The expanding spectrum for uterine fibroid treatment – the most common benign gynaecological tumour

Introduction
Uterine fibroids (leiomyomata) are the most common benign tumours of the uterus. It is believed that up to 70% of women have uterine fibroids at some stage of their life. Fibroid tumours have been demonstrated in the paediatric and adolescent uterus, and in women with genital streaks [XO]. Benign tumours are traditionally known not to ‘metastasize’. It is not clear therefore what to make of the entity described as a ‘benign metastasizing leiomyoma’: three months after an elective caesarean delivery and hysterectomy, a woman with known uterine fibroids presented with symptoms due to a right cardiac ventricular mass.

It was subsequently found that the mass was of the same pathologic type as the uterine primary. It is to be noted that ‘fibroids’, as a histo-pathologic entity are not confined to females. A giant primary leiomyoma of the right cardiac ventricular wall has been reported in a 13 year old boy. The promising animal model for fibroid research is the Potbellied pig. Histological, hormonal and comparative-age characteristics are strikingly similar.

Some important background information
Smooth muscle tumours of the uterus cover a broad histological spectrum, from benign leiomyomata to frankly malignant leiomyosarcomata. Within this spectum lies STUMP – smooth muscle tumours of unknown malignant potential. The mitotic index was previously used as a prognostic factor, but it would appear that the presence of atypia and coagulative tumour cell necrosis are the factors most associated with malignant behaviour. STUMP is usually a post operative histological diagnosis, and there is little evidence regarding optimal treatment. In one series, however, only 27% of patients had recurrence, and the majority of these had good long term survival.

Leiomyosarcomas account for 3-7% of malignant disease of the uterus. They are found in about 0.5% of women who have hysterectomies for fibroids, and are usually an incidental finding (the increasing use of conservative management of fibroids may have an impact on the detection and treatment of leiomyosarcomas). They are the most common sarcoma (25-36% of uterine sarcomas) and tend to be aggressive and have a poor prognosis.

The blood supply of the myometrium facilitates metastasis, particularly to the lungs. Fibroids are not thought to develop into leiomyomas, although leiomyosarcomata may co-exist within fibroids. There can be difficulty in distinguishing between leiomyosarcomata and degenerating fibroids on routine imaging. Gadolinium enhanced MRI, combined with lactate dehydrogenase isozymes can increase diagnostic accuracy. Stage 1 disease has a five year survival rate of 62-62%, whereas in advanced disease this is around 29%.

Genetics of fibroids
It has long been observed that women of Afro-Carribean ethnicity have a higher incidence of fibroids. There are also familial dispositions to fibroid formation – the incidence in monozygotic twins being twice that in dyzygotic twins, women with a first degree relative with fibroids have a 2 – 6 fold increased incidence, and rare syndromes such as Reed syndrome – (subcutaneous leiomyomata, uterine leiomyomata and renal clear cell carcinoma), all of which suggest a genetic component to fibroid formation. Recent studies have isolated mutations in two genes, HMGI(C) and HMGI(Y) which appear to have a role in the fibroid formation, influencing myometrial response to growth factors and ovarian steroids.

Presentation
Most uterine fibroids are asymptomatic. They are only discovered in the course of clinical or imaging investigation of other conditions. Fibroids are clinically apparent in up to 25% of women, and a US study of random ultrasound examination of asymptomatic women showed fibroids in over 50%. Growth rates differ with race – in white women the rate of growth reduces towards the menopause, whereas for women of afro-carribean ethnicity the rate of growth remains constant; this may influence the decision for intervention in women in later reproductive life.

Clinical symptoms are directly related to size and site of the fibroids. Symptoms are typically suprapubic or iliac fossa pain, back ache, menorrhagia, dysmenorrhoea or urinary symptoms due to significant pressure effects. The symptoms generally reflect the site, size, secondary changes and mobility of the fibroids.

Menorrhagia is caused by the increased area of the endometrial cavity by submucosal fibroids, and also by congestion and endometrial venous plexus dilatation caused by intramural fibroids. Fibroids do not disrupt the bleeding cycle, unless there is a fibroid polyp, which may cause intermenstrual bleeding.

