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Pathological findings of uterine leiomyomas and adenomyosis following uterine artery embolization
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Pathology – Research and Practice 202 (2006) 721–729 www.elsevier.de/prp
ORIGINAL ARTICLE
Pathological findings of uterine leiomyomas and adenomyosis following uterine artery embolization Pavel Dundra,, Michal Ma´rab, Jana Masˇ kova´c, Zuzana Fucˇı´ kova´b, Ctibor Povy`sˇ ila, Daniel Tvrdı´ ka a
Department of Pathology, 1st Medical Faculty, Charles University, Studnicˇkova 2, Prague 12800, Czech Republic Department of Obstetrics and Gynecology, 1st Medical Faculty, Charles University, Apolina´rˇska´ 18, Prague 12800, Czech Republic c Department of Radiology, Central Military Hospital, U Vojenske´ nemocnice 1200, Prague 16902, Czech Republic b
Received 13 April 2006; accepted 5 July 2006
Summary Uterine artery embolization (UAE) is an effective and accepted treatment option for symptomatic uterine leiomyoma. Between 2000 and 2005, 91 women were treated using this method, and were prospectively followed at our institution. Twenty of them subsequently underwent surgery. One of these patients was subjected to four surgical procedures. We describe the pathological findings of 23 surgical specimens obtained from these 20 patients. The embolic material used consisted of tris-acryl gelatin microspheres (TGMS) in 15 patients (18 surgical specimens), polyvinyl alcohol particles (PVA) in three patients, and a combination of PVA and TGMS in two patients. Histologically, of the 23 specimens examined, 20 were diagnosed as leiomyomas, and three as adenomyosis. Particles used for embolization were found in all but three specimens. Necrosis was present in 15 of 20 leiomyoma specimens. Hyaline necrosis was found in 12 specimens, coagulative necrosis in one case, and a combination of hyaline and coagulative or suppurative necrosis in two cases. The foci of adenomyosis remained unaltered. r 2006 Elsevier GmbH. All rights reserved. Keywords: Leiomyoma; Adenomyosis; Embolization; Uterus
Introduction Uterine artery embolization (UAE) is an accepted method used for the treatment of symptomatic uterine leiomyomas [1,11,12,16,17]. Although the success rate is high, some patients still require repeated embolization or following surgical treatment because of an embolization treatment failure. In addition, post-UAE complications, including infectious complications, necrotizing Corresponding author. Tel.: +420224968624.
E-mail address: [email protected] (P. Dundr). 0344-0338/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2006.07.001
endometritis, myometrial necrosis, acute hemorrhage, and others, can result in a necessity for surgical intervention [2,9,20]. To the best of our knowledge, only few large-scale studies describing morphological findings in post-UAE specimens have been reported to date. Most of them focus mainly on changes induced by polyvinyl alcohol particles (PVA) [5,10,13]. Only one study has recently described morphological changes in surgical specimens of eight women treated by UAE using tris-acryl gelatin microspheres (TGMS) [21]. In addition, there are several reports on single cases of morphological changes in post-UAE specimens
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[3,6,7,18]. We describe the pathological findings of 23 surgical specimens obtained from 20 patients treated by UAE. The embolic material used was either TGMS or PVA, or a combination of both.
Patients and methods Ninety-one patients underwent UAE between 2000 and 2005. The median patient age was 35 years (range 20–60 years). The same interventional radiologist experienced in vascular interventions in gynecology performed all the embolizations. Size reduction of the fibroids was determined on ultrasonography. Sixty-eight of these women were treated with TGMS, 18 with PVA, and 5 with a combination of TGMS and PVA. Because of embolization treatment failure or persisting volumi-
Table 1.
nous fibroid/s prior to the planned conception, 18 patients underwent subsequent surgical treatment. One of them required repeated embolization because of spasms of uterine artery (case no. 16). In addition, two patients underwent UAE 1 day before laparoscopic myomectomy to prevent blood loss during surgery (case no. 17 and 18). The characteristics of these patients are summarized in Table 1. Patient age ranged from 26 to 44 years (mean 35.4, median 35). Nine of these 20 women underwent abdominal (open) myomectomy, five patients were subjected to laparoscopic myomectomy, and three patients were treated with hysteroscopic (transcervical) myomectomy. Two patients underwent an elective, nonurgent hysterectomy, one of them with and the other without bilateral salpingo-oophorectomy. One patient (case no. 4) underwent four surgical procedures; three hysteroscopic myomectomies and one open myomectomy. All surgical procedures were carried out in one
Patients’ characteristics
Case
Age (years)
Surgical procedure
Type and size (mm) of particles
Occlusion of uterine artery
Time after UAE
Size reduction (measured on USG)
1
34
OM
Unilateral
3 mths
11%
2 3 4
26 42 27
Bilateral Unilateral Bilateral
32
Bilateral
6 7 8 9 10 11 12
37 44 36 33 39 38 29
OM AHBS LM OM OM AH OM
Unilateral Bilateral Unilateral Unilateral Bilateral Bilateral Bilateral
15 mths 25 mths 3 mths 2 mths 5 mths 16 mths 7 mths
18% 28% 10% 5% 26% 36% 19%
13
37
LM
Bilateral
8 mths
38%
14
38
OM
Bilateral
10 mths
28%
15 16
32 39
OM HM
37% 38%
42
LM
Bilateral Unilateral Bilateral Bilateral
9 mths 5/4 mths
17
1 day
na
18 19
37 31
LM OM
Bilateral Bilateral
1 day 14 mths
na 16%
20
34
OM
TGMS 500–700 PVA 300–700 TGMS 500–700 PVA 500–700 TGMS 500–700 TGMS 500–700 TGMS 500–700 TGMS 300–500 TGMS 500–700 TGMS 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700 PVA 700–900 PVA 700–900 TGMS 500–700 TGMS 700–900 PVA 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700
6 mths 8 mths 3 mths 6 mths 11 mths 21 mths 7 mths
12% 25% 54% (after 6 mths)
5
OM LM HM HM HM OM OM
TGMS 700–900 PVA 500–700 TGMS 500–700 TGMS 500–700 TGMS 300–500
Bilateral
29 mths
20%
7%
UAE, uterine artery embolization; USG, ultrasonography; mths, months; OM, open (transabdominal) myomectomy; LM, laparoscopic myomectomy; AHBS, abdominal hysterectomy with bilateral salpingo-oophorectomy; AH, abdominal hysterectomy; HM, hysteroscopic myomectomy; PVA, polyvinyl alcohol particles; TGMS, tris-acryl gelatin microspheres; na, not applicable.
