in vivo measurements Angelo Pierangelo 1 Jérémy Vizet 1 Jean Rehbinder 1 Stanislas Deby 1 Stéphane Roussel 1 Tatiana Novikova 1 Ranya Soufan 2 Catherine ID: 789918
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Slide1
Mueller polarimetric imaging for early detection of uterine cervix cancer: from proof of principle experiments to
in vivo measurementsAngelo Pierangelo1Jérémy Vizet1, Jean Rehbinder1, Stanislas Deby1, Stéphane Roussel1, Tatiana Novikova1, Ranya Soufan2, Catherine Genestie2, Christine Haie-Meder2, Hervé Fernandez3, André Nazac4, François Moreau1(1) Laboratoire de Physique des Interfaces et des Couches Minces (UMR 7647) - Ecole Polytechnique (Palaiseau)(2) Gustave Roussy Institute (Jussieu)(3) Teaching hospital of Kremlin Bicêtre (Kremlin Bicêtre))(4) Teaching hospital of Brugmann (Bruxelles)
Slide2Epithelial
cancersEpithelial tissueEpitheliumConnectivetissue
Slide3Cells genetically
alteredHyperplasiaSevere dysplasiaCarcinoma in situInvasive cancerEpitheliumConnective tissue(collagen, elastin…)VesselsTimeEpithelial cancers90% of cancersEpithelial tissueEpitheliumConnectivetissue
Epithelial cancer development
Slide4Cells genetically
alteredHyperplasiaSevere dysplasiaCarcinoma in situInvasive cancerEpitheliumConnective tissue(collagen, elastin…)VesselsTimeEpithelial cancers90% of cancersEpithelial tissueEpithelium
Connectivetissue
Epithelial cancer development
Detection of precancerous stage
Recovery of patients in 95% of cases
Slide5Cervical cancer
Major health problem: the second most common female cancer in the world with 275 000 deaths per year, mainly in developing countries (but not only)Slow evolution (10 - 20 years): ideal case for screeningDirect access to cancerModel for other epithelial cancers
Slide6Cervical cancer screening
ColposcopyConizationSignificant improvement of colposcopy can make the early detectionand surgery both more effective and affordableColposcopy : inefficient technique (generating supplementary costs)(60-70% sensitivity and 50% specificity for high-grade dysplasia detection)Visualization of dysplastic areas for biopsy is very difficult and operator dependentResection margins to achieve a cone biopsy (conization) are poorly definedCurrent practice
Slide7Electric field (Polarization)
Magnetic field
x
y
x
y
x
y
Linear polarization
Elliptical polarization
Depolarized light
Polarization of light
Slide8Polarimetric properties
RetardanceDiattenuationDifference of transmission for two polarization eigenstatesPhase difference between two polarization eigenstatesDepolarizationIntroduction of « disorder » in the evolution of the electric fieldBirefringence : refraction index varies with polarizationDichroïsm : Absorption coefficient varies with polarizationStochastic process (multiple-scattering)Biological origins :Single scatteringTransmission anisotropy of some moleculesBiological origins :Collagen, elastin, muscle fibers (myosin, actin…)
Biological origins :
Organelles, cytoplasm, fibers…
slow
fast
Slide9Mueller polarimetry