Bothersome features of uterine fibroids especially with advancing age, include rapid unexplained growth, preferably corroborated by imaging techniques, and unexplained anaemia typically out-of-proportion to blood loss. Rarely, histopathology after myomectomy may confirm mitosis consistent with STUMP or sarcoma.

Diagnostic work-up and counselling
Treatment is most often sought for either menorrhagia or subfertility, or both. The desire for fertility to be preserved, or enhanced, will mitigate against certain treatment options.

Imaging is important in planning specific treatment, identifying co-existing pelvic pathology and counselling the patient. The extent of investigation depends on the patient’s age, fertility intentions and previous surgery or surgical complications.

Generally, is reasonable to exclude anaemia, treat it if present, and arrange for blood to be available if needed intra-operatively or afterwards.

Ultrasonography – transabdominal or transvaginal – is the first line diagnostic tool for assessing the size and location of uterine fibroids. Submucous fibroids can be more accurately assessed by using intracavity saline as a contrast medium. The European Society of Hysteroscopy has produced a classification of submucous fibroids: class 0 describes a fibroid with no intra-mural extension; class I with less than 50% intramural extension and class II having 50% or more. Class 0 would be amenable to hysteroscopic myomectomy, whereas class II would be more appropriately treated medically. Three-dimensional ultrasonography can be used to more accurately assess the location of fibroids prior to UAE. Magnetic resonance imaging (MRI) is useful prior to MRI guided percutaneous laser ablation or high intensity focused ultrasound ablation.

If there has been extensive pelvic surgery in the past, or a fixed and large fibroid particularly close to the cervix, it may be wise to have a pre-operative urogram to exclude ureteric distortion or to pick up the occasional congenital malformation.

	A. Multiple fibroids on a uterus, lifted up from the laparotomy access. Note the gross distortion in shape	B. A fibroid nodule is enucleated from the uterus. The ensuing defect is closed thereafter
	C. Enucleated fibroids laid out. Note the varying sizes and surface contour	D. Appearance of the uterus after myomectomy and serosal re-constitution
Images reproduced with kind permission of the British Fibroid Trust©

Treatment options
It is important to understand the woman’s priorities and expectations in managing her symptoms – what she would like to attain, and to what lengths she wishes to pursue this. Laparotomies are becoming increasingly un-popular.

The options could be grouped as follows:

• Medical: Intra uterine systems, Inject- ables, oral medication
• Radiological: Uterine Artery Embolisa- tion of Fibroids
• Non-invasive pulsed energy therapies: Ultrasound, MRI guided laser ablation
• Myolysis
• Myomectomy: Hysteroscopic resection, laparoscopic myomectomy, open myo- mectomy
• Hysterectomy;
• Conservative: Non-active observation

Mifepristone:
This anti-progestin is given orally as 5mg daily for six months; it can bring about 40% reduction in size and volume of uterine fibroids. The long term effectiveness is not known and the procedure is still under clinical trial.

Mirena IUS:
The progesterone-eluting intra-uterine system reduces uterine size by up to 20-30% and uterine bleeding by 40%. It offers good contraception in addition to the management of menorrhagia. It is obviously not a solution for women wishing to conceive. However, distortion of the uterine cavity is a relative contra-indication to the use of Mirena for uterine fibroids. It is most likely to be successful for small fibroids adjacent to the endometrial cavity.

GnRH analogues:
GnRH analogues are most commonly used as a short term (up to six months) measure to reduce fibroid volume, usually prior to surgical intervention. Long term (more than 18 months) use is restricted because of the risk of bone density loss and menopausal symptoms. In studies the use of GnRH analogues has been shown to reduce the intraoperative blood loss (as shown by post operative haemoglobin levels) and increase the use of transverse rather than vertical abdominal incisions for open myomectomy.

GnRH analogues may make surgery for small fibroids more difficult It has not been shown to have any effect on the rate of post operative complications. Current recommendations are that GnRH analogues be used when the uterus is very large, where there is anaemia and when a transverse incision is planned for open myomectomy.

