Is fibroid heterogeneity a significant issue for clinicians and researchers?

Reproductive BioMedicine Online (2013) 27, 64– 74

www.sciencedirect.com www.rbmonline.com

REVIEW

Is fibroid heterogeneity a significant issue for clinicians and researchers? Dong Zhao

a,b

, Peter AW Rogers

b,*

a Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, PR China; b Department of Obstetrics and Gynecology, University of Melbourne, Royal Women’s Hospital, Level 7, 20 Flemington Rd, Parkville, Melbourne, Victoria 3052, Australia

* Corresponding author. E-mail address: [email protected] (P AW Rogers). Dong Zhao is an associate professor of obstetrics and gynaecology at the department of minimally invasive gynecological surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. He is currently a visiting associate professor in the department of obstetrics and gynaecology of University of Melbourne studying the role of fibroblasts in the pathogenesis of uterine leiomyomata. His research concerns various benign gynaecological conditions: endometriosis, uterine leiomyomata and chronic pelvic pain.

Abstract The clinical and scientific literature overwhelmingly deals with fibroids as a single entity or disease. This convenient

assumption of homogeneity may be an important oversight given that substantial evidence exists for heterogeneity between fibroids at many levels. Failure to recognize and accommodate fibroid heterogeneity can have significant ramifications for both clinical treatment decisions and research protocol design. The aim of this article is to review the current knowledge of fibroid heterogeneity and to identify key areas where fibroid heterogeneity should be taken into consideration both clinically and when designing research protocols. Uterine leiomyomata display significant and well-documented heterogeneity in symptoms, diagnostic imaging appearance, pathology, genetic background and therapeutic requirements. Additional research is needed to better understand fibroid heterogeneity as it relates to pathogenesis, molecular targets for potential new therapies, patient symptoms and, ultimately, treatment. To this list should also be added heterogeneity of genetics, lifestyle and individual clinical characteristics of the fibroid. Increasingly, an understanding of uterine leiomyoma heterogeneity will be of importance for clinicians who see patients with this common and costly disease. RBMOnline ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: genetics, heterogeneity, pathogenesis, therapy, uterine leiomyoma

Introduction Uterine leiomyomata, or fibroids, are benign myometrial neoplasms that are typically enriched in extracellular matrix (Stewart, 2001). They are a common tumour, occurring in up to 77% of women of reproductive age (Cramer and

Patel, 1990). Among women of African descent, there is an even higher incidence (Baird et al., 2003; Marshall et al., 1997), with African Americans experiencing more severe symptoms, presenting with larger tumours and having a 3-fold higher risk of hysterectomy than American whites (Kjerulff et al., 1996).

1472-6483/$ - see front matter ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rbmo.2013.04.001

Heterogeneity of uterine leiomyomata Uterine leiomyomata are a significant cause of reproductive and gynaecological problems, including heavy menstrual bleeding, chronic pelvic pain, dysmenorrhoea, infertility, recurrent miscarriage, preterm delivery and post-partum haemorrhage (Flake et al., 2003; Stewart, 2001) Uterine fibroids are the primary indication for hysterectomy, with over 200,000 such procedures performed annually on US women (Farquhar and Steiner, 2002). Figures from the USA based on year 2000 data calculate an estimated annual direct healthcare cost for fibroids of US$ 2.15 billion (Flynn et al., 2006). There are approximately 400,000 new cases diagnosed each year for US women of all races aged 25–44 (Hartmann et al., 2006). The clinical and scientific literature overwhelmingly deals with fibroids as a single entity or disease. This convenient assumption of homogeneity may be an important oversight given that substantial evidence exists for heterogeneity between fibroids at many levels, including aetiology, symptoms and pathogenesis (Peddada et al., 2008; Walker and Stewart, 2005). Failure to recognize and accommodate fibroid heterogeneity can have significant ramifications for both clinical treatment decisions and research protocol design. This in turn will hinder progress in understanding the pathogenesis and developing new treatments for this common and costly disease. The aim of this article is to review current knowledge of fibroid heterogeneity and to identify key areas where fibroid heterogeneity should be taken into consideration both clinically and when designing research protocols.

Symptoms Uterine leiomyomata are asymptomatic in at least 50% of afflicted women (Divakar, 2008; Gupta et al., 2008; Levy, 2008), while other studies estimate that only 20–25% of women with leiomyomata are symptomatic (Babaknia et al., 1978; Buttram and Reiter, 1981; Cramer and Patel, 1990; Hunt and Wallach, 1974). Symptoms are more likely to occur with large fibroids, multiple fibroids or fibroids at specific locations and tend to alleviate after the menopause. The common symptoms of fibroids can be divided into three major categories: abnormal bleeding, pelvic pressure and pain, and problems with fertility and pregnancy.

