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Thermal balloon endometrial ablation: safety aspects evaluated by serosal temperature, light microscopy and electron microscopy
European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63–68
Thermal balloon endometrial ablation: safety aspects evaluated by serosal temperature, light microscopy and electron microscopy a, a b b b a Lars F. Andersen *, Lars Meinert , Carsten Rygaard , Jette Junge , Poul Prentø , Bent S. Ottesen a
Department of Obstetrics and Gynaecology 537, University of Copenhagen, Hvidovre Hospital, DK 2650 Hvidovre, Denmark b Department of Pathology, University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark Received 27 November 1996; accepted 22 January 1998
Abstract Objectives: Thermal balloon endometrial ablation is a new method for treating menorrhagia. The technique appears to be less difficult compared to standard hysteroscopic ablation techniques and to be significantly safer. The influence into the uterine wall of the thermal balloon ablation procedure was investigated with special reference to the ability of total destruction of the endometrium and the thermal action on the myometrium and the serosa. Study design: Temperatures were measured at the uterine serosal surface during thermal balloon endometrial ablation for 8–16 min in eight patients. After subsequent hysterectomy the extent of thermal damage into the myometrium was assessed by light and electron microscopy. Results: The highest temperature measured on the uterine serosa was 39.18C. Coagulation of the myometrium adjacent to the endometrium could be demonstrated by light microscopy in all patients, with a maximum depth of 11.5 mm. By electron microscopy no influence of heat could be demonstrated beyond 15 mm from the endometrial surface. Conclusion: Up to 16 min of thermal balloon endometrial ablation therapy can destroy the endometrium and the submucosal layers. The myometrium is only coagulated to a depth where full thickness necrosis or injury is unlikely. 1998 Elsevier Science Ireland Ltd. Keywords: Thermal balloon; Endometrial ablation; Menorrhagia
1. Introduction Menorrhagia can be treated either medically or surgically. Medical therapy is often inconvenient, ineffective and associated with side effects. The fact that menorrhagia mostly occurs during the last reproductive years and in the perimenopause, when fertility is no longer a viable option, often prompts the choice of a surgical approach. Until recently, the only alternatives to medical therapy were either simple D&C or hysterectomy. In the treatment of menorrhagia, D&C is often ineffective and associated with a high recurrence rate. Hysterectomy is effective but associated with high costs, considerable morbidity and
*Corresponding author. Tel.: 145 36322744 (office), 145 39623690 (private); fax: 145 36 323361 (office); e-mail: [email protected]
even mortality, and may be a drastic and complicated solution to a passing condition. To improve efficiency and to reduce morbidity, inconvenience and costs, various methods to destroy the endometrium have been developed. Due to the very high potential for regeneration, irreversible destruction of the endometrium must include the entire stratum basale, which often demands destruction of the submucosal layers of the myometrium too. Recently, hysteroscopic techniques, such as laser ablation, endometrial diathermy and resection under direct vision, have made such total and selective destruction of the endometrium possible. These new therapeutic options have so far demonstrated relatively good results concerning safety, effectiveness and costs [1]. However, the hysteroscopic techniques entail some drawbacks. The procedures are technically difficult and require operator training. Consequently, these ablation methods are
0301-2115 / 98 / $19.00 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0301-2115( 98 )00030-X
L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
64
only practical for larger clinics with sufficient flow of patients to ensure adequate experience. Furthermore, complications from fluid overload, infections, uterine perforations, and injury to surrounding organs can cause morbidity and even mortality. In order to solve some of these problems, a new thermal balloon method for endometrial ablation has recently been developed. The thermal balloon ablation method is a simple procedure that requires minimal operator training; all indications are that it is very safe. In preliminary experimental and clinical studies [2–8] the method has shown almost the same efficacy in relieving menorrhagia as the currently used hysteroscopic techniques. The Thermal Balloon Therapy System TM has been investigated in pre-clinical experiments [2,6] and in clinical studies [3,7,8]. No significant rise in uterine serosal temperature was registered during 6–12 min thermal balloon therapy. The standard treatment time has accordingly been fixed at 8 min. In preliminary clinical studies the Thermal Balloon Therapy System TM seems to be effective in reducing menorrhagia, although apparently a little less effective than the hysteroscopic ablation techniques in producing amenorrhea [7,8]. One reason for this might be that the treatment time currently used is not always optimal; and a more thorough destruction of the endometrium may be achieved by increasing the treatment time during thermal balloon ablation. Before examining the effect of more prolonged treatment times in clinical trials, we have tested the safety of thermal balloon therapy during two consecutive 8-min standard treatment cycles, i.e. during 16 min heating. The effect on the uterus was assessed by monitoring uterine serosal temperature during treatment and by examining the extent of thermal coagulation into the myometrium by light and electron microscopy.
2. Material and methods
2.1. Heating equipment The Thermal Balloon Therapy System TM consists of a plastic catheter with a heating element at the one end surrounded by a protective heat shield and a latex balloon. A control unit connected to the catheter regulates the temperature and measures the pressure of the fluid in the balloon. The balloon catheter is inserted in the uterine cavity and the balloon is filled with a non-electrolyte water solution to a pressure of approximately 160 mmHg, aiming at adapting the shape of the balloon to the uterine cavity. The heating element raises the temperature to approximately 878C, and this temperature is automatically maintained during a preset treatment period of 8 min.
