Breast sonoelastography Clinical cases discussion Dr. Antonio Pio Masciotra Campobasso

Correct tissue elasticity quantification Aims of elastography Correct tissue elasticity quantification Identification of ‘cut off’ elasticity values for the right diagnostic workup of diffuse and focal diseases

Tessuto fibroso normale 96-244 Breast Tissue Young’s modulus (kPa) Normal fat 18-23 Normal gland 28-66 Normal fibrous tissue 96-244 Carcinoma 22-560 Mammella Tessuto Modulo di Young (kPa) Grasso normale 18-23 Ghiandola normale 28-66 Tessuto fibroso normale 96-244 Carcinoma 22-560 Breast Tissue Speed of sound (m/s) Whole breast post-menopausal 1.468 (5.2%) Whole breast pre-menopausal 1.510 (2.5%) Normal fat 1.478 (4.7%) Normal gland Benign tumors 1.513 (2.3%) Carcinoma 1.548 Breast Tissue Speed of sound (m/s) Mammella intera post-menopausa 1.468 (5.2%) Mammella intera pre-menopausa 1.510 (2.5%) Grasso normale 1.478 (4.7%) Ghiandola normale Tessuto fibroso normale 1.513 (2.3%) Carcinoma 1.548

Feature Longitudinal plane Fibrous tissue Fat Ratio Echogenicity 116.9 45.4 2.57 Stiffness 26.6 kPa 21.3 kPa 1.30 Feature Transverse plane Fibrous tissue Fat Ratio Echogenicity 121.8 37.4 3.26 Stiffness 20.0 kPa 14.2 kPa 1.40

Breast papillary carcinoma 2008 2011 2010 2009 2008 2009 2010 2011

Woman 41 years old

Woman 41 years old

Woman 41 years old

ATOMIC FORCE MICROSCOPE

Normal cell toward cancer cell Single cell’s progressive stiffness reduction Normal cell Less invasive cell The distribution of the actin network plays an important role in determining the mechanical properties of single cells. As cells transform from non-malignant to cancerous states, their cytoskeletal structure changes from an organized to an irregular network and this change subsequently reduces the stiffness of single cells. Further progressive reduction of stiffness corresponds to an increase in invasive and migratory capacity of malignant cells. Single cell’s progressive stiffness reduction More invasive cell

Dalla cellula normale alla cellula cancerosa Riduzione progressiva della rigidità della cellula Cellula normale Cellula meno invasiva La distribuzione della trama di actina è fondamentale nella determinazione delle proprietà meccaniche delle singole cellule. Nella trasformazione da cellula normale a cellula cancerosa la struttura del citoscheletro da ben organizzata diventa irregolare con conseguente perdita della rigidità. L’ulteriore riduzione progressiva della rigidità della cellula maligna le conferisce un progressive aumento delle sue capacità invasive e migratorie con conseguente metastatizzazione. Riduzione progressiva della rigidità della cellula Cellula più invasiva

Tumor cells’ stiffness decreases

La rigidità delle cellule neoplastiche diminuisce La rigidità della matrice extracellulare aumenta

On the SWE image for each ROI selected (described both in its dimension and in its depth from the surface) in the colored box are displayed different information on stiffness quantification expressed in kPa (Young’s modulus) or in m/s (SW speed) : Mean value Minimum value (softest) Maximum value (stiffest) Standard deviation Mean Stiffness ratio if 2 ROIs are selected - < or > 1 with numeric value depending on the unit of measurement applied (kPa or m/s)

Feature (kPa) Ratio (circ.ROI) Ratio (free ROI) Mean stiff. 7.0 5.6 Nodule (circ. ROI) Fat Ratio Mean stiff. 58.9 5.8 10.1 Minimun stiff. 47.1 4.8 9.8 Maximum stiff. 65.5 8.2 8.0 Standard Deviation 5.2 0.9 Feature (kPa) Ratio (circ.ROI) Ratio (free ROI) Mean stiff. 7.0 5.6 Minimun stiff. 14.4 0.02 Maximum stiff. 5.1 9.0 Standard Deviation 1.3 18.0 Feature (kPa) Nodule (free ROI) Fat Ratio Mean stiff. 32.6 5.8 5.6 Minimun stiff. 0.1 4.8 0.02 Maximum stiff. 72.1 8.2 9.0 Standard Deviation 16.2 0.9 18.0

SW Elastography precision and repeatibility Breast lipoma Time of sampling Mean stiffness Lipoma Fat Lipoma/Fat Ratio 10:07:09 20.5 kPa 19.9 kPa 1.03 10:07:34 8.0 kPa 7.8 kPa

