Reasons For Different Therapeutic Effects Of High-intensity Focused Ultrasound Ablation For Uterine Fibroids With Different Signal Intensities On T2-weighted MRI: A Study Of Acoustic, Thermal Properties And Histopathological Characteristics

Uterine leiomyoma,a benign clonal tumour arising from the smooth-muscle cells of the human uterus,is one of the most common benign gynaecological tumors.High-intensity focused ultrasound?HIFU?is a minimally-noninvasive treatment and can ensure uterine integrity,so it is welcomed by the general female patients and have been extensively applied in the clinic at present.Clinical observations have found HIFU ablation has significantly different therapeutic effects on uterine fibroids with different signal intensities on T2-weighted MRI,but the reasons for the difference is unclear,so our study was to investigate the reasons for different therapeutic effects of HIFU ablation from the perspectives of acoustics,thermal properties and pathological characteristics.Objective1)To study the acoustics,thermal properties and pathological characteristics of uterine fibroids with different signal intensities on T2-weighted MRI.2)To establish the relationship between HIFU therapeutic effect on uterine fibroids with different signal intensities on T2-weighted MRI and imaging features,acoustic,thermal properties and histopathological characteristics.3)To investigate the reasons for different therapeutic effects of HIFU ablation of uterine fibroids with different signal intensities on T2-weighted MRI from the perspectives of acoustics,thermal properties and pathological characteristics.Materials and Methods1)From December 2014 to June 2015,47 patients were diagnosed with uterine fibroids by gynecologist in the First Affiliated Hospital of Chongqing Medical University,and underwent myomectomy or hysterectomy afterwards.47 fresh specimens of uterine leiomyomas were taken out after operation as the research subjects.Uterine fibroids were classified into 4 categories according to signal intensity on pretreatment T2-weighted MRI:hypo-intense,isointense,heterogeneous hyper-intense and homogeneous hyper-intense.The sound speed,acoustic impedance and attenuation,organization density,specific heat capacity and thermal conductivity were quantitatively measured in different groups.The sound speed and acoustic attenuation were measured by using a pulse transmission technique;Organization density was measured by the law of Archimedes;Acoustic impedance was calculated by using the results of sound speed and organization density;Specific heat capacity was measured by differential scanning calorimetry?DSC?;Thermal conductivity was measured by using the linear heat-source method.2)47 uterine fibroids specimens collected from the first part of study was for histopathologic observation and quantitative research of histopathologic characteristics.The smooth muscle cell?SMC?and collagen fiber of fibroids were observed by using hematoxylin and eosin?HE?staining and sirius red staining respectively.Photographs were taken for each slide from 3 to 5 randomly selected microscopic fields under 4�10?10�10?40�10 times optical microscope respectively.The pathological images were processed with imaging software?Image-Pro Plus/Photo shop?and the cell counts of SMC and the collagen fiber content were calculated.Results from all the fields were averaged and compared in different groups.The correlation between cell counts of SMC,collagen fiber content and sound speed,acoustic attenuation,specific heat,thermal conductivity was analyzed respectively.3)Therapeutic effects of fibroids in different signal group after HIFU irradiation was calculated by using numerical simulation method combined with the acoustic,thermal properties of uterine fibroids with different signal intensity on T2-weighted MRI from the first two parts of study,Khokhlov-Zabolotskaya-Kuznetsov?KZK?equation,Pennes bio-heat transfer equation and CEM43??the Cumulative number of Equivalent Minutes at 43??thermal dose model.The simulation results were compared with the results of in vitro HIFU irradiation.30 of 47 specimens from the first part were under HIFU irradiation by the focused ultrasound treatment system?JC200?,with the irradiation parameters as follows:acoustic power of 200 w,irradiation mode of single point irradiation with continuous-wave,irradiation time of 4 seconds.Necrosis area was stained by using triphenyl tetrazolium chloride?TTC?staining after irradiation and the diameters of necrosis lesion were measured,then the necrosis volume and Energy efficiency factor?EEF?were calculated.From November 2013to June 2015,115 patients underwent HIFU treatment in HIFU Center of the First Affiliated Hospital of Chongqing Medical University,the ultrasound monitor video of HIFU treatment process were retrospectively analyzed.The first therapy point of the first treatment slice was considered as the research object.The volume of necrosis area and EEF were calculated by the size of gray scale change.The volume of necrosis area and EEF were