2.2. Patients Uterine thermal balloon ablation was performed in eight
premenopausal women (median age 42 years (range 39– 53)) undergoing hysterectomy due to benign meno-metrorrhagia and / or dysmenorrhea. All patients had benign histology by D&C performed within 6 months preoperatively, and all patients were in good general health. Intrauterine processes (polyps, fibromyomas, septa) were excluded preoperatively by vaginal ultrasonography and hysteroscopy. Patients with a uterine cavity measuring .10 cm or intramural or subserosal fibromyomas .2 cm were excluded. None of the patients received any pretreatment preoperatively, and the operations were scheduled without consideration for timing in menstrual cycle. Informed consents were obtained and the study was approved by the local ethical committee.
2.3. Ablation technique All patients were operated under general anaesthesia in the dorsal lithotomy position. The depth of the uterine cavity was measured by sounding. The thermal balloon catheter was inserted into the uterine cavity until contact with the fundus, matching the sounded length. Subsequently, the balloon was filled (5–15 ml) leading to an initial intrauterine pressure of approximately 160 mmHg. The abdomen was opened and the uterus exposed. Thermistor probes were placed through needles 1.2 mm in diameter approximately 1 mm into the subserosal tissue in the right and left uterine cornual region, at the lateral cervicocorporal junction and next to the urinary bladder. Once the balloon pressure was stabilized between 100 and 160 mmHg, the heating element was activated and heating carried out. The temperature in the balloon was 878C (82–928C) during the heating procedure. Temperatures were recorded every minute during the treatment. The first patient was treated for the conventional 8 min. As the thermal ablation procedure was found to cause only slight increase of temperature at the uterine serosa, treatment time was gradually increased to 14, 15 and 16 min. Hysterectomy was subsequently performed according to routine procedures. No complications occurred during surgery or postoperatively.
2.4. Macroscopical evaluation The hysterectomy specimens were sent without fixation for pathological examinations immediately after removal. The uteri were opened by a sagittal section in the pathology laboratory. The thickness of the uterine wall and the depth of the coagulation zone, which appeared dark discolored contrasting the normal myometrium were measured in mm.
2.5. Light microscopical evaluation All uteri were evaluated by light microscopy and, in patients nos. 2 and 5, additional electron microscopy evaluations were performed. After fixation in formalin
L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
sections for microscopy through the uterine walls for H&E (alhematein / eosin) stain were taken from: the anterior and posterior wall at the cervico–corporal junction, the anterior and posterior wall in the middle of the uterine corpus, the mid-fundal region, and from the right and left cornual region medial to the outset of the Fallopian tubes. Thermal coagulation was defined by the presence of nuclear shrinkage and hyperchromasia and cytoplasmic vacuolization in the myometrial muscle cells. The depths of the thermal coagulation zones into the myometrium were measured by two pathologists without knowledge of the thermal balloon ablation data.
2.6. Electron microscopical evaluation A transverse strip 253232 mm through the posterior wall was removed 1 h after surgery. The slice was split longitudinally and one half of the strip was processed for light microscopy, the other half for electron microscopy. The formaldehyde-fixed material was further treated in Karnovsky’s formaldehyde–glutaraldehyde fixative. After 1 h the slice was trimmed down to 0.5 mm thickness, cut into pieces of 1 mm in length, and placed in separate vials. Thus, the average spatial resolution for the electron microscopical description is 1 mm. The pieces were rinsed in three changes of phosphate buffer and postfixed in 1% buffered osmium tetroxide, dehydrated and embedded in epon. Silver sections were cut on an LKB ultramicrotome and contrasted with uranyl acetate and lead citrate, and examined in a Jeol 1010 electron microscope.
2.6.1. Criteria The criteria from which the degree of thermal injury was judged were: chromatin structure, membrane preservation, and organelle preservation. Regarding the latter, rough endoplasmatic reticulum (rER) was considered the least, and mitochondrial ultrastructures the most sensitive marker for cell injury. The degree of thermal injury was graded progressively as the following: No cell damage: cells appear normal in all respects
65
except for small changes in the mitochondria. Some deterioration of mitochondrial crista structure is probably inevitable due to ischemia during ablation, surgery and transport. Thus, cells presenting mitochondria with recognizable crista structure and electron-dense matrix were considered unaffected by the thermal therapy. Moderate cell damage: euchromatin slightly condensed. Some membrane ruptures. Most mitochondria with electron-lucent matrix, but with recognizable crista. Severe cell damage: membranes, including plasma membranes, not intact. mitochondria generally not recognizable. Nuclei and cytoplasm with ‘empty’ spaces. Partial coagulation: nuclei condensed, chromatin coarse. Cell demarcations present, but cell membranes absent or discontinuous. Most organelles absent except for remnants of rER. Cytoplasm coarse and with ‘empty’ areas. Total coagulation: nuclei condensed and ruptured. Chromatin coarse, no recognizable organelles, cell demarcations generally indistinct, cytoplasm coarsely granular.
3. Results
3.1. Temperature measurements The maximal temperatures registered on the uterine serosa during thermal balloon ablation are shown in Table 1. Minimal rise in serosal temperature was found in the first patient, treated for only 8 min. Variable increase in serosal temperatures were found among the patients treated for 14–16 min. The rate of increase and the gradients of serosal temperature varied between the patients; however, the rise in temperature showed a tendency to reach its peak at 10–12 min, after which the temperature tended to drop a bit and stabilize 1–28C above the starting point of 34– 358C. The highest temperature recorded was 39.18C at the left cornuum after 13 min treatment; the temperature subsequently fell to 38.58C after 16 min. Among the four anatomical positions chosen for temperature registration no
Table 1 Maximal serosal temperatures and depth of coagulation zones in the myometrium assessed macroscopically and light microscopically Pt. no.