Mueller matrix M Complete polarimetric response of a sample (including depolarization)[1] : “Interpretation of Mueller matrices based on polar decomposition” , S.-Y. Lu and R. A. Chipman, JOSA A 13 (5) (2012)Stokes vector4-component vector which describes completely the polarization of lightLu and Chipman [1] : M = Md MR MDReverse : M = MDr MRr MdrSymmetric : M = MD2 MR2
Mds M
R1
M
D1
…
Decompositions based on hypothesis on
the
physical structure of the
sample
Intensity measurements
Slide10Mueller polarimetric imaging
PSG : 4 probing polarization statesAnalysis through 4 different configurations of the PSA16 measured intensitiesMueller matrix imageMueller polarimetric imagerProbing polarization statesBackscattered polarization statesPSG (Polarization State Generator): linear polarizer, followed by retarders with changing characteristics over time (rotating waveplates, liquid crystal cells, etc ...)PSA (Polarization State Analyzer): the same elements as PSG, but in the reverse order
Slide11Quartz plate
MilkTilted glass
Mueller Matrix
Lu-Chipman decomposition
Dichroism
Retardance
Depolarization
2cm
Mueller polarimetric imaging
…on “ad hoc” samples
ex
vivo
Slide12…on biological samples
ex vivo2cmCancerous zone
5cm
Uterine cervix
(500nm)
Colon (500nm)
Pure Depolarizer
(diagonal matrix)
M22=M33>M44
Rayleigh Scattering
Depolarization
Retardance
Dichroism
(
non-diagonal matrix
)
Mueller polarimetric imaging
Slide13Mueller polarimetric imaging :is sensitive to the microscopic morphology of the tissue
is realized using simple optical elements in the visible range (450 – 700 nm) : different depths in the tissue can be reached using different wavelengths (due to different light absorption by hemoglobin for different wavelengths, hemoglobin being more absorbing for shorter wavelengths) ;is well suited for « full field » (few cm²) modality (fundamental for in vivo applications) can be easily implemented at low cost Mueller polarimetric imaging
Slide14Application to cervical cancer
Ex vivo proof of principle measurements1 Full field Mueller imaging polarimeter~10 samples analyzed2013
Slide15Application to cervical cancer
Ex vivo proof of principle measurementsEx vivo statistical evaluationIn vivo preliminary results1 Full field Mueller imaging polarimeter3 Full field Mueller imaging upgraded polarimeters~10 samples analyzed~100 samples analyzed1 monochromatic Mueller colposcope (550nm)
~15 patients
analyzed
2013
2013-2017
Slide16Application to cervical cancer
Ex vivo proof of principle measurementsEx vivo statistical evaluationIn vivo preliminary resultsIn vivo statistical evaluation1 Full field Mueller imaging polarimeter3 Full field Mueller imaging upgraded polarimeters~10 samples analyzed~100 samples analyzed
1 monochromatic Mueller colposcope (550nm)
~15 patients
analyzed
Color Mueller colposcope
(450 - 550 - 650nm)
~300 patients
t
o analyze
2013
2013-2017
2018-2020
Slide17Application to cervical cancer
Mueller matrix imageand polarimetric parameters2cmCharacteristics Field of view ≈ 5 x 4 cm²Wavelengths : 400 nm to 700 nm (50 nm step)Time required to acquire a full Mueller matrix Image : several tens of secondsEx vivo analysis
Slide180°
90°Retardance (550nm)
Depolarization (550nm)
Healthy
Glandular
CIN 3
0
1
2cm
Conventional image
A.
Pierangelo
et al.
Opt.Exp
. (2013)
J.
Rehbinder
et
al
. J.
Biomed
.
