Table of content PART A

Table of content PART A

CHAPTER 1. BACKGROUND 5

1.1 HISTOPATHOLOGY OF NORMAL AND DISEASED SKIN 5

1.1.1 NORMAL SKIN 5

1.1.2 ILLUSTRATED GLOSSARY OF DERMATOPATHOLOGICAL TERMS (adapted from (2): all sections are

stained with haematoxylin & eosin). 12

1.2 NON-INVASIVE IMAGING 17

1.2.1 NORMAL SKIN AS OPTICAL MEDIUM 19

1.2.2 NEAR-INFRARED SPECTRUM: THE DIAGNOSTIC/THERAPEUTIC WINDOWS 20

1.2.3 DIAGNOSTIC CHALLENGES IN DERMATOLOGY AND NON-INVASIVE IMAGING 22

1.2.4 ESTABLISHED NON-INVASIVE IMAGING TECHNIQUES 31

1.3 HIGH-DEFINITION OPTICAL COHERENCE TOMOGRAPHY 36

1.3.1 FOUR BASIC DESIGN PRINCIPLES 36

1.3.2 HOW IT WORKS 41

CHAPTER 2. OBJECTIVES OF THE THESIS 45

CHAPTER 3. MATERIALS AND METHODS 46

3.1 STUDY DESIGN 46

3.2 STUDY SAMPLES 48

3.3 HISTOPATHOLOGY 49

3.3.1 STUDIES 2 & 3 49

3.3.2 STUDIES 5-17 49

3.4 SPECIFIC METHODS AND IMAGE EVALUATON CRITERIA 50

3.4.1 CELLULAR RESOLUTION AND REAL TIME 3-D IMAGING OF MICRO-ENVIRONMENT 50 3.4.2 HD-OCT MORPHOLOGY DESCRIPTORS FOR CELLS AND MICRO-ARCHITECTURAL STRUCTURES 51

3.4.3 HD-OCT IN VIVO TISSUE OPTICAL PROPERTIES ANALYSIS 59

3.4.4 THICKNESS MEASUREMENTS OF THE SKIN 62

3.5 DIAGNOSTIC POTENTIAL OF HD-OCT 63

3.5.1 TRAINING AND VALIDATION SETS: 63

3.5.2 TESTING SETS 64

3.6 STATISTICAL ANALYSIS 65

CHAPTER 4. RESULTS 68

4.1 CELLULAR RESOLUTION AND REAL TIME 3-D IMAGING OF MICRO-ENVIRONMENT 68

4.2 MORPHOLOGICAL FEATURES FOR CELLS AND STRUCTURES 75

4.2.1 NORMAL SKIN 75

4.2.2 DISEASED SKIN 78

4.3 IN VIVO OPTICAL PROPERTY ANALYSIS 100

4.3.1 NORMAL SKIN 100

4.3.2 DISEASED SKIN 102

4.4 SKIN THICKNESS MEASUREMENTS 117

4.4.1 BASED ON B-SCAN (MORPHOLOGY ANALYSIS) 117

4.4.2 BASED ON SCANNED VOLUME (OPTICAL PROPERTY ANALYSIS) 117

4.5 DIAGNOSTIC POTENTIAL OF HD-OCT 118

4.5.1 TRAINING AND VALIDATION SETS (in theory): 118

4.5.2 TESTING SETS (in practice) : 146

CHAPTER 5. DISCUSSION 147

CELLS IN THEIR 3-D MICROENVIRONMENT 147

MORPHOLOGIC DESCRIPTION OF PATTERNS AND STRUCTURES 153

QUANTIFYING MORPHOLOGICAL FEATURES OF CELLS AND STRUCTURES BY OPTICAL PROPERTY ANALYSIS 154

THICKNESS MEASUREMENTS 160

DIAGNOSTIC POTENTIAL OF HIGH-DEFINITION OPTICAL COHERENCE TOMOGRAPHY 162

TRAINING/VALIDATION AND TESTING SETS BASED ON MORPHOLOGY ANALYSIS 162

TRAINING/VALIDATION SETS BASED ON OPTICAL PROPERTY ANALYSIS 166

CONTRIBUTION OF HD-OCT TO THE NON-INVASIVE IMAGING OF THE SKIN BY NEAR-INFRARED TECHNIQUES.

COMPARISON WITH DERMOSCOPY. 170

CHAPTER 6. GENERAL CONCLUSION AND PERSPECTIVES 176

CHAPTER 7. REFERENCES 180

Table of content PART B

ABBREVIATIONS...3 CHAPTER 1. INTERACTION OF LIGHT WITH SKIN...4

1.1 OPTICAL IMAGING... 4

1.2 ABSORPTION... 5

1.3 SCATTERING... 7

1.3.1 Hierarchy of tissue ultrastructure...7

1.3.2 There are two approaches toward modelling tissue scattering...8

1.4 LIGHT PENETRATION INTO THE SKIN & TOTAL ATTENUATION COEFFICIENT...13

1.4.1 Prediction of light penetration depth...13

1.4.2 Total attenuation coefficient µ...13

1.5 IN VIVO OPTICALLY PROBING THE MICRO-ARCHITECTURE OF CELLS AND TISSUES...17

1.5.1 Wavelength dependence of diffuse light reflectance (23-25)...17

1.5.2 Axial dependence of confocal reflectance images: Specifying in vivo tissue optical properties using confocal scanning laser microscopy and optical coherence tomography...18