compared between groups and with the results of the part of in vitro study.4)The signal intensity of uterine fibroids of preoperative T2WI MRI of the 47 patients from the first part was quantified.Signal intensity of myoma and normal myometrium were measured by using the region of interest?ROI?in transverse T2-weighted MRI,then the signal intensity of myometrium was divided by the the signal intensity of fibroid for calculating the ratio of signal intensity.The correlation between the signal intensity and sound speed,acoustic attenuation,specific heat,thermal conductivity,cell counts of SMC,collagen fiber content was analyzed respectively.The correlation between the EEF and sound speed,acoustic attenuation,specific heat,thermal conductivity,cell counts of SMC,collagen fiber content was analyzed respectively.Results1)Totally 47 fibroid specimens were collected.Sample number of hypo-intense group was 7,isointense group was 9,heterogeneous hyper-intense group was 21 and homogeneous hyper-intense group was 10.The sound speed of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 1597.86�15.17m/s,1586.70�10.83m/s,1582.05�6.44m/s and 1566.15�6.91m/s,respectively.The acoustic attenuation of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 3.91�1.26dB/cm,1.58?1.74?dB/cm,1.36�0.58dB/cm,0.43�0.27dB/cm,respectively.The organization density of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 1.03?0.11?g/ml,1.03�0.05g/ml,1.01�0.05g/ml,0.97�0.01g/ml,respectively.The acoustic impedance of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 1.64?0.18?�10⁶Pa�s�m^-1,1.65�0.08�10⁶Pa�s�m^-1,1.58�0.07�10⁶Pa�s�m^-1,1.52�0.03�10⁶Pa�s�m^-1,respectively.The specific heat capacity of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were2735.9�598.5 J/k�?,2920.6�616.2 J/k�?,3357.5�368.2 J/k�?,4781.1?431.9?J/k�?,respectively.The thermal conductivity of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 0.38�0.10W/mK,0.46?0.16?W/mK,0.44�0.07 W/mK,0.51�0.01 W/mK,respectively.Acoustic and thermal characteristics in different groups of uterine fibroids in vitro were compared.The results showed that among the four groups,sound speed,organization density,acoustic impedance and acoustic attenuation progressively decreased from the hypo-intense group to the homogeneous hyper-intense group?P=0.000/0.000/0.001/0.000?;Specific heat capacity and thermal conductivity progressively increased?P=0.001/0.000?.2)The pathology results were as follows.:Fibroids with hypo-intense or isointense,especially hypo-intense signal intensity were typically composed of smooth muscle cells arranged in whorls with massive content of thick collagen;Fibroids with homogeneous hyper-intense signal intensity were mostly cellular leiomyomas consisting of abundant SMCs arranged in dense and uniform pattern and a few sparse collagen fibers;In myomas with heterogeneous hyper-intense signal intensity,the substantial areas could be both typical normal structure of fibroids and cellular leiomyomas arrangement and the degeneration parts were mostly hyaline degeneration and hemorrhage necrotic degeneration.Quantitative analysis showed that from the hypo-intense group to the homogeneous hyper-intense group the cell counts of SMC were 215.6�59.3,237.0?89.5?,232.3�72.5,330.5�30.9,collagen fiber content were 0.65�0.07,0.55�0.10,0.53�0.12,0.41�0.06,respectively.Comparison among the four groups found that cell counts of SMC progressively increased?P=0.001?but collagen fiber content progressively decreased from the hypo-intense group to the homogeneous hyper-intense group?P=0.000?.Correlation analysis sowed that cell counts of SMC were positively correlated with specific heat capacity and thermal conductivity?R=0.468/0.623,P=0.001/0.000?but negatively correlated with sound speed and acoustic attenuation?R=-0.414/-0.442,P=0.005/0.002?;Collagen fiber content were positively correlated with sound velocity and acoustic attenuation?R=0.488/0.642,P=0.001/0.000?but negatively correlated with specific heat capacity and thermal conductivity?R=-0.619/-0.327,P=0.000/0.042?.3)Totally 23 simulation calculation were conducted.Simulation number of hypo-intense group was 7,isointense group was 5,heterogeneous hyper-intense group was 5 and homogeneous hyper-intense group was 6.The necrosis volume of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were140.48�40.44mm³,131.18�32.49mm³,117.61�37.13mm³,50.22�17.46mm³,respectively.The EEF of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 6.07�1.54J/mm³,6.40�1.54 J/mm³,7.27�2.02 J/mm³,17.45�5.47 J/mm³,respectively.Comparison among the four groups found that necrosis volume progressively decreased?P=0.001?but the EEF progressively increased from the hypo-intense group to the homogeneous hyper-intense group?P=0.001?.Totally 30 specimens were irradiated by HIFU.Sample number of hypo-intense group was 7,isointense group was 8,heterogeneous hyper-intense group was 9 and homogeneous hyper-intense group was 6.The necrosis volume of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 