Abnormal uterine bleeding Approximately 30% of women with leiomyomata have been reported to have menstrual abnormalities such as heavy menstrual bleeding and prolonged bleeding (Buttram and Reiter, 1981). Anaemia is often present in association with heavy menstrual bleeding. The incidence of heavy menstrual bleeding increases as women reach their perimenopausal years (Wilcox et al., 1994). It is difficult to determine whether heavy menstrual bleeding in perimenopausal patients is attributable to fibroids because at this time dysfunctional uterine bleeding also increases. To establish whether leiomyomata are the cause of heavy menstrual bleeding, the assessment of menstrual loss should ideally be objective, because patients may underestimate or overestimate their blood loss. Rybo et al. (1985) conducted an objective study and found that 40% of women

65 who bled greater than 200 ml each period had leiomyomata; in comparison, only 10% of those who bled 80–100 ml had leiomyomata. A population-based study by Marino et al. (2004) found no association between menstrual loss and uterine leiomyomata. Since around three-quarters of women over the age of 40–45 have leiomyomata and the majority of women are asymptomatic, it is likely the sample size would need to be much larger to see a difference in a population-based study. Increased uterine bleeding is often attributed to the encroachment of one or more submucosal leiomyomata (Bukulmez and Doody, 2006; Hickey and Farquhar, 2003; Kelly and Cullen, 1909). The review by Lumsden (1998) found that only 40% of those having a hysterectomy for heavy menstrual bleeding had submucosal leiomyomata. A randomized study suggested that non-submucosal leiomyomata were associated with essentially the same increase in heavy bleeding as submuscosal leiomyomata of similar size (Wegienka et al., 2003). This observation supports the idea that the mechanisms by which some leiomyomata cause heavy menstrual bleeding are complex and heterogeneous. Theories proposed to account for fibroid-related heavy menstrual bleeding include reduced myometrial contractility, increased endometrial surface area and dilated vessels overlying the leiomyomata (Farrer-Brown et al., 1970; Lefebvre et al., 2003), abnormal vessel structure (Buttram and Reiter, 1981; Farrer-Brown et al., 1971) and differential growth factor expression (Chandrasekhar et al., 1992; Harrison-Woolrych et al., 1994; Mangrulkar et al., 1995; Vollenhoven et al., 1993). Apart from heavy menstrual bleeding, prolonged vaginal bleeding is another common bleeding symptom, although relatively little has been published on this topic in relation to fibroids. Wegienka et al. (2003) did not find an association between the length of menstruation and leiomyomata. Other abnormal bleeding symptoms include frequent bleeding and intermenstrual bleeding or spotting.

Pressure symptoms and pain Leiomyomata of different locations may cause urinary frequency, urinary retention, ureteric obstruction or constipation (Gupta et al., 2008; Kelly and Cullen, 1909). However, there are very few reports that objectively evaluate the evidence for leiomyomata causing pressure symptoms (Farquhar et al., 2001). A pedunculated subserous leiomyomata may undergo torsion or a submucosal leiomyomata prolapse through the cervix may cause acute pain. Red degeneration in pregnancy can also be associated with pelvic pain, although another study failed to find correlation between symptoms and the histological finding of degeneration (Candiani et al., 1990). A population-based study also found no association between leiomyomata and dysmenorrhoea (Lippman et al., 2003). As for abnormal bleeding symptoms, there is significant heterogeneity in pressure and pain symptoms between fibroids, with the majority being asymptomatic.

Reproductive problems To date, there has been no randomized clinical trial to address whether leiomyomata are a cause of infertility

66 (Khaund and Lumsden, 2008; Lumsden and Wallace, 1998). Available data suggest uterine leiomyomata have different impacts on fertility depending on their location. A systemic review of the literature and meta-analysis indicated that fertility outcomes are decreased in women with submucosal fibroids, and removal seemed to confer benefit (Pritts et al., 2009). It has been reported that subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit (Pritts et al., 2009). Intramural fibroids appear to decrease fertility, but the results of therapy are unclear (Pritts et al., 2009). Submucosal fibroids had the strongest association with lower ongoing pregnancy rates. Patients with intramural fibroids also experienced more miscarriages (Klatsky et al., 2008). Other complications include premature rupture of membranes, placental abruption, fetal growth restriction, obstruction of labour and postpartum haemorrhage (Muram et al., 1980; Rice et al., 1989). For the majority of women, leiomyomata do not cause any problems during pregnancy. There have been few if any studies to date that have investigated why only a proportion of leiomyomata are symptomatic and the characteristics of symptom-causing fibroids. A large, preferably multicentre, study investigating the relationship between fibroid heterogeneity and clinical symptoms would make a major contribution to the field.

