Cryothermic and Hyperthermic Treatments of Human Leiomyomata and Adjacent Myometrium and Their Implications for Laparoscopic Surgery

doi:10.1016/S1074-3804(05)60241-1

The Journal of the American Association of Gynecologic Laparoscopists

Volume 10, Issue 1, February 2003, Pages 90-98

The Journal of the A...

https://doi.org/10.1016/S1074-3804(05)60241-1 Get rights and content

Abstract

Study Objective

To evaluate the effects and feasibility of direct cryothermic and hyperthermic therapy on leiomyomata and adjacent myometrium, and to contribute to evidence-based treatment thresholds based on measurements of direct cell injury.

Design

Experimental study (Canadian Task Force classification II-2).

Setting

University hospital.

Subjects

Leiomyoma and myometrium tissue from 10 women undergoing total abdominal hysterectomy with or without bilateral salpingo-oophorectomy.

Intervention

In vitro cryothermic or hyperthermic therapy was performed with representative leiomyoma and myometrium tissue samples. Using a directional solidification stage to simulate cryothermic therapy, 10 leiomyoma and 6 myometrium specimens were cooled in vitro at a rate of −5°C/minute to end temperatures of −20°, −40°, −60°, and −80°C with a 15-minute hold period and then rapidly thawed to 21°C. Hyperthermic therapy was simulated using a preheated 45°, 55°, 60°, 65°, 70°, 75°, and 80°C constant temperature copper heating block with a 10-minute treatment period. In conjunction with tissue culturing and control tissues, cell death was assessed with routine histology and viability dyes (ethidium homodimer/Hoechst).

Measurements and Main Results

In cryothermic results, leiomyomata cell death (LCD) increased from 12% to 27% by histology and 26% to 38% by viability dye assay over the thermal range from −20° to −80°C, respectively. Myometrial cell death (MCD) increased from 10% to 12% and 4% to 20% for the same measurements, respectively. Whereas MCD appeared relatively stable from −40° to −80°C, it was significantly less than LCD over this range (p <0.05). For hyperthermic results, LCD increased from 17% to 88% by histology with progressive temperature increase from 45° to 80°C, respectively. The MCD showed a similar increase from 16% to 91% by histology over this temperature range. Hyperthermic histology and dye assay results were similar for LCD and MCD.

Conclusion

In comparison with myometrium, leiomyomata showed greater direct cryothermic and equal hyperthermic cell injury. Whereas cell death increased up to 70°C and down to −80°C, the interval increases in cell injury diminished with more extreme temperatures. In vivo studies of combined direct and ischemic vascular injury thresholds have yet to be performed, but direct LCD matrixes determined in this study will help provide guidelines for minimally invasive surgical techniques for the treatment of leiomyomata.

Section snippets

Materials And Methods

After approval from the institutional human subjects committee, fresh tissue samples from human leiomyomata and adjacent myometrium were obtained from hysterectomies performed for primary ovarian neoplasms (4), symptomatic leiomyomata (2), invasive cervical squamous cell carcinoma (2), endometrial adenocarcinoma (1), and endometriosis (1). Mean patient age was 56 years (range 42–75 yrs). Two women had received oral conjugated estrogen 0.625 mg plus medroxyprogesterone 5 mg/day until 2 weeks

Cryothermic Injury

Histologic leiomyomata cell death rates (LCD) at −20°, −40°, −60°, and −80° C and LN₂ were significantly greater than those of controls (p <0.01) and LCD significantly increased from −20° to −80° C (p <0.01). The viability dye assay also showed a significant increase in cell death with decreasing temperature exposures (p <0.01) and were consistently higher than corresponding histologic results (Table 1). After normalizing for control results (Figure 3), the maximum histologic LCD was 27% and

Discussion

Recent advances in cryothermic and hyperthermic probe designs and in situ monitoring technologies enhance opportunities for minimally invasive surgical treatment of several benign and malignant neoplasms. As a uterus-sparing option for symptomatic leiomyomata, interest in cryothermic and hyperthermic procedures is increasing. These procedures are designed to induce localized, irreversible cell injury through a combination of two mechanisms: direct cell injury and ischemia secondary to