1 2 3 4 5 6 7 8
Treatment time (min)
8 14 14 14 15 16 16 16
Max. temp. (8C)
36.6 38.5 36.7 36.7 35.9 38.8 39.1 37.6
(B,L) (B) (R) (B) (R) (C) (L) (B)
Max. temp. end of treatment (8C)
36.6 38.2 36.7 36.5 35.7 38.8 38.5 36.2
(B,L) (B) (R) (B) (R) (C) (L) (B,C)
Myometrium thickness (mm)
23 20 20 15 20 25 20 17
Macroscopic coag. zone (mm)
NR 4 3 2 4 1 4 3
Microscopic coagulization zone (mm) Cervical–corporal junction
Corpus
Anterior wall (mm)
Posterior wall (mm)
Anterior wall (mm)
Posterior wall (mm)
Fundus (mm)
Right (mm)
Left (mm)
0 0 0 0 0 4.1 1.8 2.0
0 NR 1.2 0 0 0 0.6 NR
3.8 4.1 3.2 2.7 2 6.7 3.9 3.0
0.5 5.0 3.0 0.1 2.9 7.1 3.9 3.8
0 5.0 2.1 1.0 2.0 11.5 3.8 2.1
0 0 1 2.1 0 NR 0 0
0 0 0 0 0 NR 0 0
NR, not registered; B, bladder; C, cervico–corporal junction; R, right cornuum; L, left cornuum.
Cornuum
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L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
Fig. 1. Myometrium with nuclear shrinkage and hyperchromasia and vacuolization in the cytoplasm (left) compared to the normal myometrium (right). Both photographs from the same H&E stained section. Original magnification 3250.
pattern of predominance for rise in serosal temperature could be identified.
3.2. Light microscopical evaluation The depths of the coagulation zones in the myometrium measured by LM are shown in Table 1. A coagulation zone including the endometrium and the myometrium adjacent to the uterine cavity was found in all patients. The profound myometrium and the serosa showed no thermal damage. The average coagulation zone in the corpus wall was 3.5 mm (ant. wall 3.7 / post. wall 3.3), with a variation of 0.1–7.9 mm. Patient no. 6 showed the most extensive coagulation zone, with a maximum of 11.5 mm in the fundus. This patient had the highest temperature increase of 38.88C at the end of 16 min treatment. Coagulation of one of the uterine corners was seen in only two patients,
Fig. 2. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 0–1 mm depth: total nuclear and cytoplasmic coagulation (grade 5). In most cases cell demarcations indistinct. Collagen fibres swelled.
with a maximum depth of 2.1 mm after 14 min treatment. Coagulation in the cervical–corporal junction was seen in four of eight patients, and was most pronounced in the anterior uterine wall with a maximum coagulation zone of 4.1 mm following a treatment of 16 min. The macroscopic coagulation zone correlated well with the light microscopic measurements in all patients (Fig. 1).
3.3. Electron microscopical evaluation The degree of cell damage moving from the mucosal towards the serosal surface was: 0–4 mm (Grade 5), total coagulation (Fig. 2), collagen fibres mostly unrecognizable; 4–6 mm (Grade 4), widespread coagulation (Fig. 3), collagen fibres only slightly disorganized; 6–9 mm (Grade 3), severe cell damage (Fig. 4), the cells appeared dead or dying, muscle actin organization much disturbed, collagen
Fig. 3. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 4–5 mm depth: coagulation predominant (grade 4), But cell borders and collagen fibres are preserved. Note empty spaces in nuclei and cytoplasm.
L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
Fig. 4. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 7–8 mm depth: severe (left) to moderate (right) cell damage (grade 3-2). Note granular endoplasmatic reticulum, and dense plaques on the plasma lemmas of the best preserved muscle cells.
fibres normal; 9–15 mm (Grade 2), moderate to slight cell damage (Fig. 5), actin organization approached normal; 15 mm–out (Grade 1), cells unaffected by the heat treatment (Fig. 6). Judged from ultrastructures, or rather the absence thereof, the zone of cytoplasmic coagulation reached a depth of 5–6 mm. Deeper in the myometrium, from 3 to about 12 mm, the cells often exhibited empty spaces, both in the nucleus and cytoplasm. These spaces probably correspond to the vacuolization found by light microscopy.
4. Comment The gradients of serosal temperatures showed a ten-
Fig. 5. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 10–11 mm depth: slight cell damage (grade 2). Nuclear and organelle structure slightly coarsened, with ‘empty’ spaces in euchromatin areas and cytoplasm. Actin fibre organization slightly disturbed.
67
Fig. 6. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 15–16 mm: no obvious cell damage (grade 1). Note the uniform distribution of euchromatin, and of focal densities in the cytoplasm. (The occasional electron-lucent vacuole is artefactual, and represents a hole in the embedding resin).
