobronchial ultrasound-guided transbronchial needle aspiration; EUS: endoscopic ultrasound guided
aspiration;
USG: ultrasonography
Cancer (Cancer Cytopathol) 2011;119:80-91.
Which Mutations Need to be Tested?
At minimum must test for:
• Exon 19 deletions
• Exon 21 L858R mutation
Sharma S et al (2007) Nat Rev Cancer 7(3): 169.
EGFR Mutation Rates among
Different Histologies of NSCLC (Multiinstitutional)
Reference
Study
ADC , %
(total pts)
SQC , %
(total pts)
LCC/others , %
(total pts)
Non-ADC , %
(total pts)
Zhu et al (2008)
BR.21
20%(107)
-
-
13%(97)
Tamura et al (2008)
WJTOG0403
40%(97)
-
-
5%(20)
Douillard et al (2010)
INTEREST
20% (169)
-
-
8% (128)
Asahina et al (2006)
Phase 2 (NEJ)
26% (72)
-
-
10% (10)
Yang et al (2008)
NCT173875
61%(82)
-
-
63%(8)
Bell et al (2005)
IDEAL/INTACT
17% (213)
-
5% (178)
-
Rosell et al (2009)
Spanish LCG
17%(1634)
-
11%(287)
-
Herbst et al (2005)
TRIBUTE
17%(120)
6%(31)
9%(77)
-
Richardson et al (2009)
RADIANT
25% (337)
2%(191)
4%(53)
-
20%(2641)
4%(222)
9%(595)
11%(263)
TOTAL
ADC: Adenocarcinoma; SQC: Squamous cell carcinoma; LCC: Large cell carcinoma.
Low among SQC but significant among LCC or NSCLC NOS patients
Which Patients to Test for EGFR
Mutation
• Advanced (stage IIIB-IV) or recurrent nonsquamous histology:
– Adenocarcinoma
– Large cell carcinoma
– Poorly differentiated NSCLC (NOS)
• Squamous, if clinical factors favour higher
chance for finding a mutation, e.g. never
smoker
Summary of Current Practice for EGFR mutation testing in
Canada
•
•
•
•
Advanced NSCLC with non-squamous
histology
Testing is performed in a certified clinical
diagnostic laboratory (follows recognized
laboratory standards)
Minimum test includes exon 19 deletion
and exon 21 L858R mutation
A pathologist examines one HE section to
determine tumour cellularity and identify
areas for microdissection or coring
On the Horizon
Mutation-specific antibodies for the detection of EGFR mutations in nonsmall-cell lung cancer.
Yu J, Kane S, Wu J, Benedettini E, Li D, Reeves C, Innocenti G, Wetzel R, Crosby K,
Becker A, Ferrante M, Cheung WC, Hong X, Chirieac LR, Sholl LM, Haack H, Smith BL,
Polakiewicz RD, Tan Y, Gu TL, Loda M, Zhou X, Comb MJ.
Clin Cancer Res. 2009 May 1;15(9):3023.
CST Antibodies: Highly Specific but
More Sensitive
for L858R
than 19 deletions
Mutation +
Mutation -
Total
IHC+
23 (74%)
2 (1%)
25
IHCTotal
8 (26%)
161 (99%)
169
31 (100%)
163 (100%)
194
IHC+
IHC-
20 (95%)
2 (1%)
22
1 (5%)
171 (99%)
172
Total
21 (100%)
173 (100%)
194
E19 deletion
E21 L858R
Brevet, M et al (2010) J Mol Diagn 12(2): 169.
Other Investigated Candidate
Predictive Markers
for Erlotinib/Gefitinib Therapy
•
•
•
•
EGFR immunohistochemistry
EGFR high gene copy number
KRAS mutation
Serum proteomic signature
EGFR IHC, FISH and KRAS
• EGFR IHC is not a good predictive marker for
response or survival benefit
• FISH for EGFR gene copy number increase is
not currently
used due to technical
challenges and unconfirmed value as a
predictive biomarker
• KRAS role in EGFR TKI therapy is currently
uncertain
New Therapies in Advanced NSCLC
Patient Selection
Marker
Reason for
Selection
EGFR mutation (1st line)
Efficacy
Bevacizumab +
cisplatin doublet
Non-squamous
Toxicity
Pemetrexed +
cisplatin
Non-squamous
Efficacy
Cetuximab
Possibly EGFR IHC
Efficacy
Crizotinib
ALK rearrangement
Efficacy
Agent
Gefitinib
Erlotinib
Important Points about Histology
Diagnoses
• WHO diagnostic classification system
(Edition 4)
– Is intended for diagnosis based on examination
of the whole tumour
– Does not include immunohistochemical data
(IHC)
– Does not include NSCLC NOS as an
independent category
– Does not include guidelines of diagnosing
NSCLC in small biopsies
• Up
to 75% of lung cancers present at
1. http://csqi.cancercare.on.ca/cms/one.aspx?portalId=63405&pageId=67837
International Association for the Study of Lung
Cancer/American Thoracic Society/European
Respiratory Society International Multidisciplinary
Classification of Lung Adenocarcinoma.
J Thorac Oncol. 2011 Feb;6(2):244.