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Alternative therapies in management of leiomyomas
2014, Fertility and Sterility
Leiomyomas are benign soft-tissue neoplasms that arise from smooth muscle. Relief of symptoms (abnormal uterine bleeding, pain, pressure) is the major goal in management of women with significant symptoms. For symptomatic myomas, hysterectomy is a definitive solution; however, there are emerging less-invasive options. Magnetic resonance imaging–guided focused ultrasound surgery, cryomyolysis, and temporary occlusion of the uterine arteries are treatment options that are minimally invasive interventions with the benefit of preserving the uterus. This review summarizes procedure techniques, eligibility, complications, and outcomes of these alternate therapies.
Calcium concentration response to uterine ischemia: A comparison of uterine fibroid cells and adjacent normal myometrial cells
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In 2009, Burbank reported that UAE and UAO reproduce the ischemia that occurs naturally throughout the uterus during childbirth [8]. Fibroid cells have been shown to be more sensitive to hot and cold [9]. Tissue plasminogen activator concentration is higher in myometrium than in fibroids [10].
Uterine artery occlusion by laparoscopy (UAOL) has been used for the treatment of uterine fibroids and beneficial effects to patients have been shown in clinical studies since 2000. Fibroid cells are more susceptible to apoptosis than myometrial cells under hypoxic conditions, but the molecular mechanisms underlying this effect remain unclear. The aim of this study was to investigate the role of intracellular calcium (Ca²⁺) release mediated by Ca²⁺ channel inositol 1,4,5 trisphosphate receptor1 (IP3R1)/ryanodine receptor1 (RYR1) in the apoptosis of uterine fibroid cells under hypoxia.
We compared the expressions of IP3R1 and RYR1 in fibroid and surrounding myometrial tissue from 20 patients before UAOL. After 6 h treatment under hypoxia (1% O₂) with or without Ca²⁺ channel blockers (heparin or/and ruthenium red), the intracellular Ca²⁺ concentration, cytochrome c (Cytc) protein and cell apoptosis were determined.
IP3R1 and RYR1 mRNA and protein levels were significantly higher in fibroid than in myometrial tissues. Under hypoxic conditions, Ca²⁺ concentration in fibroid cells was significantly higher than in myometrial cells (Ca²⁺: 82.69 ± 16.92 nmol/L vs 46.14 ± 9.11 nmol/L, P < 0.05), and Cytc increased similarly in fibroid cells. These increases in Ca²⁺ concentration, Cytc and cell apoptosis were significantly reversed by calcium blocker in fibroid cells.
This study demonstrated that intracellular calcium release mediated by IP3R1/RYR1 could induce apoptosis in uterine fibroid cells under hypoxic conditions, and was responsible for the susceptibility to apoptosis of fibroid cells under UAOL.
Uterine Leiomyomas, Current Concepts: Pathogenesis, Impact on Reproductive Health, and Medical, Procedural, and Surgical Management
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The relative uniformity of cell death in the zones that reach −20° C or lower suggests that the principal clinical impact of cryomyolysis is one that is secondary to the vascular impact on tissue.119 There is also evidence that leiomyomata may be more sensitive to freezing than normal myometrial tissue, whereas the effects of laser or radiofrequency electrical energy are similar in myoma and adjacent healthy myometrium.120 If this evidence is accurate, hypothermic ablation techniques may have a degree of tissue specificity and could aid the clinician in preserving neighboring myometrium.
Laparoscopically assisted uterine fibroid cryoablation
2009, American Journal of Obstetrics and Gynecology
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There is a central zone of necrotic tissue, an intermediate zone of regenerative and inflammatory tissue, and a peripheral zone of partly damaged cells. A single report attempts to guide evidence-based cryoablation treatment thresholds on the uterus, based on measurements of direct cell injury following cryotherapy.31 In this study, cryothermia at –80°C produced fibroid cell death of 27% measured by histology and 38% measured by viability dye assay compared with the –20°C observations of 12% and 26%, respectively.
The objective of the study was to develop a safe and effective cryoablation technique for the treatment of uterine fibroids.
This was a multicenter pilot case series to evaluate cryoablation of uterine fibroids using laparoscopically assisted placement of 17-gauge cryoablation needles. Patient satisfaction was documented with a validated Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire. Procedural efficacy was evaluated by assessing fibroid shrinkage. Treatment was followed by assessments at 3, 6, and 12 months.
Median fibroid volume reduction was 43.3% (19 patients) and 66.4% (15 patients) at 6 and 12 months, respectively. Median UFS-QOL score improvement was 61.9% and 66.7% at 6 and 12 months, respectively. Additionally, patients experienced marked improvement of bleeding and fibroid bulk symptoms. The median Symptom Severity Score at baseline was 50, 25.0 (–59%) at 6 months, and 12.5 (–66.7%) at 12 months.
