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1 From the Robert Steiner Magnetic Resonance Unit, Department of Imaging, Faculty of Medicine at Imperial College, Hammersmith Hospital, DuCane Rd, London W12 0HS, England. Received March 9, 2001; revision requested April 11; revision received May 25; accepted July 5.
ABSTRACT |
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MATERIALS AND METHODS: Eleven consecutive women underwent magnetic resonance (MR) imaging before UAE, immediately after, and at 1 and 4 months. Reduction in maximal enhancement above baseline at 90 seconds (ME90) after injection of the dominant leiomyoma immediately after embolization was correlated with its volume reduction at 4 months and with clinical response at 12 months.
RESULTS: Forty-five leiomyomas were noted (mean, four per patient). Myometrium enhanced briskly (ME90 of 110%), with a reduction in ME90 to 26% immediately after embolization. Initial leiomyoma ME90 was lower (P < .001), but it suppressed to baseline levels immediately after embolization. At 1 and 4 months, myometrial perfusion returned to normal, but leiomyoma perfusion remained suppressed (P < .001). Immediate reduction in leiomyoma ME90 correlated with clinical response (Spearman = 0.64). Leiomyomas initially high in SI on T2-weighted images showed significantly greater volume reduction than those low in SI (P = .006). Well-perfused leiomyomas did not show greater volume reduction than those that were poorly perfused. Volume reduction did not correlate with improvement in clinical symptom score.
CONCLUSION: Immediate reduction in leiomyoma perfusion after bilateral UAE correlates with clinical response, whereas leiomyomas initially high in SI on T2-weighted images indicate a likely greater volume reduction.
Index terms: Arteries, therapeutic embolization, 969.1264 • Arteries, uterine, 969.12 • Leiomyoma, 854.318 • Uterine neoplasms, MR, 854.121411, 854.121412, 854.12143 • Uterine neoplasms, therapy, 854.1264
INTRODUCTION |
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MATERIALS AND METHODS |
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Imaging was performed before and within 30 minutes of the completion of embolization and 1 and 4 months after the procedure. MR imaging consisted of coronal and sagittal T1-weighted spin-echo sequences (496/20 repetition time msec/echo time msec) obtained before and after contrast material administration, sagittal T2-weighted fast spin-echo sequences (4,000/84 , echo train length of 16), and single-section dynamic gadolinium-enhanced (Omniscan [0.1 mmol per kilogram of body weight of gadopentetate dimeglumine]; Nycomed Amersham, Oslo, Norway) sequences (31/13; 90° flip angle) obtained with a temporal resolution of 4 seconds. In the patient who underwent MR imaging with the 1.5-T system, an echo time of 8 msec was used for dynamic contrast-enhanced sequences (192 x 256 matrix, two signal averages, 35-cm field of view, and 8-mm section thickness). At least 5 hours had elapsed between the administration of the preembolization dose of gadolinium-enhanced contrast material and the immediate acquisition of postembolization images. In eight cases, preembolization imaging was performed the day prior to the procedure.
Embolization was performed with a femoral approach by using a 5-F cobra (Cordis, Miami, Fla) catheter. Both uterine arteries were selectively catheterized in all cases. Embolization was achieved by injecting 355–500-µm polyvinyl alcohol particles (Contour Emboli, St Albans, England) into each uterine artery until the flow had ceased. Pain was managed with intravenously administered opiates, either as a bolus or with a patient-controlled pump. In two cases, no intravenous postprocedural analgesia was required.
A postal questionnaire on clinical symptoms was completed by each patient before embolization and at 12 months after embolization. All recorded data were related to the symptoms of menses: namely length, blood loss, and associated pain. Each symptom was scored from 1 to 3 to produce a total final clinical response score of 9. Menses length of less than 3 days was scored 1; 4–5 days, 2; and 6 or more days, 3. Light menstrual loss (spotting) was scored 1; loss requiring one to two changes of sanitary napkins per 24 hours, 2; and heavy loss with or without clots and requiring more than two changes of sanitary napkins per 24 hours, 3. Occasional twinges of pain were scored 1; cramps, 2; and cramps requiring analgesia, 3. The change in the clinical score at 12 months from that at preembolization levels was calculated as a percentage with the following formula: difference in score/preembolization score x 100.
Serum follicle-stimulating hormone (FSH) levels were measured by using a microparticle enzyme immunoassay before embolization and at the same stage of the menstrual cycle 4 months after the procedure.
Image Analyses
In each patient, the number of leiomyomas and the individual signal intensities (SIs) relative to the myometrium were recorded on initial, immediate, and 1- and 4-month postembolization T2-weighted images as hypointense, isointense, or hyperintense. All leiomyoma-to–adjacent myometrium SI ratios were also recorded on T1-weighted images obtained before embolization, immediately after, and at 1 and 4 months. Leiomyoma locations (submucous, myometrial, and subserosal) were also recorded.