William D. Travis, MD, Elisabeth Brambilla, MD, Masayuki Noguchi, MD, Andrew G. Nicholson,
MD, Kim R. Geisinger, MD, Yasushi Yatabe, MD, David G. Beer, PhD, Charles A. Powell, MD,
Gregory J. Riely, MD, Paul E. Van Schil, MD, Kavita Garg, MD, John H. M. Austin, MD, Hisao
Asamura, MD, Valerie W. Rusch, MD, Fred R. Hirsch, MD, Giorgio Scagliotti, MD,Tetsuya
Mitsudomi, MD, Rudolf M. Huber, MD, Yuichi Ishikawa, MD, James Jett, MD, Montserrat
Sanchez-Cespedes, PhD, Jean-Paul Sculier, MD, Takashi Takahashi, MD, Masahiro Tsuboi, MD,
Johan Vansteenkiste, MD, Ignacio Wistuba, MD, Pan-Chyr Yang, MD, Denise Aberle, MD,
Christian Brambilla, MD, Douglas Flieder, MD, Wilbur Franklin, MD, Adi Gazdar, MD, Michael
Gould, MD, MS, Philip Hasleton, MD, Douglas Henderson, MD, Bruce Johnson, MD, David
Johnson, MD, Keith Kerr, MD, Keiko Kuriyama, MD, Jin Soo Lee, MD, Vincent A. Miller, MD,
Iver Petersen, MD, PhD, Victor Roggli, MD, Rafael Rosell, MD, Nagahiro Saijo, MD, Erik
Thunnissen, MD, Ming Tsao, MD, and David Yankelewitz, MD
IASLC/ERS Classification for
Resected NSCLC (2011)
Strong Pathologic
Recommendations
1. The use of term “BAC” be discontinued
2. Adenocarcinoma in situ (AIS) defines small (≤3 cm)
solitary ADC with pure lepidic growth and
potentially 100% disease-specific survival (DFS) if
completely resected
3. Minimally invasive adenocarcinoma (MIA) defines
small (≤3 cm) solitary ADC with pure lepidic growth
and small foci of invasion measuring ≤0.5 cm, and
near 100% DFS if completely resected
Strong Pathologic
Recommendations – cont’d
4. Lepidic Predominant ADC replaces “mixed
subtype” to define invasive ADC with
predominantly non-mucinous lepidic pattern
(formerly non-mucinous BAC)
5. Addition of “micropapillary predominant ADC” as a
major histologic subtype due to its association
with poor prognosis
Strong Pathologic
Recommendations – cont’d
6. For small biopsies/cytology, NSCLC be further
classified into more specific histologic types (e.g.
adeno, squamous), whenever possible
7. The term NSCLC-NOS be used as little as
possible and only applied when a more specific
diagnosis is NOT possible by morphology/special
stains
Minimally Invasive Adenocarcinoma
(MIA)
• Small, solitary (≤ 3 cm) adenocarcinoma with
predominantly lepidic pattern and ≤ 5 mm
invasion in greatest dimension in any one focus
• Great majority are non-mucinous
• Can be applied to multiple tumors only if others
are regarded as synchronous primaries and not
intrapulmonary metastasis
MIA (Criteria of Invasion)
• Invasive components:
– Histological patterns other than lepidic (e.g. acinar, papillary,
micropapillary, solid)
– Tumor cells infiltrating myofibroblastic stroma
• MIA excluded with presence of:
– Lymphatic, blood vessels or pleural invasion
– Tumor necrosis
• Microinvasive areas found in one tumor:
– Multiple foci of MIA invasive areas possible
– Individual invasive areas measured separately
– Size of largest invasive area measured in largest dimension ≤
0.5 cm
Recommendations on Tumor Size
and Specimen Processing
• AIS/MIA diagnosis requires entire histologic sampling of
entire tumor
• Evidence for AIS and MIA with 100% disease-free
survival mainly from tumors ≤ 2.0 or 3.0 cm
• The terms AIS and MIA should not be used for small
biopsies or cytology specimens
– If a noninvasive pattern is present in a small
biopsy, it should be referred to as a lepidic
growth pattern
Invasive Adenocarcinoma – Lepidic
and Micropapillary prodominant
•
Lepidic predominant ADC replaces “mixed subtype” to define invasive ADC
with predominantly non-mucinous lepidic pattern (formerly non-mucinous
BAC)
– If tumor has lepidic growth yet alveolar spaces are filled with
papillary or micropapillary structure, tumor is classified as
papillary or micropapillary ADC, respectively
•
“Micropapillary predominant ADC” is added as a major histologic subtype
and is associated with poor prognosis
Predominant Patterns Recognized
lepidic
acinar
lepidic
micropapillary
solid
Solid + mucin
Histological Variants
• Invasive Mucinous Adenocarcinoma:
– Majority have invasive component and high association with KRAS mutation
– Most tumors formerly classified as “mucinous BAC” belong to this category
• Colloid Carcinoma:
– Abundant extracellular mucin
– Includes rare mucinous cystic adenocarcinoma
• Fetal Adenocarcinoma:
– Distinct histological, clinical (younger age) and genetic (b-catenin mutation)
features
– Mostly low grade with good prognosis
• Enteric Adenocarcinoma:
– Rare as primary lung ADC
– Need to exclude gastrointestinal primary
Variants of Invasive
Adenocarcinoma
Invasive
mucinous
ADC
Fetal
Colloid
Enteric