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clinical setting by the same group of gynecological surgeons. The clinical and reproductive outcomes of the whole study will be separately published after an adequate follow-up period. Twenty-three post-UAE specimens obtained from 20 patients were evaluated. The material was routinely processed, and sections from formalin-fixed, paraffinembedded tissue blocks were stained using hematoxylin–eosin. Immunohistochemical analysis with monoclonal antibody MIB-1 (1:50, Dako, Glostrup, Denmark) was used for assessing proliferative activity only in those cases where vital leiomyoma tissue was present. Selected sections with identifiable particles were stained with Elastica van Gieson. On average, 1.75 (range 1–3) tissue blocks and 9.8 (range 4–18) tissue blocks were processed for the evaluation of hysteroscopic myomectomy specimens and for the evaluation of laparoscopic and abdominal myomectomy specimens, respectively. Fourteen tissue blocks obtained from the simple hysterectomy specimens and 16 tissue blocks from the hysterectomies with bilateral salpingo-oophorectomy were processed. Particle density was scored semiquantitatively as follows: single particles (+), small number of particle aggregates (++), or large number of particles (+++). The histopathological changes of embolized vessels were classified as focal intimal damage (+), more extensive vessel damage (++), or complete vessel destruction (+++) according to Weichert et al. [21]. Embolized vessels and particles were measured using an objective magnification of 10 and an eyepiece magnification of 10. The eyepiece contained a calibrated micrometer. The histopathological features were assessed for the smooth muscle tumors or adenomyosis and for adjacent tissues if they were available. In presence of necrosis, it was classified as hyaline necrosis, coagulative necrosis, and/or acute suppurative necrosis.
Results Particle localization and vascular changes A summary of particle localization, their amount and vascular changes, as well as the histopathological changes in leiomyoma or adenomyosis are shown in Table 2. TGMS were used in 18 specimens examined. Three specimens were obtained from patients embolized with PVA, and in two specimens, both particles (TGMS and PVA) were combined. Particles were identified in all but three specimens (cases no.1, 3, and 4c). The first of these cases was laparotomically removed leiomyoma treated with a combination of TGMS and PVA, the other two cases represented hysteroscopically removed leiomyoma tissue fragments, for which only TGMS were used. The identification of TGMS was easy in all the
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other cases; the particles appeared as homogenous eosinophilic spheroids in hematoxylin–eosin-stained sections and were brightly red on Elastica van Giesonstained slides. The identification of PVA was more difficult. In two cases (nos. 16 and 18), the particles were present in a small amount and appeared as basophilic, partly fragmented spheroids that were grayish-black on Elastica van Gieson-stained slides (Figs. 2a, b, d). In another case, (no. 7), we identified only few fragments of basophilic non-refractile material with foreign body reaction. In case no. 5, where TGMS and PVA were combined, only TGMS were identified in the tissue sections. In leiomyomas, the particles were accumulated in medium-sized vessels within the lesions, particularly on the periphery. In addition, in some cases, the particles were found in adjacent myometrium when available for examination (8 of 11 cases). In the endometrium, if present, neither particles nor regressive changes were found. In one case (the hysterectomy specimen, case no. 11), single particles could be found in the vessels of the uterine cervix. In adenomyosis, the particles were found to be randomly distributed throughout the myometrium. Small thrombi developed on the surface of some particles 1 day after UAE, and there were signs of focal intimal damage with moderate polymorphonuclear inflammation in the vessel wall and perivascularly (case no. 17). Within few weeks (from 8 weeks onwards), in most cases, partial or complete vessel destruction occurred, which was eventually accompanied by a granulomatous foreign body reaction, a chronic inflammatory reaction composed of lymphocytes and plasma cells (Fig. 1b), and thrombi in the vicinity of the particles (Fig. 1a). The size of the TGMS particles observed on the histological slides ranged from 0.22 to 0.57 mm (mean 0.384, median 0.395). The diameter of occluded vessels ranged from 0.25 to 1.45 mm (mean 0.612 mm, median 0.570 mm). In two cases (case nos. 6 and 15), the particles became completely incorporated in the vessel wall, with formation of arterial pseudoaneurysms (Fig. 1e), or there was complete destruction of the arterial wall, and the particles could be seen in tissue without identifiable rests of the vessels (Fig. 1d). However, if the particles were present in the areas of hyaline necrosis, the vessels were completely necrotic, but without inflammation or other changes regardless of the time after UAE (Fig. 2d).
Pathological findings The pathological features of the surgical specimens are summarized in Table 2. The pathological examination revealed leiomyoma in 18 specimens, cellular leiomyoma in one, lipoleiomyoma in another one, and
Diagnosis
Leiomyoma Leiomyoma Leiomyoma Leiomyoma
Leiomyoma
Leiomyoma
Leiomyoma
Leiomyoma
Adenomyosis
Lipoleiomyoma
Leiomyoma Leiomyoma
Leiomyoma
Case no.