919.21�126.24mm³,678.98�248.28mm³,582.80�364.41mm³,151.96�76.01mm³,respectively.The EEF of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 0.62�0.08J/mm³,0.93�0.36 J/mm³,1.38�0.83 J/mm³,4.55�2.20 J/mm³,respectively.Comparison among the four groups found that necrosis volume progressively decreased?P=0.000?but the EEF progressively increased from the hypo-intense group to the homogeneous hyper-intense group?P=0.000?.Totally 97 of 115 cases were retrospectively analyzed and the necrosis volume and EEF were calculated.Sample number of hypo-intense group was 31,isointense group was 17,heterogeneous hyper-intense group was 30 and homogeneous hyper-intense group was 19.The necrosis volume of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 111.82?373.28?mm³,108.05?88.70?mm³,71.25?148.49?mm³,34.20?96.85?mm³,respectively.The EEF of the hypo-,iso,heterogeneous hyper-intense and homogeneous hyper-intense uterine fibroids were 13.40?29.68?J/mm³,23.68?39.49?J/mm³,38.16?146.84?J/mm³,215.42?311.76?J/mm³,respectively.Comparison among the four groups found that necrosis volume progressively decreased?P=0.001?but the EEF progressively increased from the hypo-intense group to the homogeneous hyper-intense group?P=0.000?.Compared with the actual irradiation results,necrosis volumeofsimulationinallfourgroupsweresmaller?P=0.000/0.001/0.030/0.021?and the EEF value were higher?P=0.000/0.001/0.008/0.000?.EEF of clinic study in all four groups were higher than the in vitro irradiation experiment?P=0.000/0.000/0.000/0.001?.Results of in vitro irradiation experiment and clinical trials showed that necrosis volume and EEF value of heterogeneous hyper-intense group were diversity within group.4)Quantitative analysis of signal intensity of uterine fibroids showed that signal intensity of hypo-intense group was 0.67�0.14,isointense group was 0.71�0.07,heterogeneous hyper-intense group was 0.76?0.43?,homogeneous hyper-intense group was 1.17�0.17.Comparation among four groups showed that signal intensity progressively increased from the hypo-intense group to the homogeneous hyper-intense group?P=0.000?.Correlation analysis showed that specific heat capacity,thermal conductivity and cell counts of SMC were positively correlated with signal intensity?R=0.428/0.535/0.561,P=0.003/0.000/0.000?;Sound speed,acoustic attenuation and collagen fiber content were negatively correlated with signal intensity?R=-0.473/-0.424/-0.437,P=0.001/0.004/0.002?.Specificheat capacity,thermal conductivity and cell counts of SMC were positivelycorrelatedwithEEF?R=0.406/0.730/0.573,P=0.026/0.000/0.001?;Sound speed,acoustic attenuation and collagen fiber content were negatively correlated with EEF?R=-0.454/-0.636/-0.494,P=0.012/0.000/0.008?.Conclusions1)Sound speed,acoustic impedance,acoustic attenuation,specific heat capacity,thermal conductivity,cell counts of SMC and collagen fiber content of uterine fibroids with different signal intensities on T2-weighted MRI are different.From the hypo-intense group to the homogeneous hyper-intense group,sound speed,acoustic impedance,acoustic attenuation and collagen fiber content progressively decreased but the specific heat capacity,thermal conductivity and cell counts of SMC progressively increased.2)Therapeutic effects of HIFU ablation of uterine fibroids with different signal intensity on T2WI MRI are different from three aspects of numerical simulation calculation,in vitro irradiation and clinical treatment.From the hypo-intense group to the homogeneous hyper-intense group,necrosis volum progressively decreased but the EEF progressively increased,which indicate that difficulty of HIFU ablation progressively increases;Necrosis volum and EEF value in heterogeneous hyper-intense group of both in vitro irradiation and clinical treatment are diversity within groups,which indicate that difficulty of HIFU ablation in heterogeneous hyper-intense group is diversity.3)There are correlations between signal intensity,acoustic and thermal properties,histopathological characteristics and HIFU therapeutic effects of uterine fibroids with different signal intensities on T2-weighted MRI.Specific heat capacity,thermal conductivity and cell counts of SMC were positively correlated with signal intensity but sound speed,acoustic attenuation and collagen fiber content were negatively correlated with signal intensity.There are correlations between acoustic and thermal properties,histopathological characteristics and HIFU therapeutic effects of uterine fibroids with different signal intensities on T2-weighted MRI.Specificheat capacity,thermal conductivity and cell counts of SMC were positively correlated with EEF,sound velocity,acoustic attenuation and collagen fiber content were negatively correlated with EEF.Therapeutic effects of HIFU ablation of uterine fibroids could be predictive by signal intensity of T2-weighted MRI.Differences in acoustic,thermal properties and histopathological characteristics may be one of the reasons for different therapeutic effects of HIFU ablation of uterine fibroids with different signal intensities on T2-weighted MRI.