Christine Hoeffel update on imaging gastroenteropancreatic neuroendocrine tumors jfim ifupi milan 2018

1. Update on imaging gastroenteropancreatic
neuroendocrine tumors
Pr Christine HOEFFEL, CHU Reims,FRANCE
1st Italian-French Update Imaging – IFUPI
Advanced Multiparametric Imaging - How to use in daily practice
MILAN March 23-24 2018

2. Gatsrointestinal pancreatic NETs
} NET=Umbrella term for a group of heterogeneous cancers
} Epithelial neoplasms with neuroendocrine differentiation expressing
} multiple SSTR subtypes
} High cellularity
} Hypervascular stroma (MVD variable)
Singh S. Eur J Surg Oncol. 2014

3. Pathology
WHO 2000 WHO 2010
1.Well differentiated endocrine tumor Neuro endocrine tumor Grade 1
2.Well differentiated endocrine carcinoma Neuroendocrine tumor Grade 2
3. Poorly differentiated endocrine
carcinoma/ small cel neuroendocrine
carcinoma (PDEC)
Neuroendocrine carcinoma Grade 3 (large
or small cell type)
4. Mixed exocrine-endocrine carcinoma
(MEEC)
Tumor like lesions
Mixed adenoneuroendocrine carcinoma
(MANEC)
Hyperplastic and preneoplastic lesions
Grading Mitosis
10 HPF
KI67
index (%)
Grade 1 <2 ≤2
Grade 2 2-20 >2-20
Grade 3 >20 >20
Ki 67 strongly correlated to 5-year survival rates

4. } Management based on size, local invasiveness, distant metastases, and
Grading system.
} Well-differentiated G1-G2: surgical resection when possible, and
nonoperative management for asymptomatic sporadic non functioning
tumor<2 cm.
} Poorly differentiated G3: First-line systemic chemotherapy
} Ki 67 mandatory before treatment, but prone to sampling errors due to
intra and intertumor heterogeneity
Pathology

5. } Various clinical presentations
} Pancreas:
} Functional tumors: small-symptoms
} Non functional- several centimeters- mass effect, vague symptoms
} Notably common in Inherited disorders (NEM, NF,VHL)- often multiple
} Small bowel
} Small, often multiple
} Unknown Primary
General Considerations
Lawrence B. Endoc Metab Clin N Am 2011

6. Detection-Characterization
} Small bowel:
} CT enteroclysis
} MR-enterography
Caramella . Eur Radiol 2010 Amzallag-Bellenger…..Hoeffel C. Eur Radiol 2013

7. } Identify non or borderline resectable forms (III and IV)
Detection-Characterization
Lardière-Deguelte S…..Hoeffel C….Kianmanesh R. Neuroendocrinology 2016
Stage II Stage III
Stage I Stage IV

8. } Pancreas
} Multiphase MDCT early-late arterial- portal- Se/Sp 73-96%
} Dual-energy dual phase? improves conspicuity of CE
} Well-defined lesion most prominent on arterial phases
} Cystic change up to 20%- calcification
} Mismatch tumor size and size MPD
Detection-Characterization
Lin XZ. Eur J Radiol 2012. Kawamoto AJR 2013

9. } Endoscopic US
} Se 90 %- FNA
} Histology necessary or inherited disorder
} MRI
} Se 93 % and specificity 88 % (when CT not conclusive)- Bonferroni
} 94 p with 108 p tumors- 17 functioning, 55 G1 (p<0.017)
¨ Size increase with grade and is correlated with Ki 67; all G3 >3 cm
¨ Hypo T1/Hyper T2 70 %
¨ Cystic component 22 % correlated with grade (G1)
¨ Most G1-2 hypervascular (80 %) while G3 hypo/isointense on art phase; and portal-
delayed phase=> hyper/hyper G1-2 vs G3 and hypo/hypo G3 vs G1-2
¨ Dilatation of MPD more frequent in G3
Detection-Characterization
Lotfizadeh…VilgrainV. Eur Radiol 2017
Poultsides GA.Ann surg Oncol 2012
Kim D, et al. Eur Radiol 2016-

10. } Non hypervascular Net vs adenocarcinoma
¨ Well-defined margins
¨ Hyper or iso enhancement in PVP more common in NH NET than in ADK
¨ Mass with little upstream dilatation in NET
¨ Presence of calcification 16 %
} Arterial or venous encasement, peritumoral fat invasion, lymph nodes
and hepatic metastases are associated with tumoral grade
Detection-Characterization
Jeon Radiology 2017- 36 vs 82

11. } Improves detection of primary?
} No for small bowel
} Unclear for pancreas
Detection-Characterization-Added value of MRI-DWI
Brenner R. Eur J Radiol 2012.
Amzallag-Bellenger…..Hoeffel C. Eur Radiol 2014

12. 4 years later- four additional < 7 mm at EUS-

13. 60 year-old woman, NEM1, fifteen tumors<10 mm at EUS

14. } Differentiation between accessory spleen and small islet cell
tumor
} 11 AIPS versus 51 Pnet
} Differentiation on the basis of
ADC value
Detection-Characterization-Added value of MRI-DWI
Panday Eur Radiol 2018