Uterine Artery Embolisation of Fibroids (UAE):
UAE has been used to treat fibroids since 1991. The EMMY (EMbolisation versus hysterectoMY) and REST (Randomised trial of Embolisation vs Surgical Treatment for fibroids) trials have shown that UAE is a safe and effective alternative to hysterectomy for the treatment of fibroid related symptoms. Short term side effects include pain and low grade fever.

Infection complicates less than 1% of cases, but may result in the need for hysterectomy, and deaths have been reported. Catheters are threaded up into the uterine arteries via the femoral arteries and embolic material – polyvinyl alcohol particles, gelfoam, or microspheres are injected into both arteries until blood flow ceases.

A study of 79 consecutive cases of UAE for fibroids from Bristol showed a reported improvement in symptoms in 84% of women. Ultrasound examination showed fibroid size was reduced in 84% of women, with an average reduction in size of 47%. There were subsequently four pregnancies in three women amongst the Bristol group, one of which was terminated, and three had successful outcomes. Homer et al collated data comparing pregnancy outcomes following

UAE against those of the general population. There was a higher spontaneous miscarriage rate (35% vs 10-15%), a higher preterm delivery rate (16% vs 5-10%), a higher caesarean section rate (67% vs 22%) and higher post partum haemorrhage rate (14% vs 4-6%). The authors recommend a cautious approach when considering UAE in women desiring further pregnancies.

This procedure is not suitable for submucosal fibroids, as transcervical expulsion may be very painful. In up to 10% of cases intramural fibroids are passed vaginally some time after UAE, and this can cause severe pain. Women over the age of 45 are at higher risk of ovarian failure following UAE, but for women under the age of 40 this appears to be less of a risk.

A review of RCTs comparing UAE and hysterectomy for treatment of fibroids reported shorter duration of procedure, less intra-procedure blood loss, shorter hospital stay and quicker resumption of normal activities in the UAE group; there was no significant difference in the satisfaction with treatment or intra-procedural complication rate between the two groups, although readmission rates favoured hysterectomy. UAE was also cost-effective, with mean costs at one year being £1685 for UAE and £2566 for hysterectomy.

MRI guided percutaneous laser ablation:
This is carried out under local anaesthetic. Laser fibres are threaded through needles which are placed within the fibroid under MRI guidance. Thermal ablation of the fibroid is carried out with infra-red diode laser under real time imaging. Follow up at 12 months has shown a 40% reduction in fibroid volume. An alternative to MRI guided ablation is the laparoscopic placement of the laser fibres – thus avoiding the need for MRI equipment.

High intensity focused ultrasound:
This causes tissue necrosis through the use of high intensity ultrasound. A beam of 1.0 – 1.5 MHz is directed to the fibroid under MRI guidance. It has a good safety profile and causes less collateral damage than UAE. Further studies are needed to determine long term benefits.

Laparoscopic myolysis:
Laser, diathermy or cryotherapy has been used to coagulate myomata. It causes devascularisation of the fibroids. It should not be used in women wanting further pregnancies as there is a higher risk of uterine rupture due to devacularisation of the myometrium. There is also concern about the formation of bowel-uterine adhesions which may cause bowel obstruction.

Myomectomy:
Myomectomy can be done hysteroscopically, laparoscopically or by laparotomy.

Transcervical resection of fibroids:
Submucosal fibroids which are causing menorrhagia or are interfering with fertility may be resected hysteroscopically. Hysteroscopic myomectomy appears to be a satisfactory treatment, with low complication rates, particularly in women who wish to retain fertility.

Laparoscopic myomectomy can be used for intramural and subserous fibroids. There has been concern that the use of diathermy may predispose to a weaker scar which may rupture in subsequent pregnancy or labour. This risk is reduced by the use of high frequency ultrasound scissors and blades to minimise damage to the surrounding myometrium. Laparoscopic myomectomy is associated with lower morbidity rates, and less adhesion formation than open myomectomy (NICE), but with a much higher recurrence rate than open myomectomy – 50% vs 10%.

Open myomectomy
It is difficult to predict a straightforward myomectomy for subserosal or intramural fibroids. Pre-operative discussion with the patient should include the risk of intractable bleeding which may necessitate further intervention – up to and including hysterectomy.