1 2 3 4a
4b
4c
4d
5
6
7
8 9
10
95 80 75/314
Multiple fragments/114 65 65 65/122
110 100 80
50 40 30/36
100 90 75/378
50 50 50/44
Multiple fragments
Multiple fragments
70 65 45/— 80 70 60/— Multiple fragments/122 Multiple fragments
Size (mm)/weight (g)
Histopathological changes post-UAE
+++
+ +
+
+++
+++ (only TGMS)
++
None
++
None + None ++
Amount of particles
Vessel destruction +++
Vessel destruction +++, arterial pseudoaneurysms Vessel destruction +++ None Vessel destruction +++
Vessel destruction +
Vessel destruction +++
na
Vessel destruction +
na None na Vessel destruction +
Vessel changes
None FB reaction +++, strong chronic inflammation FB reaction +++, moderate chronic inflammation, multiple thrombi
FB reaction +
FB reaction +++, mild chronic inflammation FB reaction ++, mild chronic inflammation FB reaction ++
Na None Na FB reaction +++, mild chronic inflammation FB reaction +++, mild chronic inflammation Na
Particle reaction
20% h
30% hn
5% cn
5% h, focal c None
95% hn None
30% h
None
None
None
None
10% h
None
20% h
20% h, focal c None 10% h, focal c None
Other regressive changes
95% hn
10% hn
None
80% hn
80% hn 100% hn 40% hn None
Necrosis
NA
Normal/ Proliferative NA NA
-/NA
NA
Normal/ Proliferative Normal, particles ++/NA
NA
NA NA NA Normal, particles ++/Proliferative
Myometrium/ endometrium
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Table 2.
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Leiomyoma
Leiomyoma
Leiomyoma
Cellular leiomyoma
Leiomyoma
Adenomyosis
Leiomyoma
Leiomyoma
Adenomyosis
12
13
14
15
16
17
18
19
20
Multiple fragments 90 60 40, 197 g
100 90 80
Multiple fragments/36
Multiple fragments/48
Multiple fragments/28
60 45 40/60
110 90 75/316
50 50 45/40
95 95 95/376
35 35 35/—
++
+++
+
+
+
+
+++
++
++
+++
Vessel destruction +++
Vessel destruction +++
None
Vessel destruction +
None
Vessel destruction ++, arterial pseudoaneurysms
Vessel destruction +++
Vessel destruction +++
Vessel destruction +++
Vessel destruction +++
FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation
Multiple thrombi, moderate polymorphonuclear inflammation None
FB reaction +++, mild chronic inflammation FB reaction +, minimal chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi None
None
40%h
30%hn
None
None
None
70% hn None
10% cn
None
20% h
30% sn
None
5% h
40% h
None
90% hn
30% h, stromal edema
20% h
10% hn
30% hn
FB, foreign body; hn, hyaline necrosis; cn, coagulative necrosis; sn, suppurative necrosis; h, hyaline fibrosis; c, calcification; NA, not available; na, not applicable.
Leiomyoma
11
Normal, particles +/Normal proliferative
Normal, particles +/NA Normal, particles+/ NA
NA
Normal/Normal proliferative
Normal, particles++/ Inactive, hyperplastic polyp Normal, particles +++/Normal proliferative
NA
NA
Normal, particles ++/Secretory
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Fig. 1. TGMS particles and associated changes. (a) Foreign body reaction and thrombi on the surface of particles (case no. 10, H&E, 200 ). (b) Partial vessel destruction accompanied by mild chronic inflammation and foreign body reaction near the particles (case no. 9, H&E, 200 ). (c) Hyaline necrosis with vacuolar changes (case no. 2, H&E, 40 ). (d) Complete destruction of vessel wall. The particles are located outside the vessels in fibrous tissue. Note the hyalinized area on the right side (case no. 11, H&E, 40 ). (e) TGMS located in the arterial wall (case no. 6, H&E, 100 ). (f) Adenomyosis without regressive changes (case no. 6, H&E, 100 ).
adenomyosis in three. Leiomyomas treated with UAE showed coagulative necrosis, hyaline necrosis, suppurative necrosis, or no change at all. Most cases showed large areas of hyaline necrosis that ranged from 10% to 100% and could be identified between 3 and 24 months after UAE. In cases with hyaline type of necrosis, we noted hematoidin pigment and vacuolar changes attributed to myocytolysis (Fig. 1c). The coagulative necrosis was found in only two specimens, ranging from 5% to 10% (Fig. 2c). These cases were identified 1 day and 5 months after UAE, respectively (cases nos. 10 and 18). The suppurative necrosis was noted only in one case 4 months after UAE, and it was found together with hyaline necrosis (case no. 16). The other findings represented focal hyaline fibrosis of the leiomyomas (12 specimens), focal calcifications (case no. 1 and 3), and prominent stromal edema (case no. 12). In all cases examined, immunohistochemical analysis of the proliferative activity using monoclonal antibody MIB-1
(Ki-67 index) showed nuclear positivity in less than 2% of the leiomyoma cells, and there was neither nuclear atypia nor increased mitotic activity. The three cases of adenomyosis remained unaltered (Fig. 1f).
Statistical analysis The Spearman rank correlation coefficient test was used for the correlation analyses of size reduction of leiomyoma and extent of necrosis (p ¼ 0.579); size reduction and extent of necrosis together with hyaline fibrosis (p ¼ 0.952); the amount of particles and extent of necrosis (p ¼ 0.487); and the amount of particles and extent of necrosis together with hyaline fibrosis (p ¼ 0.485). The results were statistically not significant. The extent of necrosis and hyaline fibrosis in leiomyomas showed no correlation with the amount of particles or the size reduction measured by ultrasonography.
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Fig. 2. PVA particles and associated changes. (a) Freshly infused PVA particle with central fragmentation (case no.18, H&E, 200 ). (b) PVA particle stained grayish-black on Elastica van Gieson-stained slides (case no. 18, 200 ). (c) Coagulative type of necrosis. Note the abrupt transition between necrotic and preserved cells (case no. 18, H&E, 200 ). (d) Leiomyoma with hyaline necrosis. Intravascular location of PVA particle without inflammation or other changes (case no. 16, H&E, 150 ).