Diagnostic imaging The most common modalities used for imaging fibroids are ultrasound and magnetic resonance imaging. The diagnostic imaging of uterine leiomyomata displays well-documented heterogeneity. The image characteristics of leiomyomata depend on a number of factors, including proportion of extracellular matrix, amount of smooth muscle, blood supply and different types of degeneration. Further research is required before heterogeneity as demonstrated by diagnostic imaging can be translated into different clinical management strategies. Transvaginal ultrasound is the standard imaging modality for detection of uterine leiomyomata, especially in obese patients and those patients with a retroverted uterus (Caruso et al., 1998; Fleischer, 2003; Mendelson et al., 1988; Sladkevicius et al., 1995, 1996). Sonographic appearances of uterine leiomyomata range from hypoechoic to hyperechoic, depending on the amount of smooth muscle and connective tissue. Secondary changes, such as haemorrhagic, cystic or myxoid degeneration or calcification, display specific ultrasonographic patterns (Gross et al., 1983). The blood vessels that feed leiomyomata and the uterine blood flow patterns within them can be detected by colour Doppler ultrasound (Kurjak et al., 1992; Shimamoto et al., 1987), although the use of Doppler ultrasound has typically been limited to the research context rather than becoming part of routine clinical practice. During development of leiomyomata, the pre-existing blood vessels undergo regression (Walocha et al., 2003) and new vessels invade the tumour from the periphery, where intense angiogenesis, probably promoted by growth factors secreted by the tumour, leads to the formation of a ‘vascular capsule’ responsible for supply of blood to the growing tumour (Walocha et al., 2003). Significant heterogeneity exists in

D Zhao, PAW Rogers vascularity and blood flow between individual fibroids, as well as in the surrounding myometrium (Tsiligiannis et al., 2012). Whether these individual differences relate to menstrual blood loss volumes or other fibroid-related symptoms is unknown. Significant heterogeneity was also observed in fibroid and perifibroid echogenicity by B-mode ultrasound (Tsiligiannis et al., 2012). Similarly to sonographic images, magnetic resonance imaging signal intensities of leiomyomata at T2 and T1 depend on a number of different variables, including the amount of smooth muscle, connective tissue and possible degeneration (Ha et al., 1997; Murase et al., 1999; Swe et al., 1992). Leiomyomata free of degenerative changes give homogeneous signals of low intensity (Hricak et al., 1986). Various degenerative changes occur in approximately 65% of uterine leiomyomata. The presence of degenerative changes within leiomyomata can be predicted from magnetic resonance imaging by heterogenous signal intensity on T2-weighted images (Bazot et al., 2002; Ha et al., 1997; Ueda et al., 1999). Pretreatment magnetic resonance characteristics can predict treatment efficacy before gonadotrophin-releasing hormone (GnRH) agonist administration (Matsuno et al., 1999; Takahashi et al., 2001a; Yamashita et al., 1993), uterine embolization (Burn et al., 2000; Cura et al., 2006; Harman et al., 2006; Jha et al., 2000; Katsumori et al., 2008) or focused ultrasound thermal ablation (Lenard et al., 2008; Pilatou et al., 2009). To date, magnetic resonance imaging is the most accurate imaging technique for detection and localization of leiomyomata, and it also has a role in the treatment of leimyomata by assisting surgical planning and monitoring the response to medical therapy. A recent paper reported that magnetic resonance elastography appeared feasible for studying leiomyomata in uteri and demonstrated significant heterogeneity in elasticity between lesions (Stewart et al., 2010).

Pathology Uterine leiomyomata are typically intramural, less frequently submucosal or subserosal and rarely are found in the lower uterine segment or cervix. On low-power examination, classic leiomyomata are typically well circumscribed. They are composed of intersecting fascicles of cells with relatively abundant eosinophilic cytoplasm and elongated nuclei (Oliva, 2009). Degenerative changes are frequent and include ulceration, oedema, cyst formation, calcification and red degeneration (Oliva, 2009). There are different leiomyomata variants that can share one or more histological features with leiomyosarcoma, such as high cellularity, cytological atypia and increased mitotic activity (Oliva, 2009). At a histological and immunohistochemical level, significant heterogeneity can be evident both regionally within a fibroid and between fibroids.

Growth rate Few studies have examined the growth rate of leiomyomata in vivo over time. Tsuda et al. (1998) suggested that the vascularity of leiomyomata might be useful as a predictor of leiomyomata growth. DeWaay et al. (2002) found that