dency to reach their peak after 10–12 min heating and subsequently stabilize, probably due to a compensatory increase in uterine blood flow. This may reflect the capacity for auto-regulation of uterine blood flow, and may suggest that the uterus has a large potential for absorption of heat, once auto-regulation mechanisms are given sufficient time for redistribution of the blood flow. If the pressure in the balloon is increased beyond the 160 mmHg used in our set up, increased compression of the uterine vessels may perhaps reduce this regulatory and cooling effect. Furthermore, one may speculate that if the steadystate situation was continued beyond the 16 min investigated in this study, more prolonged thermal injury may be possible. It remains to be investigated, however, whether any additional clinical effect can be achieved from prolonging the treatment time. It may be that once a steady state is reached, heating may continue without additional coagulation. The recorded temperatures, in all cases, started from approximately 358C. These levels below normal body temperature were presumably due to the exposure of uterus in the operating field with uterus subjected to the cooling effect of room temperature. This cooling effect may represent a source of error, the significance of which, however, is considered of minor importance regarding assessment of the highest temperatures reached on the uterine serosal surface during the ablation procedure. The light microscopical evaluations of the myometrium showed coagulation of the submucosal layers of the myometrium in all cases. However, the extent of the coagulation varied considerably concerning distribution and depth, generally with little effect on the lower uterine segment and on the cornual areas. The fluid in the investigated thermal balloon system is circulated passively during the ablation procedure, and preliminary clinical
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L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
testings have suggested that a heterogeneous heat distribution may occur in the balloon due to the property of heat to ascend. In order to overcome any such effect, active circulation of the fluid by a pump has been included in another thermal balloon ablation system [4–6]. Uneven distribution of the heat in the balloon would be expected to result in a stronger effect of heat on the anterior (upper) uterine wall than on the posterior (lower) uterine wall. No such effect could be demonstrated in our material. The defective coagulation achieved in the cornual regions may be an important reason for the fact that only a minority of the patients so far treated with the thermal balloon ablation system gained complete amenorrhea [7,8]; and the remaining intact endometrium in the cornual region may predispose to the subsequent development of haematometra. Application of higher pressures in the balloon may enable it to adapt more completely to the shape of the uterine cavity, thus improving coagulation of the cornual endometrium; and increased pressure from the balloon may compress myometrial blood vessels, reducing the cooling effect from myometrial blood flow. Concerning the safety of the prolonged treatment time, the deepest coagulation zone in the myometrium was 11.5 mm in the fundus, as assessed by light microscopy. However, the assessment of cell viability might be difficult by light microscopy. By electron microscopy, the zone of coagulative cell damage reached a depth of 5–6 mm, judged from cellular ultrastructures, or their absence. This zone of total cell injury corresponds to or contains the 4–5-mm zone where NADH-diaphorase, a predominantly mitochondria enzyme system, is destroyed [2]. However, moderate heat exposures, which affect enzymes only slightly, may still lead to homeostatic break-down and cell death. In the present material total cell death probably occurred to a maximum depth of 11–12 mm. Obviously, electron microscopy gives a more detailed picture of cellular heat changes and the depth of penetration than enzyme histochemistry. Judged from mitochondrial ultrastructure and plasma membrane integrity, heat damage was absent or insignificant at a distance exceeding 14–15 mm from the endometrial surface.
5. Conclusions Evaluated macroscopically and by light and electron microscopy, up to 16 min of thermal balloon endometrial ablation can destroy the endometrium and the submucosal layers of the myometrium—at least where the thermal balloon is in close contact with the endometrium. Conversely, the myometrium is only coagulated to a depth where full thickness necrosis or injury is unlikely. The safety of the procedure is additionally substantiated by the finding of only minor, clinically insignificant increases in temperature on the uterine serosal surface during balloon ablation, making accidental thermal injury to surrounding organs, even if adherent to the uterus, unlikely. Thermal
balloon endometrial ablation seems to be a simple, easy and safe procedure not requiring special skills or operative facilities. The efficiency of the treatment remains to be proven through properly designed, controlled clinical trials with a sufficient number of patients and adequate follow up. The procedure may still need development, especially concerning optimization of balloon pressure, shape, heat distribution and treatment time. Thermal balloon ablation for 16 min was found to be safe.
6. Condensation Serosal temperatures were monitored during thermal balloon endometrial ablation, and thermal influence into the uterine wall was investigated by light and electron microscopy.
Acknowledgements We are indebted to the patients for their readiness to co-operate in the study; to Erik Schmidt, ELLAB AS, Rødovre, Denmark, for the loan of thermometer equipment; to Birgit Nielsen Johannsen, Dr. Phil., Lab. of Human Physiology, The August Krogh Institute, University of Copenhagen, for the loan of thermosensor probes; to Jan Hansen NIKOMED AS, Rødovre, Denmark, and to Milton B. McColl, GYNECARE Inc., USA, for the loan of the EASy TM -endometrial balloon ablation system.
References [1] Garry R. Good practice with endometrial ablation. Obstet Gynecol 1995;86:144–51. [2] Neuwirth RS, Duran A-A, Singer A, MacDonald R, Bolduc L. The endometrial ablator: A new instrument. Obstet Gynecol 1994;83:792–6. [3] Singer A, Almanza R, Guttierez A, Haber G, Bolduc LR, Neuwirth R. Preliminary clinical experience with a thermal balloon endometrial ablation method to treat menorrhagia. Obstet Gynecol 1994;83:732–4. ´ R, Ahlgren M. A new technique for [4] Friberg B, Petersson F, Willen endometrial destruction by thermal coagulation; clinical results with 12–24 months follow-up. Abstract; Presented at the 4th Congress of the European Society For Gynaecological Endoscopy, Brussels, Belgium, 6–9 December 1995. ´ R, Ahlgren M, Petersson F. Cavaterm TM —A new [5] Friberg B, Willen technique for endometrial ablation by thermal coagulation. Abstract; Presented at World Congress Of Hysteroscopy, Miami, FL, 9–11 February 1996. ´ R, Ahlgreen M. Endometrial [6] Friberg B, Persson BRR, Willen destruction by hyperthermia—a possible treatment of menorrhagia. Acta Obstet Gynecol Scand 1996;75:330–5. [7] Vilos GA, Fortin C, Sanders B, Prendley L, McColl M. Uterine balloon therapy for the treatment of menorrhagia. J Am Assoc Gynecol Laparosc 1996;3(Suppl 4):S54. [8] Vilos GA, Fortin C, Sanders B, Prendley L, Stabinsky SA. Clinical trial of the uterine balloon therapy for treatment of menorrhagia. J Am Assoc Gynecol Laparosc 1997;4(5):559–65.