Similar elasticity ratio Different kPa Similar elasticity ratio FA Echogeniciity Mean stiffness FA Gland FA/Gland Ratio Low 26.0 kPa 12.2 kPa 2.13 Medium 53.0 kPa 33.4 kPa 2.48

SW Elastography elasicity features Breast fibroadenoma FA Echogeniciity Mean stiffness Gland Ratio Low 26.0 kPa 12.2 kPa 2.13 Medium 53.0 kPa 33.4 kPa 2.48 FA Echogeniciity Standard deviation Gland Ratio Low 3.0 kPa 1.6 kPa 1.87 Medium 5.7 kPa 17.2 kPa 0.33

Breast multiple fibroadenomata – Directional PD Mother (58 years old) Daughter (29 years old)

Breast multiple fibroadenomata – SW Elastography Mother (58 years old) 41-66 kPa Daughter (29 years old) 70-83 kPa

Representative case of a tumor with significant changes in mitotic index according to the tumor cells’ location with regard to surrounding adipose tissues. The gland-side tumor cells show significantly higher mitotic index especially in ER-negative tumors.

Echogenicity Comparation Cancer Other tissue B Ratio Ca Vs Fat 14.6 42.5 0.35 Ca Vs. Fibrous tissue 38.8 111.4

Echogenicity based data Woman 48 years old Feature Echogenicity based data Stiffness based data Perimeter 5,42 cm 6,63 cm Area 1,52 cm² 2,45 cm² Diameter 1 1,48 cm 2,19 Diameter 2 1,45 cm 1,88 The tumor area traced according echogenicity is large smaller than the area traced according the stiffness.

Echogenicity based data Plane Feature Echogenicity based data Stiffness based data Difference (%) Coronal Perimeter 5,89 cm 5,78 cm -1,87% Area 1,47 cm² 2,06 cm² 40,1% Axial 3,03 cm 6,48 cm 80,9% 0,47 cm² 1,35 cm² 187,2% Sagittal 4,06 cm 5,39 cm 32,8% 0,69 cm² 1,71 cm² 147,8% Woman 48 years old The tumor’s dimensions traced according echogenicity are always smaller than the ones traced according the stiffness in all planes. Breast cancer is staged by the TNM System : Tumor Size, node status, and metastasis. Tumor Size is divided into four classes based on the maximum diameter: T-1 is from 0 to 2 centimeters. T-2 is from 2 to 5 cm. T-3 is greater than 5 cm . T-4 is a tumor of any size that has broken through (ulcerated) the skin, or is attached to the chest wall. So it would be wise to check which is the most reliable imaging technique of measurement of the ‘T’ parameter relating it to the more accurate prognostic significance and to the right choice in the therapeutic approach. T1mi Tumor ≤1 mm in greatest dimension. T1a Tumor >1 mm but ≤5 mm in greatest dimension. T1b Tumor >5 mm but ≤10 mm in greatest dimension. T1c Tumor >10 mm but ≤20 mm in greatest dimension.

Aims of elastography Precise tissue elasticity quantification stiffness quantification Identification of ‘cut off’ elasticity values for the right diagnostic workup of diffuse and focal diseases Identification of elasticity features for the right diagnostic workup of diffuse and focal diseases

Ultrasonography of breast focal diseases : a true Multiparametric Diagnostic Modality Mode Features Informations B Mode Shape ‘Taller-than-wide’ and “wider-than-tall” Morphology and Structure Internal component  solid, mixed or cystic Margins  Well circumscribed, lobulated or irregular Echogenicity (B Ratio Nodule/Parenchyma) “hyperechogenicity”,“isoechogenicity”,  “hypoechogenicity”and “marked hypoechogenicity” Evidence of calcifications  Micro-calcifications (< 3 mm) Macrocalcifications (> 3 mm with acoustic shadowing) Doppler Mode CDI, PDI , dPDI Number, density and distribution of the vessels Vascular Pulsed Wave Blood flow characterisation and quantification Blood Flow – Functional (?) Sonoelastography Strain Relative Stiffness Mechanical properties Shear Wave Relative stiffness and Stiffnes quantification

Thanks for your attention Conclusion The contribute offered by the new emerging tools in Ultrasound technology are really innovative in : Ultrafast doppler acquisition (with detection of low resistivity flow in more vessels) 2D Shear Wave Elastography (with qualitative and quantitative information on elasticity features) 3D Shear Wave Elastography (with information on the topographical distribution of the stiffest sites) Thanks for your attention Antonio Pio Masciotra Campobasso – Molise – Italy Website www.masciotra.net YouTube Channel https://www.youtube.com/channel/UCgCj21nKGAhR997Ia3-QegQ