15. DWI vs DOTATATE
23 pts (pNET) :
15/23 (DWI) vs 23/23 (PET) Eur J Nucl Med Mol Imaging
2013;40:897-907.
DWI vs DOTANOC
25 pts (30 pNET) :
88% vs 88% (NS)
Combined MRI/PET : 100%
Farchione A. Pancreas 2016
PET versus DWI MRI for detection of pancreatic
TNE

16. Staging
D’assignies G…Vilgrain V. Radiology 2013
Addition of dw sequences to standard MRI=>additional lesions and change in treatment
in 19 % of cases Moryoussef F…..Hoeffel C…Cadiot G. Neuroendocrinology 2017

17. } Ax T2 FS
} Ax diffusion
} Coro T1 Spine
} Injection of gadolinium: Ax T1 EG arterial, portal covering from liver to
pelvis
} Look for liver, nodes, peritoneal mets, bone and lungs
Positionnement des coupes
Axiales
T2 FS-diff
Coronales T1
Role of MR + DWI for Follow-up
Schraml. Cancer Imaging. 2013
IRM vs 68 Ga-DOTATOC, 51 patients-
WMRI~PET 68 Ga

18. Dr Rousset- remerciements

19. } MRI more reproducible than CT for follow-up measurements
} T2 and diffusion-weighted MRI provide the best reproducibility
Moalla S. Dig Liver disease 2017. LestraT…Hoeffel C. Diagnostic interventional imaging 2018
Role of MR + DWI for Follow-up
2015 January 7 2015 July 9
RECIST : Σd 85 mm Σd 107 mm + 26% P
m-RECIST : Σd 85 mm Σd 53 mm - 38% RP

20. } Agonists targeted at the somatostatine receptors -well-differentiated NET cells
} Gallium labelled radiopharmaceuticals- DOTA-conjugated peptide
} Good uptake correlates with improved survival Particularly if primary unknown or clinically suspected but invisible
or if peptide receptor radionuclide therapy
Nuclear medicine imaging-Detection and
characterization
Johnbeck CB. Future Oncol
2014
Castellucci P. J Nucl Med 2011
111In-Octreoscan
SRS Spect imaging 68Ga-DOTATOC 68Ga-DOTATATE 68Ga-DOTANOC

21. } 12 consecutive patients with G1-G2 GEP-NETs
- 4 pancreas
- 8 midguts
} Radiotracers :
- 68Ga-DOTATOC (agonist)
- 68Ga-OPS202 15 µg / 50 µg (antagonist)
} Results :
- Lesion-based sensitivity : 88-94% (antagonist) vs 59% (agonist)
- Improved tumor-to-liver ratio
Agonists versus antagonists
Nicolas G. Comparison of 68Ga-OPS202 and 68Ga-DOTATOC PET/CT in Patients with GEP NETs: Evaluation of Sensitivity in a Prospective Phase II
Imaging Study. J Nucl Med. 2017

22. } FDG avidity reflects tumor activity
} Prognostic utility (prospective-98 p)
} Tumors demonstrating higher SUV max associated with
significantly poorer overall survival
} Correlation to Ki 67- not proven yet
Nuclear medicine imaging
BinderupT. Clin Cancer Research 2010- Chan D.Theranostics 2017.

23. Imaging Work-up
} CECT
} If patient considered for hepatic resection, liver MRI +
DWI
} SRS or 68 Ga PET imaging if Ki<20 % and if poorly
differentiated tumor 18FDG PET
} Follow-up CECT or MRI

24. } Radiomics: Non invasive characterization of molecular and cellular biological
mechanisms for a tailored medical approach (intertumoral and intratumoral
heterogeneity)
} Morphological parameters
} DWI-IVIM
} Perfusion MRI-CECT
} Texture analysis
¨ Signal distribution - Histogram analysis
¨ Spatial distribution of the gray levels in the ROI (gray level co-occurence matrix
or run length matrix)
Prediction of agressiveness

25. Strong significant and negative relationship between ADC and D and Ki 67 index
Lotfalizadeh. Eur Radiol 2017. Min Ji. Eur Radiol 2018
63 p. Only independent predictor for OS
is a low ADC value (HR: 3.37, p=0.01)

26. Texture Analysis
} Based on patterns in gray level distribution
pixels/voxels
} Analysis of histogram of signal distribution
} mean= location
} standard deviation = scale
} Skewness=symmetry
} kurtosis = magnitude, i.e degree of flatness
or pointiness
} Uniformity
} Entropy= irregularity of the distribution

27. Canellas R.AJR
2018
Retrospective
101 p
CT Gr 2-3/1 Entropy filter 2 Accuracy 79 %
Morphological +
TA
De Robertis
R….
D’onofrio M.
Eur Radiol
2018
Retrospective 42
p
DWI
ADC value
Gr 2-3/1 Entropy
kurtosis
Choi T 2018
Acta
radiologica
Retrospective
66 p
CT Gr 2-3/1 Higher
skewness and
lower kurtosis

28. } Role of the multiple imaging modalities well assessed for
current diagnosis of gastroenteric and pancreatic Nets
} On our way to towards understanding and exploiting tumor
heterogeneity
} Still many challenges to overcome for radiomics
} Acquisition variations/reconstructions/segmentations/methodology
variations
} Need for standardization
} Need to minimize overfitting
} Need for validation on ad hoc cohorts and prospectively
Conclusion