Opt
. (2015)
Prix de l’innovation de l’Ecole Polytechnique 2012
Application to cervical cancer
Ex vivo
proof of principle measurements
Healthy zones are characterized by a strong
Retardance
(~60°) and
Depolarization
(~1)
Abnormal zones are characterized by a very low
Retardance
(< 10°)
Different degrees of
Depolarization
enable to distinguish malignant lesions from benign transformations of the cervix
Slide19Application to cervical cancer
12345Cut ACut BCut CCut ECut D
1
2
3
4
5
Automatic reconstruction of the histological mapping
Statistical evaluation of
sensitivity
and
specificity
of the technique
using
Retardance
as a polarimetric diagnostic parameter to distinguish healthy tissue from severe dysplasia (CIN3) on
25
pieces of
conizations
Ex vivo
statistical evaluation
Histology is the gold standard for
the diagnosis
of pre-cancerous lesions
Slide20Pre-sliced
Polarimetric imageHistological diagnosisApplication to cervical cancerEx vivo statistical evaluation
Slide21Application to cervical cancer
Uncertainty positioning cut (~1mm) : this introduces an error of 10 – 15% on sensitivity and specificityWe selected subzones between two adjacent lines labeled by the same histological diagnosisEx vivo statistical evaluation
Slide22Application to cervical cancer
Ex vivo statistical evaluationComparison of polarimetric imaging with the gold-standardPathologicHealthyPositive testTPFPNegative testFNTN
Conventional colposcopy : Se~60-70%
60-70% of cancers detected
Conventional colposcopy : Sp<50%
Less than 50% of healthy zones are properly identified
Slide23We fixed a threshold
Rs for RetardanceWe considered that : pixels with R>Rs healthy tissuepixels with R<Rs precancerous stageTrue positive TP are the pixels with R<Rs detected as abnormal zones by pathologists We calculated Se et Sp by varying Rs Application to cervical cancerEx vivo statistical evaluation
Slide24Application to cervical cancer
Ex vivo statistical evaluationJ. Rehbinder et al. J. Biomed. Opt. (2015)
Slide25T
he comparison between Mueller polarimetric microscopy and SHG microscopy proved that the strong anisotropy observed in healthy cervix is due to the existence of a highly ordered layer in the connective tissue under the epithelium S. Bancelin et al. Opt. Express 22(19), 22561 (2014)Microscopy and interpretation of the resultsApplication to cervical cancer
Healthy
CIN3
Modeling of anisotropic media in progress
Strong
Retardance
of healthy tissues is the signature of
collagen
Slide26Mueller polarimetric
macroscope (Ex vivo)Mueller polarimetric colposcope (In vivo)16 images in 20s16 images in 1.6sApplication to cervical cancerIn vivo measurementsLinear polarizersAnalyzed lightIncident light
Slide27Application to cervical cancer
In vivo measurements on a cohort of patients from January 2018 to January 2020 in hospital setting (CHU Kremlin Bicêtre, CHU Brugmann)Presence of a precancerous lesion (CIN3) confirmed by the biopsyHealthy zones are characterized by a strong Retardance (~80°) and Depolarization (~0.8)Abnormal zones are characterized by a very low Retardance (< 10°)Different degrees of Depolarization enable to distinguish malignant lesions (CIN3) from benign transformations of the cervix (glandular tissue)These results are compatible with ex vivo0°90°01
Algebraic methods (LPICM)
Adaptative polarimetry (SPIM)
Statstical approach (ICUBE, Arizona University)
Retardance
Depolarization
Intensity image
In vivo
measurements
Image obtained combining
550 and 650 nm
Slide28New version of colposcope that is compact, user friendly, fast (16 images in 0.5s) and enables simultaneous acquisition of images at 450, 550 and 650nm December
2017Measurements by using Mueller colposcopy in vivo on a cohort of patients in two different hospitals (CHU of the Kremlin Bicêtre and CHU Brugmann of Brussels) January 2018Modeling of anisotropic tissues (Monte Carlo) In progressExploration of new applications…Conclusions and perspectives
Slide29New perspectives and applications
Cancerous pathologiesGastroenterologyPneumologyGynecology (Uterus…)UrologyDermatology…Other non-cancerous pathologiesPreterm delivery (30 patients analyzed at CHU Brugmann of Bruxelles)…
Slide30Piezoelectric
ScanningOptical fiber0°120°MicroscopyMuscular tissue of colon1mm
Retardance (630nm)
New perspectives and applications
Mueller Microendoscope
(collaboration LPICM – Xlim)
… towards Mueller polarimetric endoscopy
Slide31Mininvasive surgery
GynecologyChallenge: Mueller polarimetric rigid endoscopeNew perspectives and applications…in progress
Slide32Thanks to:
Special thanks to:Antonello De Martino