Thermal balloon endometrial ablation: safety aspects evaluated by serosal temperature, light microscopy and electron microscopy a, a b b b a Lars F. Andersen *, Lars Meinert , Carsten Rygaard , Jette Junge , Poul Prentø , Bent S. Ottesen a
Department of Obstetrics and Gynaecology 537, University of Copenhagen, Hvidovre Hospital, DK 2650 Hvidovre, Denmark b Department of Pathology, University of Copenhagen, Hvidovre Hospital, Hvidovre, Denmark Received 27 November 1996; accepted 22 January 1998
Abstract Objectives: Thermal balloon endometrial ablation is a new method for treating menorrhagia. The technique appears to be less difficult compared to standard hysteroscopic ablation techniques and to be significantly safer. The influence into the uterine wall of the thermal balloon ablation procedure was investigated with special reference to the ability of total destruction of the endometrium and the thermal action on the myometrium and the serosa. Study design: Temperatures were measured at the uterine serosal surface during thermal balloon endometrial ablation for 8–16 min in eight patients. After subsequent hysterectomy the extent of thermal damage into the myometrium was assessed by light and electron microscopy. Results: The highest temperature measured on the uterine serosa was 39.18C. Coagulation of the myometrium adjacent to the endometrium could be demonstrated by light microscopy in all patients, with a maximum depth of 11.5 mm. By electron microscopy no influence of heat could be demonstrated beyond 15 mm from the endometrial surface. Conclusion: Up to 16 min of thermal balloon endometrial ablation therapy can destroy the endometrium and the submucosal layers. The myometrium is only coagulated to a depth where full thickness necrosis or injury is unlikely. 1998 Elsevier Science Ireland Ltd. Keywords: Thermal balloon; Endometrial ablation; Menorrhagia
1. Introduction Menorrhagia can be treated either medically or surgically. Medical therapy is often inconvenient, ineffective and associated with side effects. The fact that menorrhagia mostly occurs during the last reproductive years and in the perimenopause, when fertility is no longer a viable option, often prompts the choice of a surgical approach. Until recently, the only alternatives to medical therapy were either simple D&C or hysterectomy. In the treatment of menorrhagia, D&C is often ineffective and associated with a high recurrence rate. Hysterectomy is effective but associated with high costs, considerable morbidity and
*Corresponding author. Tel.: 145 36322744 (office), 145 39623690 (private); fax: 145 36 323361 (office); e-mail: [email protected]
even mortality, and may be a drastic and complicated solution to a passing condition. To improve efficiency and to reduce morbidity, inconvenience and costs, various methods to destroy the endometrium have been developed. Due to the very high potential for regeneration, irreversible destruction of the endometrium must include the entire stratum basale, which often demands destruction of the submucosal layers of the myometrium too. Recently, hysteroscopic techniques, such as laser ablation, endometrial diathermy and resection under direct vision, have made such total and selective destruction of the endometrium possible. These new therapeutic options have so far demonstrated relatively good results concerning safety, effectiveness and costs [1]. However, the hysteroscopic techniques entail some drawbacks. The procedures are technically difficult and require operator training. Consequently, these ablation methods are
0301-2115 / 98 / $19.00 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0301-2115( 98 )00030-X
L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
64
only practical for larger clinics with sufficient flow of patients to ensure adequate experience. Furthermore, complications from fluid overload, infections, uterine perforations, and injury to surrounding organs can cause morbidity and even mortality. In order to solve some of these problems, a new thermal balloon method for endometrial ablation has recently been developed. The thermal balloon ablation method is a simple procedure that requires minimal operator training; all indications are that it is very safe. In preliminary experimental and clinical studies [2–8] the method has shown almost the same efficacy in relieving menorrhagia as the currently used hysteroscopic techniques. The Thermal Balloon Therapy System TM has been investigated in pre-clinical experiments [2,6] and in clinical studies [3,7,8]. No significant rise in uterine serosal temperature was registered during 6–12 min thermal balloon therapy. The standard treatment time has accordingly been fixed at 8 min. In preliminary clinical studies the Thermal Balloon Therapy System TM seems to be effective in reducing menorrhagia, although apparently a little less effective than the hysteroscopic ablation techniques in producing amenorrhea [7,8]. One reason for this might be that the treatment time currently used is not always optimal; and a more thorough destruction of the endometrium may be achieved by increasing the treatment time during thermal balloon ablation. Before examining the effect of more prolonged treatment times in clinical trials, we have tested the safety of thermal balloon therapy during two consecutive 8-min standard treatment cycles, i.e. during 16 min heating. The effect on the uterus was assessed by monitoring uterine serosal temperature during treatment and by examining the extent of thermal coagulation into the myometrium by light and electron microscopy.
2. Material and methods
2.1. Heating equipment The Thermal Balloon Therapy System TM consists of a plastic catheter with a heating element at the one end surrounded by a protective heat shield and a latex balloon. A control unit connected to the catheter regulates the temperature and measures the pressure of the fluid in the balloon. The balloon catheter is inserted in the uterine cavity and the balloon is filled with a non-electrolyte water solution to a pressure of approximately 160 mmHg, aiming at adapting the shape of the balloon to the uterine cavity. The heating element raises the temperature to approximately 878C, and this temperature is automatically maintained during a preset treatment period of 8 min.
2.2. Patients Uterine thermal balloon ablation was performed in eight
premenopausal women (median age 42 years (range 39– 53)) undergoing hysterectomy due to benign meno-metrorrhagia and / or dysmenorrhea. All patients had benign histology by D&C performed within 6 months preoperatively, and all patients were in good general health. Intrauterine processes (polyps, fibromyomas, septa) were excluded preoperatively by vaginal ultrasonography and hysteroscopy. Patients with a uterine cavity measuring .10 cm or intramural or subserosal fibromyomas .2 cm were excluded. None of the patients received any pretreatment preoperatively, and the operations were scheduled without consideration for timing in menstrual cycle. Informed consents were obtained and the study was approved by the local ethical committee.
