Characterisation of Tissue Stiffness to Improve the Diagnosis and Management of Uterine Fibroids
Phase: NA
Conditions: Leiomyoma
Sponsor: Dr. Linda McLean

 
 
 
 
 
 
 
 
 
Characterisation of Tissue Stiffness to Improve the Diagnosis and 
Management of Uterine Fibroids 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
University of Ottawa 
NCT #: NCT03369600 
December 6, 2017 

 
Characterization of tissue stiffness to improve the diagnosis and management of uterine 
fibroids 
 
Principal Investigator: Sukhbir Singh, MD, FRCSC  
Co-investigators: Vincent della Zazzera, MD, FRCSC  
Linda McLean, BSc, MSc, PhD  
Michel Labrosse, PhD, PEng  
Teresa Flaxman, PhD 
Catriona Czyrnyj, PhD Candidate 
 
 
Background: 
Uterine fibroids are the most common gynecological tumors, with a prevalence up to 70% in 
premenopausal women 1,2. Although these tumors are benign, 20% – 50% of women with uterine 
fibroids are symptomatic 1 and morbidities are significant, including menstrual abnormalities 
(e.g. heavy and prolonged bleeding leading to iron deficiency anemia), bulk symptoms (e.g. 
pelvic pain, bowel and bladder obstructions, abdominal protrusion), and infertility 1–5. 
Symptomatic fibroids can negatively impact women’s quality of life and results in loss of 
productivity 6,7. The management of uterine fibroids is estimated to cost the healthcare system 
between $2200 and $15,952 per patient, per year 8.  
 
Uterine fibroids are globular masses composed of disordered myometrial cells contained within 
abundant extracellular matrix 9,10. Fibroids degenerate as they outgrow their blood supply 11, and 
can take on a range of characteristics while presenting on a spectrum of very soft to extremely 
hard masses 4,11–13. Fibroid degeneration state is currently not considered in diagnosis, 
management or surgical planning. Instead, fibroids are classified based only on their location 14 
and are described by their size and shape.  
 
While medical management is advancing 5,10,12,15 surgical removal through myomectomy or 
hysterectomy is the current standard of care for uterine fibroids 5.  Myomectomy can spare the 
uterus to preserve fertility, yet complications occur in 2-35% of cases 16–18. Fibroid mechanical 
properties appear to be relevant to surgical outcome: our surgeons at TOH report very hard or 

 
very soft fibroids increase surgical time and injury risk as respective morcellation or 
identification of the dissection plane can be difficult. Surgeons who are given information of 
fibroid stiffness prior to surgery may be able to alter their approach in order to mitigate these 
reported risks. These properties cannot be determined through MRI or US. Pre-operative fibroid 
characterization through SWE would be an extremely welcomed innovation in uterine fibroid 
diagnosis, monitoring and intervention planning.  
 
Research goal: to create a sensitive and specific classification scheme to differentiate uterine 
fibroids based on their stiffness characteristics determined through SWE and to use this 
classification to guide medical and surgical management decisions 
 
Main purpose: to determine if transvaginal shear wave elastography can be used as a clinical 
tool to measure stiffness properties of uterine fibroids. 
 
Primary objectives: 
(1) To validate stiffness measured through SWE from healthy and uterine fibroid tissue 
against mechanical tissue properties of the same tissues obtained through mechanical 
testing ex-vivo,  
(2) Test the reliability of fibroid and healthy uterine tissue stiffness obtained through SWE, 
(3) To use SWE stiffness measures to differentiate between healthy tissues and the varying 
states of uterine fibroids.   
Secondary objective: 
(1) To compare 2D and 3D ultrasound volume estimates of uterine fibroids and compare 
measurement error using MRI as a gold standard.   
 
Methodology 
Study Design: This prospective observational cohort study. Two populations will be recruited 
for this study: Patients with fibroids (FIB) and healthy controls (CON). 
 