Even if all goes well intra-operatively, there is always the risk of rebound intra-peritoneal bleeding, return of patient to the theatre, endomyometritis, haematometra, pyometra, bowel-to-uterine adhesions, urinary retention, total or segmental uterine necrosis, abdominal wound dehiscence, and in the long term, recurrence of the fibroids.

Intra-operative haemorrhage is reduced by pre-operative GnRH therapy, intra-operative use of compression clamps or tourniquet or very rarely, the injection of ultra-dilute Vasopressin.

NICE reports no significant difference in perioperative morbidity comparing abdominal myomectomy and elective hysterectomy but abdominal myomectomy was associated with less intraoperative blood loss and shorter hospital stay than hysterectomy. Open myomectomy may be the optimal route for multiple fibroids, for very large fibroids, and in cases where the uterine size precludes a laparoscopic approach.

Repeat myomectomy is associated with a higher perioperative morbidity (blood loss, adhesions, and fever) and poorer fertility than primary myomectomy, but is feasible.

Hysterectomy:
Because of their size, possible involvement of contiguous organs and haemorrhage risk, hysterectomy for uterine fibroids should not be undertaken lightly. Women should also be aware that even if the ovaries are retained there is a higher incidence of premature ovarian failure in women who have had hysterectomy. There is a need to have blood available, to have a General Surgeon within reach, and to warn the patient about possible modifications to the planned procedure.

It might be necessary to first perform a myomectomy as a de-bulking procedure, to enable better access. The ureters are at risk of inadvertent trauma because of the distorted pelvic anatomy, and the bladder may suffer an avulsion injury during downward blunt reflection of the utero-vesical peritoneum. Rarely, interventional radiologic procedures may be useful if haemorrhage is proving difficult to control. Long term complications include pelvic prolapsed and adhesions.

All this notwithstanding, hysterectomy may be the desire of some women – it is the only treatment for which there is no recurrence rate. It also protects against cervical and uterine malignancy.

Conservative management
Not all women want aggressive intervention. For many, the reassurance that this is not cancer may be all that they want. For some knowledge of growth, regression, malignant change and benign effects equips them with all they need. Given that in the vast majority of cases fibroids are not life-threatening, management should be first and foremost directed towards the woman’s quality of life, and all decisions should be undertaken with this proviso.

The management of uterine fibroids in other circumstances:
Fibroids in subfertility
It would seem that fibroids contribute to difficulties in conceiving when they distort the uterine cavity. A comparison of IVF pregnancy rates in women with untreated myomata showed no difference when the uterine cavity was not impacted by the fibroids, but a lower pregnancy rate when there was cavity distortion. The consensus is that the risks and implications of myomectomy are not justified in the treatment of subfertility unless the fibroids impact on the cavity.

Fibroids in pregnancy
In a study of 64,000 of women with complete obstetric follow up, 3.2% were found to have fibroids on a second trimester scan. The presence of fibroids on scan in the second trimester was associated with an increased risk of breech presentation at delivery, placenta praevia, placental abruption, caesarean delivery, preterm delivery and in-utero fetal death.

The number of fibroids does not appear to have an effect, whereas fibroids > 5cm diameter do. Fibroids do not universally increase in size during pregnancy – many remain the same size, and most shrink in the months following delivery. The remodelling of the uterus which occurs postpartum may have a therapeutic effect on fibroids, and explain some of the reduced incidence in parous women.

Conclusion
The spectrum of treatment options of uterine fibroids has widened over the past couple of decades. Considering the heterogeneous nature of the benign tumour, it is obvious that one solution may not fit all. Clinicians need to be cognisant of over-enthusiastic patient expectations: the only true cure of the uterine fibroid is a hysterectomy [but see above].

All options are associated with complications that range from the mild, to the irritating, and to the life-threatening. There is a need for further research into the long term benefits and risks of comparative treatment modalities. Until we know how to prevent the occurrence of uterine fibroids, we need to continually guide our patients towards realistic and safe treatments.

Acknowledgements
I am grateful to Dr Nicki On and Dr Rajesh Varma of the British Fibroid Trust [www.britishfibroidtrust.org.uk] for their kind permission for use of images from their website.

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