The Mann–Whitney rank-sum test was performed for the correlation of particle size using the following parameters: amount of particles (p ¼ 0.176), vessel size (p ¼ 0.306), size reduction (p ¼ 0.322), extent of necrosis (p ¼ 0.941), and extent of necrosis together with hyaline fibrosis (p ¼ 0.521). Only two patient groups could be analyzed according to particle size (TGMS 500–700 mm and TGMS 500–700 mm used with TGMS 700–900 mm); for other particle sizes, the number of patients was too low for a statistical analysis. The results were statistically not significant.
Discussion Uterine artery embolization (UAE) as a treatment for uterine leiomyomas was first introduced in 1995 [17]. Since then, the kind and the size of the particles used for embolization, as well as the technique of procedure, have changed considerably [15,19]. The most widely used particles were composed of polyvinyl alcohol. However, these particles tended to aggregate and made the embolization less precise because the diameters of occluded vessels varied considerably. In addition, TGMS seems to penetrate deeper into leiomyomas as compared with PVA, and they may more specifically target the fibroid, allowing for an earlier end-point of embolization and minimizing ischemic damage in normal myometrium and ovaries [4]. Therefore, to apply UAE, some interventional radiologists prefer
TGMS. Another important factor seems to be the caliber of the particles, particularly for the females who desire future fertility. Adverse events after UAE, including premature ovarian failure, may be caused by unintentional embolization into the ovarian arteries through anastomoses from the uterine artery. This can lead to hypoxic damage of the ovarian tissue and amenorrhea [5,6,14]. However, the risk of unintentional embolization of ovarian arterial vasculature seems to be significantly lower for particles larger than 500 mm [15]. UAE has been reported to be an effective, safe, and alternative treatment for menorrhagia, dysmenorrhea, urinary bladder compression symptoms, and other fibroid-related symptoms, in particular for women not desiring future fertility. For the females who desire future fertility, the size reduction of leiomyomas is more important than the symptomatic effect. In our series, most of the females (60/91) desired further fertility, and this fact influenced the high frequency of surgical reinterventions. For some patients, although the fibroidrelated symptoms have improved, the size reduction of leiomyomas was insufficient for future fertility and resulted in surgical treatment. In addition, two females underwent UAE 1 day before surgery to minimize operative blood loss. In this study, 23 post-UAE specimens obtained from 20 patients were examined, and two different kinds of embolic particles (or combination of both) were used. We were able to recognize the particles in 20 of 23 specimens. In three specimens, no particles could be found. Two of these specimens represent small
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fragments of hysteroscopically removed leiomyoma tissue, where TGMS were used. The absence of the embolized particles in these cases could be explained by the fact that this kind of myomectomy focuses only on the intrauterine part of leiomyoma and is often incomplete or partial. The third specimen was laparotomically removed leiomyoma, and in this case, PVA and TGMS were combined. In our study, we found particles located preferably in the outer part of leiomyomas and adjacent myometrium if it was present. However, some particles could be found throughout the whole tumors. In adenomyosis, the particles were randomly distributed throughout the myometrium. The measured size of the TGMS particles on the histological slides was smaller than the real size, which is possibly a result of shrinkage related to tissue processing. In addition, the observed histological sections are evenly distributed between the equatorial and polar planes of the particles [8]. In most cases, a granulomatous foreign body reaction near particles accompanied by chronic inflammation, thrombi, and vessel damage was noted. However, these changes could not be found in areas of hyaline necrosis, where the particles were found in the vessels that were necrotic, but without an inflammatory or other response. Similar findings were noted in two previous reports [5,6]. Embolized arteries showed a variable endothelial damage eventually followed by partial to complete destruction of the vessel wall. In 14 of 20 specimens, the leiomyoma showed the hyaline type of necrosis. Vacuolar changes noted in this type of necrosis have been described in some previous studies and can be found in non-embolized leiomyomas with regressive changes (‘‘red degeneration’’) [5]. Coagulative and/or suppurative necrosis are rare findings and were found in two cases and in one case, respectively. The results of the previous studies varied. In one study, coagulative necrosis was typically found in those cases in which UAE had been performed [10]. In other studies and in our cases, this type of necrosis was detected as a rare finding at variable time points after UAE [5,18,21]. In one study, the authors described pleomorphic tumor cell nuclei and increased mitotic activity near coagulative necrosis areas, which could lead to the misdiagnosis of leiomyosarcoma [21]. These changes were not found in our two cases with foci of coagulative necrosis. In three cases of adenomyosis, the tissue remained unaltered, which is in accordance with previous studies [21]. In our study, the development of post-UAE complications such as endometritis and other infectious complications, necrosis of myometrium, vagina or cervix, acute hemorrhage or amenorrhea were not detected. Most of our cases were myomectomy specimens, and hysterectomy was performed in only two cases. In cases where bilateral salpingo-oophorectomy was performed, no embolized particles were found within ovarian vessels.
In our study, the extent of necrosis and/or other regressive changes in leiomyomas showed no correlation with the size reduction measured by USG. This could be related to inadequate sampling of some leiomyomas with underestimation or overestimation of the extent of regressive changes. However, grossly, the necrotic areas were usually evident as yellowish areas, and we assessed the extent of necrosis by a combination of gross and microscopic features. We favor the view that other factors related to the host response to necrotic leiomyoma tissue could play some role in tumor size reduction. In conclusion, we described the histopathological findings in 23 post-UAE specimens. We should be aware of the morphological changes associated with artificial embolization of various types of particles to achieve a correct diagnosis and to avoid misdiagnosis with leiomyosarcoma especially in the cases with coagulative necrosis, which could be accompanied by nuclear atypias and increased mitotic activity [21].
Acknowledgments This work was supported by grants from the Internal Grant Agency (IGA) of the Ministry of Health of the Czech Republic (NR 8099-3 and NR 8150-4). This work was presented on The 33rd Congress of the Czech Society of Pathologists, May 4–6, 2006, Olomouc, Czech Republic.