These pilot data indicate that uterine fibroid cryoablation is a safe and effective minimally invasive alternative to treat symptomatic uterine fibroids.
Practical Tips for Office Hysteroscopy and Second-Generation "Global" Endometrial Ablation
2009, Journal of Minimally Invasive Gynecology
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In an in vitro study, the authors found that leiomyoma cell death increases from 27% to 88% with increased temperature, from 45 °C. to 80°C, for 10 minutes [50]. This would partially explain the effect observed in myomas and the long-term success observed with treatment with the HTA system.
Hysteroscopy and endometrial ablation using the second-generation devices are safe, generally well tolerated, and effective when performed in the medical office as opposed to the ambulatory surgery center or hospital operating room. Not only does this benefit the patient and physician in terms of convenience and cost savings, and the overall economic benefit to the health care system is great. The availability of modern hysteroscopic and video equipment, the advent of second-generation “global”endometrial ablation devices, and use of minimal sedation combined with effective local anesthesia have made office procedures possible. Several states have enacted specific regulations and requirements for office based surgery. It is incumbent on the physician to be aware of which local regulations are applicable and the level of procedure he or she is willing to perform before embarking on an office-based surgery program. The AAGL ListServ discussion forum provides members with an invaluable source of clinical opinion about patient care issues in minimally invasive gynecology. These opinions come from experts around the world representing both academic centers and clinical practice who respond to questions or issues posed by colleagues. This review discusses each of the second-generation endometrial ablation devices in detail and some of the more pertinent issues related to office hysteroscopy and global endometrial ablation that were posted on the ListServ. Rollerball and transcervical resection of the endometrium are not discussed because the overwhelming majority of these procedures are performed in the operating room and there is little potential for their becoming office procedures. Practical clinical tips based on the evidence in the literature are discussed.
Endoscopic management of uterine fibroids
2008, Best Practice and Research: Clinical Obstetrics and Gynaecology
Citation Excerpt :
This creates a 3.5–5 cm ice ball, destroying the fibroid and producing subsequent hyaline degeneration. Rupp et al reported that unlike thermomyolysis, uterine fibroids are affected by the freezing technique to a greater extent than adjacent normal myometrium.27 Zupi et al found a reduction in fibroid size of up to 50% with subsequent alleviation of symptoms.28
Uterine fibroids are the most common benign tumours of the uterus. Management depends on the symptoms, location and size of the fibroids, and the patient's desire to conceive. Surgical management of uterine fibroids has changed from laparotomy to minimally invasive surgery. Uterine fibroids are usually asymptomatic and do not require treatment. Laparoscopic myomectomy is the best treatment option for symptomatic women with uterine fibroids who wish to maintain their fertility. The authors' criteria for laparoscopic myomectomy are a fibroid of <15 cm in size, and no more than three fibroids with a size of 5 cm. Compared with laparotomy, laparoscopic myomectomy has the advantages of small incisions, short hospital stay, less postoperative pain, rapid recovery and good assessment of other abdominal organs. Due to the concern of decreased ovarian reserve, uterine artery embolization is not advisable for these women. In addition, it is associated with high risks of miscarriages, preterm delivery and postpartum bleeding. Laparoscopic myolysis causes severe adhesion formation. Women with submucous fibroids receive myomectomy by hysteroscopy. For women who have completed their family, laparoscopic hysterectomy could be performed.
Most fibroids can be managed endoscopically either by laparoscopy or hysteroscopy. Surgeon expertise, especially laparoscopic suturing, is crucial. Laparoscopic myomectomy is still the best treatment option for symptomatic women with uterine fibroids who wish to maintain their fertility. Hysteroscopic myomectomy is an established surgical procedure for women with excessive uterine bleeding, infertility or repeated miscarriages.

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Original ArticlesCryothermic and Hyperthermic Treatments of Human Leiomyomata and Adjacent Myometrium and Their Implications for Laparoscopic Surgery

Abstract

Study Objective

Design

Setting

Subjects

Intervention

Measurements and Main Results

Conclusion

Section snippets

Materials And Methods

Cryothermic Injury

Discussion

Am J Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

J Am Assoc Gynecol Laparosc

J Am Assoc Gynecol Laparosc

Cryobiology

Urology

Urology

Urology

J Am Assoc Gynecol Laparosc

Cryobiology

Cryobiology

Cryobiology

Am J Obstet Gynecol

Am J Obstet Gynecol

Original Articles
Cryothermic and Hyperthermic Treatments of Human Leiomyomata and Adjacent Myometrium and Their Implications for Laparoscopic Surgery