Participants: Thirty women, aged ≥18 years, and consented for hysterectomy (due to uterine 
fibroids) or myomectomy at The Ottawa Hospital – General Campus will be recruited for the 

 
FIB group. Potential FIB participants will be excluded if they are suspected to have adenomyosis 
or leiosarcomas prior to surgery. Potential FIB participants will be screened for eligibility and 
consented for the study by the research coordinator or research assistant. The CON group will 
include women, aged ≥18 years, with no history of gynecological pathologies, have regular 
menstrual cycles, and not be pregnant at the time of data collection.  
Based on findings by 19,20, a sample size of 30 in each group was deemed appropriate to detect 
effect size of at least 12kPa with 90% power at a significance level of α=0.05. Due to the prospective 
design, we will not know the distribution of fibroid types a priori. A power analysis to confirm 
final sample size will be conducted with preliminary data collected from our first 15 participants 
in each group FIB participants and 15 CON participants. 
 
Recruitment: Prospective FIB participants will be recruited from a list of patients consented for 
myomectomy or hysterectomy due to uterine fibroids at The Ottawa Hospital – General Campus. 
Potential participants that have provided “permission to contact” by research as indicated on the 
institution’s electronic medical record (EMR) or the OBIEE dashboard will be contacted by the 
study’s research coordinator or research assistant. If “permission to contact” is not specified then 
only patients of our participating gynecologists will be recruited. In these cases, the participating 
gynecologist will contact the patient to introduce the study themselves, and if agreed, the study’s 
research coordinator or research assistant will contact them to discuss the study further. Initial 
contact will be made through telephone (see attached telephone script). If they agree to 
participate, then ultrasound imaging session(s) will be booked within one week of their surgery.  
 
CON participants will be recruited from the community. Advertisement posters will be 
placed around The Ottawa Hospital and the University of Ottawa. Individuals interested in 
participating will contact the research coordinator by phone or email. Potential CON participants 
will be screened for eligibility and if they agree to participate then experimental session(s) will 
be booked at their convenience. 
At the time of the ultrasound imaging session, a consent form containing further 
information about the purpose of the study, risks and benefits will be provided. Participants will 
be allotted as much time as they would like to review the form and ask the researchers any 
questions/concerns they may have. At time of study introduction, we will offer to send a full 
consent form prior to ultrasound imaging session so they can review the form at their 

 
convenience. Signed consent will be obtained onsite by the research coordinator or research 
assistant before data collection commences. 
 
Data Collection:  
 
Ultrasound Imaging: All participants will attend two ultrasound imaging sessions at the Motor 
Function and Movement Laboratory at the University of Ottawa. The sessions for the FIB 
participants will occur within 1 month of their planned surgery. Each session will take 
approximately 1 hour to complete. After providing signed informed consent, participants will 
complete a set of validated questionnaires about their gynecological and medical history, 
symptoms, and quality of life as it relates to uterine fibroids. The questionnaires include the 
Medical Outcomes Study 36 Item Short Form Survey21, the Uterine Fibroids Symptoms Quality 
of Life questionnaire22, and the Menstrual Bleeding Questionnaire23. 
All participants will then undergo 2D and 3D ultrasound scans with a GE ultrasound 
system (Voluson S6, General Electric, Boston, MA) as well as a SWE transvaginal ultrasound 
scan using an Aixplorer ultrasound system (Supersonic UltrafastTM Aixplorer®, Apexium 
Medical, Canada). SWE and volume measurements of their uterus as a whole, at 10 healthy sites 
and at all relevant fibroid sites deemed will be recorded. Morphologic measurements of the 
selected fibroids will be made and fibroids will be given identification numbers. SWE will be 
used to determine tissue stiffness (kPa) at 10 healthy sites and at each fibroid. Three repetitions 
of each measurement will be performed to satisfy Primary Objective 2. The second ultrasound 
imaging session will occur within one week where the imaging protocol will be repeated. This 
second data collection will be to evaluate reliability (Primary Objective 2).  
 