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Pathology – Research and Practice 202 (2006) 721–729 www.elsevier.de/prp
ORIGINAL ARTICLE
Pathological findings of uterine leiomyomas and adenomyosis following uterine artery embolization Pavel Dundra,, Michal Ma´rab, Jana Masˇ kova´c, Zuzana Fucˇı´ kova´b, Ctibor Povy`sˇ ila, Daniel Tvrdı´ ka a
Department of Pathology, 1st Medical Faculty, Charles University, Studnicˇkova 2, Prague 12800, Czech Republic Department of Obstetrics and Gynecology, 1st Medical Faculty, Charles University, Apolina´rˇska´ 18, Prague 12800, Czech Republic c Department of Radiology, Central Military Hospital, U Vojenske´ nemocnice 1200, Prague 16902, Czech Republic b
Received 13 April 2006; accepted 5 July 2006
Summary Uterine artery embolization (UAE) is an effective and accepted treatment option for symptomatic uterine leiomyoma. Between 2000 and 2005, 91 women were treated using this method, and were prospectively followed at our institution. Twenty of them subsequently underwent surgery. One of these patients was subjected to four surgical procedures. We describe the pathological findings of 23 surgical specimens obtained from these 20 patients. The embolic material used consisted of tris-acryl gelatin microspheres (TGMS) in 15 patients (18 surgical specimens), polyvinyl alcohol particles (PVA) in three patients, and a combination of PVA and TGMS in two patients. Histologically, of the 23 specimens examined, 20 were diagnosed as leiomyomas, and three as adenomyosis. Particles used for embolization were found in all but three specimens. Necrosis was present in 15 of 20 leiomyoma specimens. Hyaline necrosis was found in 12 specimens, coagulative necrosis in one case, and a combination of hyaline and coagulative or suppurative necrosis in two cases. The foci of adenomyosis remained unaltered. r 2006 Elsevier GmbH. All rights reserved. Keywords: Leiomyoma; Adenomyosis; Embolization; Uterus
Introduction Uterine artery embolization (UAE) is an accepted method used for the treatment of symptomatic uterine leiomyomas [1,11,12,16,17]. Although the success rate is high, some patients still require repeated embolization or following surgical treatment because of an embolization treatment failure. In addition, post-UAE complications, including infectious complications, necrotizing Corresponding author. Tel.: +420224968624.
E-mail address: [email protected] (P. Dundr). 0344-0338/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2006.07.001
endometritis, myometrial necrosis, acute hemorrhage, and others, can result in a necessity for surgical intervention [2,9,20]. To the best of our knowledge, only few large-scale studies describing morphological findings in post-UAE specimens have been reported to date. Most of them focus mainly on changes induced by polyvinyl alcohol particles (PVA) [5,10,13]. Only one study has recently described morphological changes in surgical specimens of eight women treated by UAE using tris-acryl gelatin microspheres (TGMS) [21]. In addition, there are several reports on single cases of morphological changes in post-UAE specimens
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[3,6,7,18]. We describe the pathological findings of 23 surgical specimens obtained from 20 patients treated by UAE. The embolic material used was either TGMS or PVA, or a combination of both.
Patients and methods Ninety-one patients underwent UAE between 2000 and 2005. The median patient age was 35 years (range 20–60 years). The same interventional radiologist experienced in vascular interventions in gynecology performed all the embolizations. Size reduction of the fibroids was determined on ultrasonography. Sixty-eight of these women were treated with TGMS, 18 with PVA, and 5 with a combination of TGMS and PVA. Because of embolization treatment failure or persisting volumi-
Table 1.
nous fibroid/s prior to the planned conception, 18 patients underwent subsequent surgical treatment. One of them required repeated embolization because of spasms of uterine artery (case no. 16). In addition, two patients underwent UAE 1 day before laparoscopic myomectomy to prevent blood loss during surgery (case no. 17 and 18). The characteristics of these patients are summarized in Table 1. Patient age ranged from 26 to 44 years (mean 35.4, median 35). Nine of these 20 women underwent abdominal (open) myomectomy, five patients were subjected to laparoscopic myomectomy, and three patients were treated with hysteroscopic (transcervical) myomectomy. Two patients underwent an elective, nonurgent hysterectomy, one of them with and the other without bilateral salpingo-oophorectomy. One patient (case no. 4) underwent four surgical procedures; three hysteroscopic myomectomies and one open myomectomy. All surgical procedures were carried out in one
Patients’ characteristics
Case
Age (years)
Surgical procedure
Type and size (mm) of particles
Occlusion of uterine artery
Time after UAE
Size reduction (measured on USG)
1
34
OM
Unilateral
3 mths
11%
2 3 4
26 42 27
Bilateral Unilateral Bilateral
32
Bilateral
6 7 8 9 10 11 12
37 44 36 33 39 38 29
OM AHBS LM OM OM AH OM
Unilateral Bilateral Unilateral Unilateral Bilateral Bilateral Bilateral
15 mths 25 mths 3 mths 2 mths 5 mths 16 mths 7 mths
18% 28% 10% 5% 26% 36% 19%
13
37
LM
Bilateral
8 mths
38%
14
38
OM
Bilateral
10 mths
28%
15 16
32 39
OM HM
37% 38%
42
LM
Bilateral Unilateral Bilateral Bilateral
9 mths 5/4 mths
17
1 day
na
18 19
37 31
LM OM
Bilateral Bilateral
1 day 14 mths
na 16%
20
34
OM
TGMS 500–700 PVA 300–700 TGMS 500–700 PVA 500–700 TGMS 500–700 TGMS 500–700 TGMS 500–700 TGMS 300–500 TGMS 500–700 TGMS 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700 PVA 700–900 PVA 700–900 TGMS 500–700 TGMS 700–900 PVA 700–900 TGMS 500–700 TGMS 700–900 TGMS 500–700
6 mths 8 mths 3 mths 6 mths 11 mths 21 mths 7 mths
12% 25% 54% (after 6 mths)
5
OM LM HM HM HM OM OM
TGMS 700–900 PVA 500–700 TGMS 500–700 TGMS 500–700 TGMS 300–500
Bilateral
29 mths
20%
7%
UAE, uterine artery embolization; USG, ultrasonography; mths, months; OM, open (transabdominal) myomectomy; LM, laparoscopic myomectomy; AHBS, abdominal hysterectomy with bilateral salpingo-oophorectomy; AH, abdominal hysterectomy; HM, hysteroscopic myomectomy; PVA, polyvinyl alcohol particles; TGMS, tris-acryl gelatin microspheres; na, not applicable.