2.3. Ablation technique All patients were operated under general anaesthesia in the dorsal lithotomy position. The depth of the uterine cavity was measured by sounding. The thermal balloon catheter was inserted into the uterine cavity until contact with the fundus, matching the sounded length. Subsequently, the balloon was filled (5–15 ml) leading to an initial intrauterine pressure of approximately 160 mmHg. The abdomen was opened and the uterus exposed. Thermistor probes were placed through needles 1.2 mm in diameter approximately 1 mm into the subserosal tissue in the right and left uterine cornual region, at the lateral cervicocorporal junction and next to the urinary bladder. Once the balloon pressure was stabilized between 100 and 160 mmHg, the heating element was activated and heating carried out. The temperature in the balloon was 878C (82–928C) during the heating procedure. Temperatures were recorded every minute during the treatment. The first patient was treated for the conventional 8 min. As the thermal ablation procedure was found to cause only slight increase of temperature at the uterine serosa, treatment time was gradually increased to 14, 15 and 16 min. Hysterectomy was subsequently performed according to routine procedures. No complications occurred during surgery or postoperatively.
2.4. Macroscopical evaluation The hysterectomy specimens were sent without fixation for pathological examinations immediately after removal. The uteri were opened by a sagittal section in the pathology laboratory. The thickness of the uterine wall and the depth of the coagulation zone, which appeared dark discolored contrasting the normal myometrium were measured in mm.
2.5. Light microscopical evaluation All uteri were evaluated by light microscopy and, in patients nos. 2 and 5, additional electron microscopy evaluations were performed. After fixation in formalin
L.F. Andersen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 79 (1998) 63 – 68
sections for microscopy through the uterine walls for H&E (alhematein / eosin) stain were taken from: the anterior and posterior wall at the cervico–corporal junction, the anterior and posterior wall in the middle of the uterine corpus, the mid-fundal region, and from the right and left cornual region medial to the outset of the Fallopian tubes. Thermal coagulation was defined by the presence of nuclear shrinkage and hyperchromasia and cytoplasmic vacuolization in the myometrial muscle cells. The depths of the thermal coagulation zones into the myometrium were measured by two pathologists without knowledge of the thermal balloon ablation data.
2.6. Electron microscopical evaluation A transverse strip 253232 mm through the posterior wall was removed 1 h after surgery. The slice was split longitudinally and one half of the strip was processed for light microscopy, the other half for electron microscopy. The formaldehyde-fixed material was further treated in Karnovsky’s formaldehyde–glutaraldehyde fixative. After 1 h the slice was trimmed down to 0.5 mm thickness, cut into pieces of 1 mm in length, and placed in separate vials. Thus, the average spatial resolution for the electron microscopical description is 1 mm. The pieces were rinsed in three changes of phosphate buffer and postfixed in 1% buffered osmium tetroxide, dehydrated and embedded in epon. Silver sections were cut on an LKB ultramicrotome and contrasted with uranyl acetate and lead citrate, and examined in a Jeol 1010 electron microscope.
2.6.1. Criteria The criteria from which the degree of thermal injury was judged were: chromatin structure, membrane preservation, and organelle preservation. Regarding the latter, rough endoplasmatic reticulum (rER) was considered the least, and mitochondrial ultrastructures the most sensitive marker for cell injury. The degree of thermal injury was graded progressively as the following: No cell damage: cells appear normal in all respects
65
except for small changes in the mitochondria. Some deterioration of mitochondrial crista structure is probably inevitable due to ischemia during ablation, surgery and transport. Thus, cells presenting mitochondria with recognizable crista structure and electron-dense matrix were considered unaffected by the thermal therapy. Moderate cell damage: euchromatin slightly condensed. Some membrane ruptures. Most mitochondria with electron-lucent matrix, but with recognizable crista. Severe cell damage: membranes, including plasma membranes, not intact. mitochondria generally not recognizable. Nuclei and cytoplasm with ‘empty’ spaces. Partial coagulation: nuclei condensed, chromatin coarse. Cell demarcations present, but cell membranes absent or discontinuous. Most organelles absent except for remnants of rER. Cytoplasm coarse and with ‘empty’ areas. Total coagulation: nuclei condensed and ruptured. Chromatin coarse, no recognizable organelles, cell demarcations generally indistinct, cytoplasm coarsely granular.
3. Results
3.1. Temperature measurements The maximal temperatures registered on the uterine serosa during thermal balloon ablation are shown in Table 1. Minimal rise in serosal temperature was found in the first patient, treated for only 8 min. Variable increase in serosal temperatures were found among the patients treated for 14–16 min. The rate of increase and the gradients of serosal temperature varied between the patients; however, the rise in temperature showed a tendency to reach its peak at 10–12 min, after which the temperature tended to drop a bit and stabilize 1–28C above the starting point of 34– 358C. The highest temperature recorded was 39.18C at the left cornuum after 13 min treatment; the temperature subsequently fell to 38.58C after 16 min. Among the four anatomical positions chosen for temperature registration no
Table 1 Maximal serosal temperatures and depth of coagulation zones in the myometrium assessed macroscopically and light microscopically Pt. no.
