Histopathological Features Of Uterine Fibroids Associated With MRI-T2WI Images And Long-term Outcomes Of High Intensity Focused Ultrasound Treatment

High-Intensity Focused Ultrasound(HIFU)has emerged as a promising non-invasive treatment approach for uterine fibroids.It has garnered significant attention due to its clinical effectiveness and post-treatment outcomes,given the risk of fibroid recurrence and the need for surgical re-intervention.There are notable variations in the histopathological characteristics of uterine fibroids,depending on their T2 WI signal types.This histopathological diversity is a crucial factor influencing the efficacy of HIFU treatment.Hyperintense fibroids belong to the T2 WI signal type that are difficulty for HIFU treatment.In order to improve the long-term outcome of HIFU treatment of uterine fibroids,further research is needed.By analyzing the histopathological features of uterine fibroids with different T2 WI signal types,the long-term outcomes and risk factors after HIFU treatment,to guide the screening of indications for HIFU treatment,clarifiy the treatment objectives,assesse the risk of re-intervention after HIFU treatment,and provide a basis for optimizing the clinical protocol for HIFU treatment of uterine fibroids.Objective(1)Evaluate the histopathological features of uterine fibroids with different T2 WI signal types to understand the characteristics of fibroids that are challenging to ablate.Additionally,assess the impact of HIFU treatment on the histopathological features of locally recurrent uterine fibroids post-HIFU treatment.(2)Assess the long-term follow-up outcomes of uterine fibroids with different T2WI signal types after HIFU treatment,identifying types with unfavorable follow-up outcomes.(3)Analyze the risk factors affecting follow-up outcomes after HIFU treatment,establish the ablation rate threshold for hyperintense fibroids,and create a risk assessment model for postoperative re-intervention in hyperintense fibroids.Materials and Methods(1)Fibroid tissues were collected from uterine fibroids treated with surgery without HIFU treatment and from locally recurrent fibroids after USg HIFU treatment at four research centers between January 2021 and January 2023.Fibroids were categorized into five types based on their preoperative MRI-T2 WI signal characteristics:hypointense,isointense,heterogeneous hyperintense,slightly homogeneous hyperintense,and markedly homogeneous hyperintense fibroids.Routine histopathological observations and quantitative measurements,including smooth muscle cell count,microvascular count,collagen fiber content,estrogen receptor(ER)expression,and progesterone receptor(PR)expression,were conducted.Differences in these quantitative markers among fibroids with different T2 WI signal types were analyzed.Histopathological features were identified for fibroids that were challenging to ablate.Additionally,quantitative markers were compared between fibroid tissues with local recurrence after HIFU treatment and those not treated with HIFU.(2)The study included patients with single-onset,symptomatic uterine fibroids treated with USg HIFU at four clinical treatment centers between January 1,2017,and December 30,2018.Ablation rates(NPVR)for different T2 WI fibroid types following USg HIFU were analyzed.Patients were followed up until December 31,2021,with assessments of symptom remission rate,fibroid volume reduction rate(VRR),and re-intervention rate for different T2 WI fibroid types.The T2 WI signal type with the least favorable follow-up outcome was identified.(3)Hyperintense fibroids were selected,and binary logistic regression analysis was utilized to explore the risk factors associated with re-intervention rate and the NPVR threshold value influencing long-term re-intervention rates following USg HIFU treatment.Kaplan-Meier survival analysis and COX proportional risk regression analysis were employed to construct a re-intervention risk assessment model for hyperintense fibroids after HIFU treatment.Patients underwent a second follow-up one year after the initial follow-up,with a cutoff date of December 31,2022,to validate the NPVR threshold and the re-intervention risk assessment model.External validation of the NPVR threshold and the re-intervention risk assessment model was conducted on hyperintense fibroids from two clinical treatment centers between January 1,2019,and June 30,2019.ROC curves were used for internal and external validation of the NPVR threshold and the risk assessment model in predicting re-intervention risk.Hosmer-Lemeshow good of fit test was used to evaluate the calibration of the re-intervention risk assessment model.Results(1)A total of 51 cases of fibroids without HIFU treatment and 30 cases of locally recurrent fibroids after HIFU treatment were collected.Fibroids exhibited varying histopathological features based on their T2 WI signal types.Hypointense and isointense fibroids had fewer smooth muscle cells,higher collagen fiber content,fewer microvascular counts,and lower ER and PR expression levels.Heterogeneous hyperintense fibroids displayed diverse histopathological characteristics,often accompanied by tissue degeneration.Slightly homogeneous hyperintense fibroids were rich in smooth muscle cells,had low collagen fiber content,high microvascular density,and high ER and PR expression levels.Markedly