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clinical setting by the same group of gynecological surgeons. The clinical and reproductive outcomes of the whole study will be separately published after an adequate follow-up period. Twenty-three post-UAE specimens obtained from 20 patients were evaluated. The material was routinely processed, and sections from formalin-fixed, paraffinembedded tissue blocks were stained using hematoxylin–eosin. Immunohistochemical analysis with monoclonal antibody MIB-1 (1:50, Dako, Glostrup, Denmark) was used for assessing proliferative activity only in those cases where vital leiomyoma tissue was present. Selected sections with identifiable particles were stained with Elastica van Gieson. On average, 1.75 (range 1–3) tissue blocks and 9.8 (range 4–18) tissue blocks were processed for the evaluation of hysteroscopic myomectomy specimens and for the evaluation of laparoscopic and abdominal myomectomy specimens, respectively. Fourteen tissue blocks obtained from the simple hysterectomy specimens and 16 tissue blocks from the hysterectomies with bilateral salpingo-oophorectomy were processed. Particle density was scored semiquantitatively as follows: single particles (+), small number of particle aggregates (++), or large number of particles (+++). The histopathological changes of embolized vessels were classified as focal intimal damage (+), more extensive vessel damage (++), or complete vessel destruction (+++) according to Weichert et al. [21]. Embolized vessels and particles were measured using an objective magnification of 10 and an eyepiece magnification of 10. The eyepiece contained a calibrated micrometer. The histopathological features were assessed for the smooth muscle tumors or adenomyosis and for adjacent tissues if they were available. In presence of necrosis, it was classified as hyaline necrosis, coagulative necrosis, and/or acute suppurative necrosis.
Results Particle localization and vascular changes A summary of particle localization, their amount and vascular changes, as well as the histopathological changes in leiomyoma or adenomyosis are shown in Table 2. TGMS were used in 18 specimens examined. Three specimens were obtained from patients embolized with PVA, and in two specimens, both particles (TGMS and PVA) were combined. Particles were identified in all but three specimens (cases no.1, 3, and 4c). The first of these cases was laparotomically removed leiomyoma treated with a combination of TGMS and PVA, the other two cases represented hysteroscopically removed leiomyoma tissue fragments, for which only TGMS were used. The identification of TGMS was easy in all the
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other cases; the particles appeared as homogenous eosinophilic spheroids in hematoxylin–eosin-stained sections and were brightly red on Elastica van Giesonstained slides. The identification of PVA was more difficult. In two cases (nos. 16 and 18), the particles were present in a small amount and appeared as basophilic, partly fragmented spheroids that were grayish-black on Elastica van Gieson-stained slides (Figs. 2a, b, d). In another case, (no. 7), we identified only few fragments of basophilic non-refractile material with foreign body reaction. In case no. 5, where TGMS and PVA were combined, only TGMS were identified in the tissue sections. In leiomyomas, the particles were accumulated in medium-sized vessels within the lesions, particularly on the periphery. In addition, in some cases, the particles were found in adjacent myometrium when available for examination (8 of 11 cases). In the endometrium, if present, neither particles nor regressive changes were found. In one case (the hysterectomy specimen, case no. 11), single particles could be found in the vessels of the uterine cervix. In adenomyosis, the particles were found to be randomly distributed throughout the myometrium. Small thrombi developed on the surface of some particles 1 day after UAE, and there were signs of focal intimal damage with moderate polymorphonuclear inflammation in the vessel wall and perivascularly (case no. 17). Within few weeks (from 8 weeks onwards), in most cases, partial or complete vessel destruction occurred, which was eventually accompanied by a granulomatous foreign body reaction, a chronic inflammatory reaction composed of lymphocytes and plasma cells (Fig. 1b), and thrombi in the vicinity of the particles (Fig. 1a). The size of the TGMS particles observed on the histological slides ranged from 0.22 to 0.57 mm (mean 0.384, median 0.395). The diameter of occluded vessels ranged from 0.25 to 1.45 mm (mean 0.612 mm, median 0.570 mm). In two cases (case nos. 6 and 15), the particles became completely incorporated in the vessel wall, with formation of arterial pseudoaneurysms (Fig. 1e), or there was complete destruction of the arterial wall, and the particles could be seen in tissue without identifiable rests of the vessels (Fig. 1d). However, if the particles were present in the areas of hyaline necrosis, the vessels were completely necrotic, but without inflammation or other changes regardless of the time after UAE (Fig. 2d).
Pathological findings The pathological features of the surgical specimens are summarized in Table 2. The pathological examination revealed leiomyoma in 18 specimens, cellular leiomyoma in one, lipoleiomyoma in another one, and
Diagnosis
Leiomyoma Leiomyoma Leiomyoma Leiomyoma
Leiomyoma
Leiomyoma
Leiomyoma
Leiomyoma
Adenomyosis
Lipoleiomyoma
Leiomyoma Leiomyoma
Leiomyoma
Case no.