In every patient, perfusion data were obtained from the dynamic enhanced series before embolization, immediately after, and at 1 and 4 months. Regions of interest were drawn over an area of maximal enhancement within the dominant leiomyoma and an adjacent area of myometrium in the same z plane (head to foot) to avoid SI variations due to the pelvic phased-array coil. Regions of interest were placed by one author (N.M.d.S.) and were between 0.3 and 1.5 cm2 in area (median, 0.5 cm2). SIs were recorded with an imaging perfusion profile software (Marconi Medical Systems, Highland Heights, Ohio). In addition, for every leiomyoma depicted on each single section of the dynamic series, the enhancement above baseline was noted. Leiomyomas were well perfused when the plateau enhancement (after 90 sec) was equivalent to or greater than that of the adjacent myometrium, or poorly perfused, when the plateau enhancement was less than that of adjacent myometrium.
Volume measurements of the dominant leiomyoma and the entire uterus (including all leiomyomas) were made by one author (N.M.d.S.) by drawing around the area with an electronic caliper and by using standard scanner software to compute the area per section. The sum of the areas was multiplied by the section thickness. Measurements were made before embolization, immediately after, and at 1 and 4 months. Individual volume measurements of all leiomyomas were made similarly on preembolization and 4-month postembolization images. Measurements obtained before and after embolization were made while viewing corresponding images simultaneously so that individual leiomyomas could be clearly identified and compared.
Statistical Analyses
Statistical analyses were done by using software (Unistat Ltd, London, England). Data were tested for normality by using normality profiles and a Shapiro-Wilk normality test to determine subsequent use of appropriate tests for statistical comparison. For each time point of the dynamic series for both myometrium and dominant leiomyoma, the percentage enhancement above baseline was calculated by using the equation (SIpost - SIpre)/SIpre, where post is after enhancement and pre is before enhancement. The calculated change in SI from that at baseline would eliminate any T2* effects in the absolute values of SI. The mean and SD of the pooled patient data were plotted before embolization, immediately after, and at 1 and 4 months. The maximal enhancement above baseline at 90 seconds (ME90) of myometrium and that of leiomyoma before embolization was compared by using a paired t test. The ME90 of myometrium and leiomyoma before embolization was similarly compared with the values obtained immediately after embolization and at 1 and 4 months.
All distributions tested normal. The percentage change in volume at 4 months between areas of high SI and those of low SI on T2-weighted images of leiomyomas or between well- and poorly perfused leiomyomas was compared by using a nonpaired two-sample t test with unequal variance. Changes in individual leiomyomas were considered independently of each other. High SI well- versus poorly perfused leiomyomas were compared as were low SI well- versus poorly perfused leiomyomas, large (50 cm3) versus small (<50 cm3) volume leiomyomas, and submucosal versus myometrial leiomyomas.
In dominant leiomyomas, the immediate reduction in ME90 (reduction in a percentage enhancement between preembolization and immediate postembolization images) was correlated with their reduction in volume at 4 months by using Spearman rank correlation coefficient. Similar correlation coefficients were obtained between immediate reduction in ME90 of myometrium and leiomyoma and clinical response (percentage change in symptom scores at 12 months) and between total volume reduction of all leiomyomas in each patient at 4 months and clinical response at 12 months.
The significance of the difference in serum FSH levels at 4 months from those obtained before embolization was assessed by using a paired t test.
RESULTS |
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SI Changes
Immediately following embolization, an increase in SI within leiomyomas, compared with the myometrium, was seen on T1-weighted images regardless of their size, location, initial SI, or perfusion characteristics. This was relatively homogenous. Mean leiomyoma-to–adjacent myometrium SI ratios had increased from 1.1 ± 0.1 before embolization to 1.4 ± 0.1 immediately after embolization. This hyperintensity on T1-weighted images persisted at 1 and 4 months, though it gradually became more heterogeneous and less marked (Fig 1). With T2 weighting, there were no observable changes in SI on the immediate postembolization images. However, after 1 and 4 months, there was a reduction in SI on T2-weighted images in 43 of 45 leiomyomas (Fig 2). Two leiomyomas remained isointense with the myometrium.
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Relationship of Initial SI and Perfusion to Late Volume Changes in Leiomyomas
In all groups, the percentage change in the volume data was normally distributed. Leiomyomas that were high in SI on T2-weighted images prior to embolization (n = 11; mean volume, 117.5 cm3 ± 154.0) showed a significantly greater reduction in volume at 4 months, compared with the 34 leiomyomas (mean volume, 81.0 cm3 ± 93.7) that were low in SI (55.8% ± 21.2 vs 32.5% ± 23.9, respectively; P = .006; Fig 8).
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DISCUSSION |
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The intrinsic vascular pattern of uterine leiomyomas appears to represent a localized expansion of the myometrial vasculature, with the vessels within these tumors oriented in the direction of the muscle cell bundles (6). Early structural studies in which methods of pigment or radiopaque dye injection were used demonstrated that small leiomyomas were generally less vascular than myometrium, whereas larger leiomyomas were more vascular (7). Findings from blood flow studies (8) in which color Doppler ultrasonography was used confirmed that vascularization of leiomyomas was largely dependent on tumor size. Huang et al (9) demonstrated a negative correlation between leiomyoma size and/or volume and pulsatility index.