The rest of the data collection protocol applies to FIB participants only. 
Surgical Intervention: The surgical approach (myomectomy or hysterectomy + abdominal or 
laparoscopic) will be recorded as well as secondary outcomes including operating time, blood 
loss, surgical technique conversions, failed/incomplete excisions, and additional procedures 
performed. These data will be used for descriptive purposes. 
 

 
Tissue Sampling: Consistent with TOH protocol, all uterine tissue will be sent to pathology for 
evaluation. For patients who receive a hysterectomy, a pathologist will surgically excise five >=1 
cm3 samples of healthy uterine tissue from the sites identified using US and each fibroid will be 
dissected out. All fibroids will be labelled with their respective identification number, measured, 
weighed, and then transported to Dr. Labrosse’s laboratory at the Ottawa Heart Institute for 
mechanical testing. 
 
Mechanical Testing: The healthy tissue samples will be cut to size while the fibroids will be 
tested intact. All samples will be loaded into a set of 3D printed clamps attached to a biaxial 
tissue testing device (Biotester, CellScale, Waterloo, Canada) and tested at body temperature, 
cyclically in compression (1 Hz, 6% pre-compression). Relevant material properties will be 
calculated, including the complex modulus of elasticity, loss factor, and stiffness contrast ratio. 
All samples will be returned to pathology. Pathology charts will be retrospectively reviewed to 
extract descriptive fibroid characteristics. 
 
Statistical Analysis Plan: All data will be tested for normality and non-parametric equivalent 
tests will be used as appropriate. Validation of stiffness measures derived from SWE will be 
done through linear regressions (Primary Objective 1) which will be performed for the healthy 
and fibroid tissues separately and combined to map the relationship between SWE outcomes and 
the results of ex-vivo mechanical testing.  
 
For the reliability analysis (Primary Objective 2), ANOVA’s will test for differences between 
measures taken across multiple sessions and visits to investigate site-specific differences in 
stiffness measures. Intra-class correlation coefficients (ICCs) will be determined for 
measurements within session, between-session, and between-site.  
 
Factorial ANOVAs will evaluate site- and group (CON vs FIB) differences in uterine tissue 
stiffness measured with SWE. ANOVAs will also investigate differences in SWE stiffness 
measures between healthy tissue, normal fibroids and degenerative fibroids (Primary Objective 
3). Appropriate post-hoc comparisons will be performed, and post-hoc power analyses will 
evaluate the effect sizes for non-significant differences.  

 
Significant differences in 2D, 3D ultrasound, and ex-vivo volume estimates will be determined 
with dependent T-tests at the p<0.05 level (Secondary Objective 1). The standard error of 
measurement (SEM) will also be computed for 2D and 3D ultrasound volume measures, using 
ex-vivo morphology and volume measurements as a reference.  
 
Clinical significance of project: Establishing SWE methods for uterine fibroid characterization 
would result in a ground-breaking advance for directing medical and surgical decision-making in 
this highly prevalent gynaecological condition.  Magnetic resonance (MRI) and ultrasound (US) 
imaging are the current standards of care for evaluating uterine fibroids. They inform about 
number, size and location of fibroids, but are not capable of characterising the degeneration state 
of a given fibroid.  Fibroid degeneration state has huge implications for determining the potential 
for and progress of medical management, and for selecting the best surgical approach. The 
degeneration state of a fibroid can drastically alter its material properties including stiffness, a 
characteristic that can be measured using SWE. Thus, SWE could provide the missing and 
necessary information on fibroid degeneration state to inform treatment decisions. Findings from 
this study has the potential to revolutionize the management of uterine fibroids, leading to more 
timely diagnoses, reduced surgical time and complications, better inform decisions for medical 
therapies and, ultimately, safer, more effective, and less costly care.   
 
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