1 2 3 4a
4b
4c
4d
5
6
7
8 9
10
95 80 75/314
Multiple fragments/114 65 65 65/122
110 100 80
50 40 30/36
100 90 75/378
50 50 50/44
Multiple fragments
Multiple fragments
70 65 45/— 80 70 60/— Multiple fragments/122 Multiple fragments
Size (mm)/weight (g)
Histopathological changes post-UAE
+++
+ +
+
+++
+++ (only TGMS)
++
None
++
None + None ++
Amount of particles
Vessel destruction +++
Vessel destruction +++, arterial pseudoaneurysms Vessel destruction +++ None Vessel destruction +++
Vessel destruction +
Vessel destruction +++
na
Vessel destruction +
na None na Vessel destruction +
Vessel changes
None FB reaction +++, strong chronic inflammation FB reaction +++, moderate chronic inflammation, multiple thrombi
FB reaction +
FB reaction +++, mild chronic inflammation FB reaction ++, mild chronic inflammation FB reaction ++
Na None Na FB reaction +++, mild chronic inflammation FB reaction +++, mild chronic inflammation Na
Particle reaction
20% h
30% hn
5% cn
5% h, focal c None
95% hn None
30% h
None
None
None
None
10% h
None
20% h
20% h, focal c None 10% h, focal c None
Other regressive changes
95% hn
10% hn
None
80% hn
80% hn 100% hn 40% hn None
Necrosis
NA
Normal/ Proliferative NA NA
-/NA
NA
Normal/ Proliferative Normal, particles ++/NA
NA
NA NA NA Normal, particles ++/Proliferative
Myometrium/ endometrium
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Table 2.
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Leiomyoma
Leiomyoma
Leiomyoma
Cellular leiomyoma
Leiomyoma
Adenomyosis
Leiomyoma
Leiomyoma
Adenomyosis
12
13
14
15
16
17
18
19
20
Multiple fragments 90 60 40, 197 g
100 90 80
Multiple fragments/36
Multiple fragments/48
Multiple fragments/28
60 45 40/60
110 90 75/316
50 50 45/40
95 95 95/376
35 35 35/—
++
+++
+
+
+
+
+++
++
++
+++
Vessel destruction +++
Vessel destruction +++
None
Vessel destruction +
None
Vessel destruction ++, arterial pseudoaneurysms
Vessel destruction +++
Vessel destruction +++
Vessel destruction +++
Vessel destruction +++
FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation
Multiple thrombi, moderate polymorphonuclear inflammation None
FB reaction +++, mild chronic inflammation FB reaction +, minimal chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi FB reaction +++, mild chronic inflammation, thrombi None
None
40%h
30%hn
None
None
None
70% hn None
10% cn
None
20% h
30% sn
None
5% h
40% h
None
90% hn
30% h, stromal edema
20% h
10% hn
30% hn
FB, foreign body; hn, hyaline necrosis; cn, coagulative necrosis; sn, suppurative necrosis; h, hyaline fibrosis; c, calcification; NA, not available; na, not applicable.
Leiomyoma
11
Normal, particles +/Normal proliferative
Normal, particles +/NA Normal, particles+/ NA
NA
Normal/Normal proliferative
Normal, particles++/ Inactive, hyperplastic polyp Normal, particles +++/Normal proliferative
NA
NA
Normal, particles ++/Secretory
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Fig. 1. TGMS particles and associated changes. (a) Foreign body reaction and thrombi on the surface of particles (case no. 10, H&E, 200 ). (b) Partial vessel destruction accompanied by mild chronic inflammation and foreign body reaction near the particles (case no. 9, H&E, 200 ). (c) Hyaline necrosis with vacuolar changes (case no. 2, H&E, 40 ). (d) Complete destruction of vessel wall. The particles are located outside the vessels in fibrous tissue. Note the hyalinized area on the right side (case no. 11, H&E, 40 ). (e) TGMS located in the arterial wall (case no. 6, H&E, 100 ). (f) Adenomyosis without regressive changes (case no. 6, H&E, 100 ).
adenomyosis in three. Leiomyomas treated with UAE showed coagulative necrosis, hyaline necrosis, suppurative necrosis, or no change at all. Most cases showed large areas of hyaline necrosis that ranged from 10% to 100% and could be identified between 3 and 24 months after UAE. In cases with hyaline type of necrosis, we noted hematoidin pigment and vacuolar changes attributed to myocytolysis (Fig. 1c). The coagulative necrosis was found in only two specimens, ranging from 5% to 10% (Fig. 2c). These cases were identified 1 day and 5 months after UAE, respectively (cases nos. 10 and 18). The suppurative necrosis was noted only in one case 4 months after UAE, and it was found together with hyaline necrosis (case no. 16). The other findings represented focal hyaline fibrosis of the leiomyomas (12 specimens), focal calcifications (case no. 1 and 3), and prominent stromal edema (case no. 12). In all cases examined, immunohistochemical analysis of the proliferative activity using monoclonal antibody MIB-1
(Ki-67 index) showed nuclear positivity in less than 2% of the leiomyoma cells, and there was neither nuclear atypia nor increased mitotic activity. The three cases of adenomyosis remained unaltered (Fig. 1f).
Statistical analysis The Spearman rank correlation coefficient test was used for the correlation analyses of size reduction of leiomyoma and extent of necrosis (p ¼ 0.579); size reduction and extent of necrosis together with hyaline fibrosis (p ¼ 0.952); the amount of particles and extent of necrosis (p ¼ 0.487); and the amount of particles and extent of necrosis together with hyaline fibrosis (p ¼ 0.485). The results were statistically not significant. The extent of necrosis and hyaline fibrosis in leiomyomas showed no correlation with the amount of particles or the size reduction measured by ultrasonography.
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Fig. 2. PVA particles and associated changes. (a) Freshly infused PVA particle with central fragmentation (case no.18, H&E, 200 ). (b) PVA particle stained grayish-black on Elastica van Gieson-stained slides (case no. 18, 200 ). (c) Coagulative type of necrosis. Note the abrupt transition between necrotic and preserved cells (case no. 18, H&E, 200 ). (d) Leiomyoma with hyaline necrosis. Intravascular location of PVA particle without inflammation or other changes (case no. 16, H&E, 150 ).