In contrast, immunohistochemical data measuring proportional area stained as an indicator of vascular density showed that myometrium had a significantly greater microvascular density than did small leiomyomas and both inner and outer regions of large leiomyomas (10). In addition, microvascular density measured on the basis of discrete microvessel count was significantly higher in myometrium than in all uterine leiomyoma groups (10). In our study, of the 35 leiomyomas included on the dynamic images, the well-perfused and the poorly perfused leiomyomas showed no significant difference in their mean volumes. It is likely that differing regions exist within these tumors in terms of blood flow and tissue perfusion, which account for the variability in reported results (8,11).
The differences in microvascular density in the myometrium and leiomyomas represent a difference in angiogenesis and vascular remodeling in these vascular beds and may be explained in two ways. They may result from a complex differential angiogenic promoter or inhibitor signals on leiomyomas and myometrium. It may also be that the presence of leiomyomas induces vascular changes within the myometrium. It has been postulated that this increase in vascular density is responsible for menorrhagia, which is observed in women with leiomyomas. However, we did not observe a significant difference in the rate or peak enhancement of the myometrium between preembolization and 4-month values.
The immediate reduction in maximal leiomyoma enhancement in the dominant leiomyoma correlated with the clinical response at 1 year. However, initially well-perfused leiomyomas compared with poorly perfused leiomyomas did not show a significant difference in volume reduction at 4 months. This is consistent with the finding that the overall volume reduction of leiomyomas (only 38% at 4 months) did not correlate with improvement in clinical scores at 1 year. Thus, the embolization process, which results in an immediate perfusion deficit in the leiomyomas, probably has a significant functional component that contributes to a favorable clinical outcome rather than the structural presence of the leiomyomas.
Sampson (12) originally suggested that an abnormal vasculature in the leiomyomatous uterus was responsible for menorrhagia. Study findings demonstrate that leiomyomas produce prostaglandins (13) and a number of growth factors, including fibroblast growth factor, vascular endothelial growth factor, heparin-binding epidermal growth factor, platelet-derived growth factor, transforming growth factor, and prolactin (14) that are regulators of angiogenesis. In patients with leiomyomas, dysregulation of growth factors and their receptors is likely to be responsible for menorrhagia (15). Switching off the production of these growth factors and prostaglandins from leiomyomas after embolization may well account for the long-term improvement in symptoms reported by these patients.
The initial SI on T2-weighted images had a significant effect on volume reduction at 4 months. Nondegenerated uterine leiomyomas have a typical appearance at MR imaging: well-circumscribed masses of homogenously decreased SI compared with the myometrium on T2-weighted images. At histologic examination, nondegenerated leiomyomas are composed of whorls of uniform smooth muscle cells with various amounts of intervening collagen (16). Cellular leiomyomas, which are composed of compact smooth muscle cells, have relatively higher SI on T2-weighted images and may demonstrate enhancement on contrast-enhanced images (17). Seven leiomyomas in our cohort were in this category. It is likely that these cellular leiomyomas undergo more necrosis as a result of the embolization process, which leads to a greater volume reduction. Degenerated leiomyomas have a variable appearance on T2-weighted images: Leiomyomas with hyaline or calcific degeneration are generally low in SI, whereas those with cystic degeneration are generally very high in SI, but the cystic areas do not enhance (18).
High SI on T1-weighted images of leiomyomas is normally associated with red degeneration due to T1-shortening effects of methemoglobin (16). In our study patients, an increase in SI on T1-weighted images was seen immediately after embolization, which is too early for the production of methemoglobin and was likely due to reduced blood volume in the leiomyomas or T1 effects of the accumulation of iodine-based contrast medium (T1 of iohexol measured in our laboratory, 850 msec at 0.5 T). However, in some patients, patchy areas of increased SI on T1-weighted images at 1 month may be accounted for by the presence of methemoglobin, as was previously suggested (19). Overall, a satisfactory clinical response was achieved in our cohort of patients (only one patient had no improvement in symptom scores) without adverse side effects, including any unwanted increase in serum FSH levels.
In conclusion, MR imaging demonstrates differential changes in perfusion between the myometrium and leiomyomas after bilateral UAE. At 1 month, there is recovery of myometrial perfusion, but perfusion of the leiomyoma remains depressed. The immediate reduction in leiomyoma perfusion correlates with the improvement in clinical score at 12 months. Leiomyoma volume at 4 months, on the other hand, remains at approximately 60% of its original value and does not correlate with clinical response. Leiomyomas high in SI on the initial T2-weighted images show a significantly greater volume reduction than those that are low in SI. Thus, dynamic MR imaging may be used to predict clinical response, while SI on T2-weighted images predicts volume reduction.
ACKNOWLEDGMENTS |
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