1 2 3 4 5 6 7 8
Treatment time (min)
8 14 14 14 15 16 16 16
Max. temp. (8C)
36.6 38.5 36.7 36.7 35.9 38.8 39.1 37.6
(B,L) (B) (R) (B) (R) (C) (L) (B)
Max. temp. end of treatment (8C)
36.6 38.2 36.7 36.5 35.7 38.8 38.5 36.2
(B,L) (B) (R) (B) (R) (C) (L) (B,C)
Myometrium thickness (mm)
23 20 20 15 20 25 20 17
Macroscopic coag. zone (mm)
NR 4 3 2 4 1 4 3
Microscopic coagulization zone (mm) Cervical–corporal junction
Corpus
Anterior wall (mm)
Posterior wall (mm)
Anterior wall (mm)
Posterior wall (mm)
Fundus (mm)
Right (mm)
Left (mm)
0 0 0 0 0 4.1 1.8 2.0
0 NR 1.2 0 0 0 0.6 NR
3.8 4.1 3.2 2.7 2 6.7 3.9 3.0
0.5 5.0 3.0 0.1 2.9 7.1 3.9 3.8
0 5.0 2.1 1.0 2.0 11.5 3.8 2.1
0 0 1 2.1 0 NR 0 0
0 0 0 0 0 NR 0 0
NR, not registered; B, bladder; C, cervico–corporal junction; R, right cornuum; L, left cornuum.
Cornuum
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Fig. 1. Myometrium with nuclear shrinkage and hyperchromasia and vacuolization in the cytoplasm (left) compared to the normal myometrium (right). Both photographs from the same H&E stained section. Original magnification 3250.
pattern of predominance for rise in serosal temperature could be identified.
3.2. Light microscopical evaluation The depths of the coagulation zones in the myometrium measured by LM are shown in Table 1. A coagulation zone including the endometrium and the myometrium adjacent to the uterine cavity was found in all patients. The profound myometrium and the serosa showed no thermal damage. The average coagulation zone in the corpus wall was 3.5 mm (ant. wall 3.7 / post. wall 3.3), with a variation of 0.1–7.9 mm. Patient no. 6 showed the most extensive coagulation zone, with a maximum of 11.5 mm in the fundus. This patient had the highest temperature increase of 38.88C at the end of 16 min treatment. Coagulation of one of the uterine corners was seen in only two patients,
Fig. 2. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 0–1 mm depth: total nuclear and cytoplasmic coagulation (grade 5). In most cases cell demarcations indistinct. Collagen fibres swelled.
with a maximum depth of 2.1 mm after 14 min treatment. Coagulation in the cervical–corporal junction was seen in four of eight patients, and was most pronounced in the anterior uterine wall with a maximum coagulation zone of 4.1 mm following a treatment of 16 min. The macroscopic coagulation zone correlated well with the light microscopic measurements in all patients (Fig. 1).
3.3. Electron microscopical evaluation The degree of cell damage moving from the mucosal towards the serosal surface was: 0–4 mm (Grade 5), total coagulation (Fig. 2), collagen fibres mostly unrecognizable; 4–6 mm (Grade 4), widespread coagulation (Fig. 3), collagen fibres only slightly disorganized; 6–9 mm (Grade 3), severe cell damage (Fig. 4), the cells appeared dead or dying, muscle actin organization much disturbed, collagen
Fig. 3. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 4–5 mm depth: coagulation predominant (grade 4), But cell borders and collagen fibres are preserved. Note empty spaces in nuclei and cytoplasm.
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Fig. 4. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 7–8 mm depth: severe (left) to moderate (right) cell damage (grade 3-2). Note granular endoplasmatic reticulum, and dense plaques on the plasma lemmas of the best preserved muscle cells.
fibres normal; 9–15 mm (Grade 2), moderate to slight cell damage (Fig. 5), actin organization approached normal; 15 mm–out (Grade 1), cells unaffected by the heat treatment (Fig. 6). Judged from ultrastructures, or rather the absence thereof, the zone of cytoplasmic coagulation reached a depth of 5–6 mm. Deeper in the myometrium, from 3 to about 12 mm, the cells often exhibited empty spaces, both in the nucleus and cytoplasm. These spaces probably correspond to the vacuolization found by light microscopy.
4. Comment The gradients of serosal temperatures showed a ten-
Fig. 5. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 10–11 mm depth: slight cell damage (grade 2). Nuclear and organelle structure slightly coarsened, with ‘empty’ spaces in euchromatin areas and cytoplasm. Actin fibre organization slightly disturbed.
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Fig. 6. Electron micrograph of the uterine wall following thermal ablation. The depth is measured from the mucosal side (10 0003 magnification). 15–16 mm: no obvious cell damage (grade 1). Note the uniform distribution of euchromatin, and of focal densities in the cytoplasm. (The occasional electron-lucent vacuole is artefactual, and represents a hole in the embedding resin).