The Mann–Whitney rank-sum test was performed for the correlation of particle size using the following parameters: amount of particles (p ¼ 0.176), vessel size (p ¼ 0.306), size reduction (p ¼ 0.322), extent of necrosis (p ¼ 0.941), and extent of necrosis together with hyaline fibrosis (p ¼ 0.521). Only two patient groups could be analyzed according to particle size (TGMS 500–700 mm and TGMS 500–700 mm used with TGMS 700–900 mm); for other particle sizes, the number of patients was too low for a statistical analysis. The results were statistically not significant.
Discussion Uterine artery embolization (UAE) as a treatment for uterine leiomyomas was first introduced in 1995 [17]. Since then, the kind and the size of the particles used for embolization, as well as the technique of procedure, have changed considerably [15,19]. The most widely used particles were composed of polyvinyl alcohol. However, these particles tended to aggregate and made the embolization less precise because the diameters of occluded vessels varied considerably. In addition, TGMS seems to penetrate deeper into leiomyomas as compared with PVA, and they may more specifically target the fibroid, allowing for an earlier end-point of embolization and minimizing ischemic damage in normal myometrium and ovaries [4]. Therefore, to apply UAE, some interventional radiologists prefer
TGMS. Another important factor seems to be the caliber of the particles, particularly for the females who desire future fertility. Adverse events after UAE, including premature ovarian failure, may be caused by unintentional embolization into the ovarian arteries through anastomoses from the uterine artery. This can lead to hypoxic damage of the ovarian tissue and amenorrhea [5,6,14]. However, the risk of unintentional embolization of ovarian arterial vasculature seems to be significantly lower for particles larger than 500 mm [15]. UAE has been reported to be an effective, safe, and alternative treatment for menorrhagia, dysmenorrhea, urinary bladder compression symptoms, and other fibroid-related symptoms, in particular for women not desiring future fertility. For the females who desire future fertility, the size reduction of leiomyomas is more important than the symptomatic effect. In our series, most of the females (60/91) desired further fertility, and this fact influenced the high frequency of surgical reinterventions. For some patients, although the fibroidrelated symptoms have improved, the size reduction of leiomyomas was insufficient for future fertility and resulted in surgical treatment. In addition, two females underwent UAE 1 day before surgery to minimize operative blood loss. In this study, 23 post-UAE specimens obtained from 20 patients were examined, and two different kinds of embolic particles (or combination of both) were used. We were able to recognize the particles in 20 of 23 specimens. In three specimens, no particles could be found. Two of these specimens represent small
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fragments of hysteroscopically removed leiomyoma tissue, where TGMS were used. The absence of the embolized particles in these cases could be explained by the fact that this kind of myomectomy focuses only on the intrauterine part of leiomyoma and is often incomplete or partial. The third specimen was laparotomically removed leiomyoma, and in this case, PVA and TGMS were combined. In our study, we found particles located preferably in the outer part of leiomyomas and adjacent myometrium if it was present. However, some particles could be found throughout the whole tumors. In adenomyosis, the particles were randomly distributed throughout the myometrium. The measured size of the TGMS particles on the histological slides was smaller than the real size, which is possibly a result of shrinkage related to tissue processing. In addition, the observed histological sections are evenly distributed between the equatorial and polar planes of the particles [8]. In most cases, a granulomatous foreign body reaction near particles accompanied by chronic inflammation, thrombi, and vessel damage was noted. However, these changes could not be found in areas of hyaline necrosis, where the particles were found in the vessels that were necrotic, but without an inflammatory or other response. Similar findings were noted in two previous reports [5,6]. Embolized arteries showed a variable endothelial damage eventually followed by partial to complete destruction of the vessel wall. In 14 of 20 specimens, the leiomyoma showed the hyaline type of necrosis. Vacuolar changes noted in this type of necrosis have been described in some previous studies and can be found in non-embolized leiomyomas with regressive changes (‘‘red degeneration’’) [5]. Coagulative and/or suppurative necrosis are rare findings and were found in two cases and in one case, respectively. The results of the previous studies varied. In one study, coagulative necrosis was typically found in those cases in which UAE had been performed [10]. In other studies and in our cases, this type of necrosis was detected as a rare finding at variable time points after UAE [5,18,21]. In one study, the authors described pleomorphic tumor cell nuclei and increased mitotic activity near coagulative necrosis areas, which could lead to the misdiagnosis of leiomyosarcoma [21]. These changes were not found in our two cases with foci of coagulative necrosis. In three cases of adenomyosis, the tissue remained unaltered, which is in accordance with previous studies [21]. In our study, the development of post-UAE complications such as endometritis and other infectious complications, necrosis of myometrium, vagina or cervix, acute hemorrhage or amenorrhea were not detected. Most of our cases were myomectomy specimens, and hysterectomy was performed in only two cases. In cases where bilateral salpingo-oophorectomy was performed, no embolized particles were found within ovarian vessels.
In our study, the extent of necrosis and/or other regressive changes in leiomyomas showed no correlation with the size reduction measured by USG. This could be related to inadequate sampling of some leiomyomas with underestimation or overestimation of the extent of regressive changes. However, grossly, the necrotic areas were usually evident as yellowish areas, and we assessed the extent of necrosis by a combination of gross and microscopic features. We favor the view that other factors related to the host response to necrotic leiomyoma tissue could play some role in tumor size reduction. In conclusion, we described the histopathological findings in 23 post-UAE specimens. We should be aware of the morphological changes associated with artificial embolization of various types of particles to achieve a correct diagnosis and to avoid misdiagnosis with leiomyosarcoma especially in the cases with coagulative necrosis, which could be accompanied by nuclear atypias and increased mitotic activity [21].
Acknowledgments This work was supported by grants from the Internal Grant Agency (IGA) of the Ministry of Health of the Czech Republic (NR 8099-3 and NR 8150-4). This work was presented on The 33rd Congress of the Czech Society of Pathologists, May 4–6, 2006, Olomouc, Czech Republic.
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