CHAPTER 2. PHYSICS BEHIND OPTICAL COHERENCE TOMOGRAPHY ...20

2.1 DEPTH INFORMATION AND INTERFEROMETRY...21

2.1.1 Time domain (used by HD-OCT) (31)...21

2.1.2 Fourier domain (31)...23

2.2 SHARP IMAGE BY SUPPRESSING SCATTERED LIGHT...25

2.2.1 Axial (depth) resolution Δz and temporal coherence length L

is defined by the bandwidth of the light source 25 2.2.2 Lateral resolution Δx and spatial coherence length d

defined by the system optics...26

2.2.3 Limit of lateral resolution for OCT systems...28

2.2.4 Suppression of coherent cross talk...31

REFERENCES...34

List of Publications PART C

1. Boone M, Jemec GB, Del Marmol V. High-definition optical coherence tomography enables visualization of individual cells in healthy skin: comparison to reflectance confocal microscopy. Exp Dermatol. 2012;21(10):740-4.

2. Boone M, Draye JP, Verween G, Pirnay JP, Verbeken G, De Vos D, et al. Real-time three-dimensional imaging of epidermal splitting and removal by high-definition optical coherence tomography. Exp Dermatol. 2014;23(10):725-30.

3. Boone M, Draye JP, Verween G, Aiti A, Pirnay JP, Verbeken G, et al. Recellularising of human acellular dermal matrices imaged by high-definition optical coherence tomography. Exp Dermatol.

2015;24(5):394-54.

4. Boone MA, Suppa M, Marneffe A, Miyamoto M, Jemec GB, Del Marmol V. High-definition optical coherence tomography intrinsic skin ageing assessment in women: a pilot study. Arch Dermatol Res.

2015;207(8):705-20.

5. Boone MA, Norrenberg S, Jemec GB, Del Marmol V. High-definition optical coherence tomography imaging of melanocytic lesions: a pilot study. Arch Dermatol Res. 2014;306(1):11-26.

6. Boone MA, Norrenberg S, Jemec GB, Del Marmol V. Imaging of basal cell carcinoma by high-definition optical coherence tomography: histomorphological correlation. A pilot study. Br J Dermatol.

2012;167(4):856-64.

7. Boone M, Suppa M, Miyamoto M, Marneffe A, Jemec GB, Pellacani G, et al. Three-Dimensional High Definition-Optical Coherence Tomography Image Acquisition Procedure For Basal Cell Carcinoma. Br J Dermatol. 2014;172(4):1153-4.

8. Boone M, Suppa M, Pellacani G, Marneffe A, Miyamoto M, Alarcon I, et al. High-definition optical coherence tomography, algorithm for discrimination of basal cell carcinoma from clinical bcc imitators and differentiation between common subtypes. J Eur Acad Dermatol Venereol. 2015;29(9):1771-80.

9. Boone MA, Norrenberg S, Jemec GB, Del Marmol V. Imaging actinic keratosis by high-definition optical coherence tomography. Histomorphologic correlation: a pilot study. Exp Dermatol. 2013;22(2):93-7.

10. Boone MA, Marneffe A, Suppa M, Miyamoto M, Alarcon I, Hofmann-Wellenhof R, et al. High-definition optical coherence tomography algorithm for the discrimination of actinic keratosis from normal skin and from squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2015;29(8);1605-15.

11. Boone M, Norrenberg S, Jemec G, Del Marmol V. High-definition optical coherence tomography:

adapted algorithmic method for pattern analysis of inflammatory skin diseases: a pilot study. Arch Dermatol Res. 2013;305(4):283-97.

12. Boone MA, Jemec GB, Del Marmol V. Differentiating allergic and irritant contact dermatitis by high- definition optical coherence tomography: a pilot study. Arch Dermatol Res. 2015;307(1):11-22.

13. Boone M, Suppa M, Dhaenens F, Miyamoto M, Marneffe A, Jemec G, et al. In vivo assessment of optical properties of melanocytic skin lesions and differentiation of melanoma from non-malignant lesions by high-definition optical coherence tomography. Arch Dermatol Res. 2016;308(1):7-20.

14. Boone M, Suppa M, Marneffe A, Miyamoto M, Jemec G, Del Marmol V. In vivo assessment of optical properties of basal cell carcinoma and differentiation of BCC subtypes by high-definition optical coherence tomography. Biomed Opt Expr 2016; doi:10.1364/BOE.7.002269.

15. Boone M, Suppa M, Marneffe A, Miyamoto M, Jemec G, Del Marmol V. A new algorithm for the discrimination of acticinc keratosis from normal skin and squamous cell carcinoma based on in vivo optical properties by high-definition optical coherence tomography. J Eur Acad Dermatol Venereol.

2016; doi: 10.1111/jdv.13720.

16. Marneffe A, Suppa M, Miyamoto M, del Marmol V, Boone M. Validation of a diagnostic algorithm for

the discrimination of actinic keratosis from normal skin and squamous cell carcinoma by means of

high-definition optical coherence tomography. Exp Dermatol. 2016; doi: 10.1111/exd.13036 .

17. Suppa M, Marneffe A, Miyamoto M, Del Marmol V, Boone M. Validation of algorithm for basal cell

carcinoma diagnosis and subtype classification by means of high-defininition optical coherence

tomography. Br J Dermatol. 2016; Submitted.