dency to reach their peak after 10–12 min heating and subsequently stabilize, probably due to a compensatory increase in uterine blood flow. This may reflect the capacity for auto-regulation of uterine blood flow, and may suggest that the uterus has a large potential for absorption of heat, once auto-regulation mechanisms are given sufficient time for redistribution of the blood flow. If the pressure in the balloon is increased beyond the 160 mmHg used in our set up, increased compression of the uterine vessels may perhaps reduce this regulatory and cooling effect. Furthermore, one may speculate that if the steadystate situation was continued beyond the 16 min investigated in this study, more prolonged thermal injury may be possible. It remains to be investigated, however, whether any additional clinical effect can be achieved from prolonging the treatment time. It may be that once a steady state is reached, heating may continue without additional coagulation. The recorded temperatures, in all cases, started from approximately 358C. These levels below normal body temperature were presumably due to the exposure of uterus in the operating field with uterus subjected to the cooling effect of room temperature. This cooling effect may represent a source of error, the significance of which, however, is considered of minor importance regarding assessment of the highest temperatures reached on the uterine serosal surface during the ablation procedure. The light microscopical evaluations of the myometrium showed coagulation of the submucosal layers of the myometrium in all cases. However, the extent of the coagulation varied considerably concerning distribution and depth, generally with little effect on the lower uterine segment and on the cornual areas. The fluid in the investigated thermal balloon system is circulated passively during the ablation procedure, and preliminary clinical
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testings have suggested that a heterogeneous heat distribution may occur in the balloon due to the property of heat to ascend. In order to overcome any such effect, active circulation of the fluid by a pump has been included in another thermal balloon ablation system [4–6]. Uneven distribution of the heat in the balloon would be expected to result in a stronger effect of heat on the anterior (upper) uterine wall than on the posterior (lower) uterine wall. No such effect could be demonstrated in our material. The defective coagulation achieved in the cornual regions may be an important reason for the fact that only a minority of the patients so far treated with the thermal balloon ablation system gained complete amenorrhea [7,8]; and the remaining intact endometrium in the cornual region may predispose to the subsequent development of haematometra. Application of higher pressures in the balloon may enable it to adapt more completely to the shape of the uterine cavity, thus improving coagulation of the cornual endometrium; and increased pressure from the balloon may compress myometrial blood vessels, reducing the cooling effect from myometrial blood flow. Concerning the safety of the prolonged treatment time, the deepest coagulation zone in the myometrium was 11.5 mm in the fundus, as assessed by light microscopy. However, the assessment of cell viability might be difficult by light microscopy. By electron microscopy, the zone of coagulative cell damage reached a depth of 5–6 mm, judged from cellular ultrastructures, or their absence. This zone of total cell injury corresponds to or contains the 4–5-mm zone where NADH-diaphorase, a predominantly mitochondria enzyme system, is destroyed [2]. However, moderate heat exposures, which affect enzymes only slightly, may still lead to homeostatic break-down and cell death. In the present material total cell death probably occurred to a maximum depth of 11–12 mm. Obviously, electron microscopy gives a more detailed picture of cellular heat changes and the depth of penetration than enzyme histochemistry. Judged from mitochondrial ultrastructure and plasma membrane integrity, heat damage was absent or insignificant at a distance exceeding 14–15 mm from the endometrial surface.
5. Conclusions Evaluated macroscopically and by light and electron microscopy, up to 16 min of thermal balloon endometrial ablation can destroy the endometrium and the submucosal layers of the myometrium—at least where the thermal balloon is in close contact with the endometrium. Conversely, the myometrium is only coagulated to a depth where full thickness necrosis or injury is unlikely. The safety of the procedure is additionally substantiated by the finding of only minor, clinically insignificant increases in temperature on the uterine serosal surface during balloon ablation, making accidental thermal injury to surrounding organs, even if adherent to the uterus, unlikely. Thermal
balloon endometrial ablation seems to be a simple, easy and safe procedure not requiring special skills or operative facilities. The efficiency of the treatment remains to be proven through properly designed, controlled clinical trials with a sufficient number of patients and adequate follow up. The procedure may still need development, especially concerning optimization of balloon pressure, shape, heat distribution and treatment time. Thermal balloon ablation for 16 min was found to be safe.
6. Condensation Serosal temperatures were monitored during thermal balloon endometrial ablation, and thermal influence into the uterine wall was investigated by light and electron microscopy.
Acknowledgements We are indebted to the patients for their readiness to co-operate in the study; to Erik Schmidt, ELLAB AS, Rødovre, Denmark, for the loan of thermometer equipment; to Birgit Nielsen Johannsen, Dr. Phil., Lab. of Human Physiology, The August Krogh Institute, University of Copenhagen, for the loan of thermosensor probes; to Jan Hansen NIKOMED AS, Rødovre, Denmark, and to Milton B. McColl, GYNECARE Inc., USA, for the loan of the EASy TM -endometrial balloon ablation system.
References [1] Garry R. Good practice with endometrial ablation. Obstet Gynecol 1995;86:144–51. [2] Neuwirth RS, Duran A-A, Singer A, MacDonald R, Bolduc L. The endometrial ablator: A new instrument. Obstet Gynecol 1994;83:792–6. [3] Singer A, Almanza R, Guttierez A, Haber G, Bolduc LR, Neuwirth R. Preliminary clinical experience with a thermal balloon endometrial ablation method to treat menorrhagia. Obstet Gynecol 1994;83:732–4. ´ R, Ahlgren M. A new technique for [4] Friberg B, Petersson F, Willen endometrial destruction by thermal coagulation; clinical results with 12–24 months follow-up. Abstract; Presented at the 4th Congress of the European Society For Gynaecological Endoscopy, Brussels, Belgium, 6–9 December 1995. ´ R, Ahlgren M, Petersson F. Cavaterm TM —A new [5] Friberg B, Willen technique for endometrial ablation by thermal coagulation. Abstract; Presented at World Congress Of Hysteroscopy, Miami, FL, 9–11 February 1996. ´ R, Ahlgreen M. Endometrial [6] Friberg B, Persson BRR, Willen destruction by hyperthermia—a possible treatment of menorrhagia. Acta Obstet Gynecol Scand 1996;75:330–5. [7] Vilos GA, Fortin C, Sanders B, Prendley L, McColl M. Uterine balloon therapy for the treatment of menorrhagia. J Am Assoc Gynecol Laparosc 1996;3(Suppl 4):S54. [8] Vilos GA, Fortin C, Sanders B, Prendley L, Stabinsky SA. Clinical trial of the uterine balloon therapy for treatment of menorrhagia. J Am Assoc Gynecol Laparosc 1997;4(5):559–65.