homogeneous hyperintense fibroids included two distinct histopathological features: degenerative fibroids and cell-rich fibroids.The presence of slight or irregular enhancement on MRI-T1 WI indicated tissue degeneration,while regular enhancement indicated histopathological features similar to slightly homogeneous hyperintense fibroids.Smooth muscle cell count,microvessel count,ER and PR expression levels increased progressively from hypointense,isointense,heterogeneous hyperintense fibroids,markedly homogeneous hyperintense fibroids and slightly homogeneous hyperintense fibroids,while collagen fiber content decreased.These differences were statistically significant(P <0.001).There were no significant differences in ER and PR expression levels,smooth muscle cell count,collagen fiber content,and microvascular count between locally recurrent fibroids treated with HIFU and those untreated(P >0.05).(2)A total of 1427 subjects were collected from four research centers.The average NPVR for hypointense,isointense,heterogeneous hyperintense fibroids,slightly homogeneous hyperintense fibroids and markedly homogeneous hyperintense fibroids were 89.0%,86.6%,82.3%,74.0%,and 82.2%,respectively.NPVR for heterogeneous hyperintense fibroids,slightly homogeneous hyperintense fibroids,and markedly homogeneous hyperintense fibroids was significantly lower than that for hypointense and isointense fibroids(P < 0.001).NPVR for slightly homogeneous hyperintense fibroids was significantly lower than that for the other four types(P<0.001).A total of1303 patients were followed up for an average of 44 months.The re-intervention rates for hypointense,isointense,heterogeneous hyperintense fibroids,slightly homogeneous hyperintense fibroids,and markedly homogeneous hyperintense fibroids were 8.8%,10.8%,21.5%,39.9%,and 19.8%,respectively.Re-intervention rates for heterogeneous hyperintense fibroids,slightly homogeneous hyperintense fibroids,and markedly homogeneous hyperintense fibroids were significantly higher than those for hypointense and isointense fibroids.Re-intervention rates for slightly homogeneous hyperintense fibroids were significantly higher than those for the other four types(P<0.001).(3)A total of 353 hyperintense fibroids undergoing follow-up for an average of 44 months were studied furtherly.Age,NPVR,and fibroid volume were identified as independent risk factors affecting long-term re-intervention rates after HIFU treatment for hyperintense fibroids.Binary Logistic regression analysis showed that the threshold value of NPVR for HIFU treatment of hyperintense fibroids was 82 %.The results after an average of 44 months of follow-up indicated that re-intervention rate in the NPVR≥82% group was significantly lower than that in the NPVR < 82% group(8.1% vs 46.6%,P < 0.001).The results after an average of 56 months of follow-up indicated that re-intervention rate in the NPVR≥82% group was significantly lower than that in the NPVR < 82% group(8.9% vs 55.9%,P<0.001).A total of 83 cases of hyperintense fibroids were included for external verify of the NPVR threshold value.The results showed that the AUC and 95 % CI were 0.726(0.587,0.865).The NPVR of 82% was used as the threshold value for HIFU treatment of hyperintense fibroids,the sensitivity and specificity of the risk of re-intervention at average of 44 months of follow-up were 0.750 and 0.701,respectively.The calculation formula of the long-term follow-up re-intervention risk assessment model after USg HIFU treatment for hyperintense fibroids is : h(t,X)=h0(t)exp(2.054X1+1.018X2+0.991X3(+0.402X3)),where X1 represents NPVR,X2 represents fibroid volume and X3 represents age.A total of 83 cases of hyperintense fibroids were included for external validation of the re-intervention risk assessment model.The results showed that the AUC and 95%CI were 0.861(0.771,0.951).When the predictive probability of the model was 0.153,the sensitivity and specificity of predicting re-intervention at 44 months of follow-up were0.811 and 0.728,respectively.The results of Hosmer-Lemeshow goodness-of-fit test showed thatχ2= 3.476,P = 0.901(P > 0.05),suggesting that the prediction model had good calibration power.Conclusion(1)HIFU treatment does not appear to significantly alter the histopathological features of locally recurrent fibroids.Hypointense and isointense fibroids are suitable candidates for HIFU treatment.Slightly homogeneous hyperintense fibroids exhibit histopathological characteristics indicative of cellular fibroids,have the lowest NPVR,and show the poorest long-term outcomes after HIFU treatment,making them unsuitable candidates.Heterogeneous hyperintense fibroids and markedly homogeneous hyperintense fibroids are viable options for HIFU treatment,but the latter,when displaying regular enhancement on MRI-T1 WI,may have histopathological features similar to slightly homogeneous hyperintense fibroids,rendering them unsuitable for HIFU treatment.(2)Age,NPVR,and fibroid volume independently influence the re-intervention rate after HIFU treatment for hyperintense fibroids.NPVR≥82% can serve as the target value for HIFU treatment.A combination of patient age,NPVR,and fibroid volume enables early risk assessment for re-intervention,facilitating optimized clinical decision-making to enhance overall long-term follow-up outcomes for HIFU treatment of uterine fibroids.