Heterogeneity of uterine leiomyomata smaller leiomyomata in older premenopausal women regressed whereas larger leiomyomata tended to grow while often remaining asymptomatic. Ichimura et al. (1998) showed that both the density and intensity of immunohistochemical staining of progesterone receptors in uterine leiomyomata tissue showed significant positive correlation with leiomyomata growth. Early in-vitro observations showed that leiomyomata cell proliferation in response to hormonal treatment was heterogeneous (Cramer et al., 1985). A detailed study of tumour growth in 72 premenopausal women with 262 uterine leiomyomata demonstrated that within the same woman leiomyomata often have different growth rates despite having a similar hormonal milieu. Each tumour appeared to have its own intrinsic growth rate. The majority of tumours grew less than 20% in 6 months. The median growth rate was 9%. Growth rates for tumours in younger white females were significantly faster than in older women (Peddada et al., 2008). At least two studies have investigated the growth of leiomyomata during pregnancy. A small prospective study found that 78% of leiomyomata had no increase in size during pregnancy and that only 22% increased in size but by no more than 25% of the initial volume. At 6 weeks post partum, the size of the fibroids did not differ significantly from the size during pregnancy (Aharoni et al., 1988). Another longitudinal study reported that increase in volume during pregnancy was observed in 31.6% of cases, with the greatest increase in volume occurring before the 10th week of gestation (Rosati et al., 1992).

Genetics Chromosomal and molecular analyses using X chromosome inactivation of glucose 6-phosphate dehydrogenase isoenzyme or androgen receptor CAG-repeat polymorphisms have provided evidence that each leiomyomata is an independent monoclonal growth (Hashimoto et al., 1995; Mashal et al., 1994; Townsend et al., 1970). Chromosomal translocation is a defect caused by rearrangement of parts between nonhomologous chromosomes. The varieties of chromosomal rearrangements predict different genetic pathologies and allow classification of leiomyomata into subgroups (Dal Cin et al., 1995; Heim et al., 1988; Hu and Surti, 1991). About 40% of leiomyomata exhibit karyotypically detectable chromosomal abnormalities, frequently involving chromosome 12 (Nilbert et al., 1988; Rein et al., 1991). Approximately 20% of karyotypically abnormal leiomyomata exhibit a rearrangement of 12q14q15. Translocations involving this chromosome have identified HMGA-2, a member of the high-mobility-group gene family of DNA architectural factors. HMGA-1 located at 6p21 rearrangements arise in less than 10% of karyotypically abnormal leiomyomata (Sornberger et al., 1999). Other genes identified include MORF (monocytic leukaemia zinc finger protein-related factor; Moore et al., 2004), DNA double-strand repair gene RAD51L1 (Takahashi et al., 2001b) and, most recently, cut-like homeobox1 (CUX1) on chromosomal band 7q22.1 (Schoenmakers et al., 2012). The remaining 60% of leiomyomata have no detectable chromosomal abnormality. Overall, chromosomal abnormalities

67 do not explain the majority of leiomyomata, unless a complex multifactorial pathogenesis is invoked. Several Mendelian syndromes, including Reed syndrome (uterine leiomyomata in association with multiple cutaneous leiomyomata; Garcia Muret et al., 1988; Reed et al., 1973; Ritzmann et al., 2006; Rongioletti et al., 2010), hereditary leiomyomatosis and renal cancer (HLRCC), tuberous sclerosis complex syndrome ((TSC) (Bayley et al., 2008; Gardie et al., 2011; Kiuru and Launonen, 2004) and Cowden syndrome (genitor-urinary tumours; Liaw et al., 1997) are associated with uterine leiomyomata. Fumarate hydratase gene mutations were found to be the cause of Reed syndrome and HLRCC (Alam et al., 2001; Launonen et al., 2001; Tomlinson et al., 2002). Many sporadic human leiomyomata exhibit loss of function of the TSC2 gene product tuberin (Wei et al., 2005). Those Mendelian syndromes with a uterine leiomyomata component are heterogenous. CYP1A1 polymorphism is reported to be associated with uterine leiomyomata (El-Shennawy et al., 2011; Herr et al., 2006; Ye et al., 2008). A meta-analysis revealed an association of CYP17A1 polymorphism with some uterine leiomyomata but not all of them (Pakiz et al., 2010–2011). Another study suggested that CYP17 polymorphism is unlikely to be associated with an increased risk of uterine leiomyomata in the Brazilian population (Tsujino et al., 2006; Vieira et al., 2008). Oestrogen receptor a polymorphisms have been reported to correlate with the occurrence of uterine leiomyomata in Asian and black women (Al-Hendy and Salama, 2006b; Hsieh et al., 2003; Kitawaki et al., 2001), but not in Caucasian women (Denschlag et al., 2006; Massart et al., 2001, 2003). Oestrogen receptor b polymorphisms are not associated with the development of uterine leiomyomata (Fischer et al., 2010; Zhai et al., 2009). The progesterone receptor polymorphic variant PROGINS is not a predisposing marker for uterine leiomyomata; on the contrary, it might be protective (Gomes et al., 2007; Govindan et al., 2007). The androgen receptor trinucleotide CAG-repeat polymorphism is reported to be associated with leiomyomata susceptibility in Chinese and Indian populations (Hsieh et al., 2004; Shaik et al., 2009). Polymorphisms in DNA repair genes XRCC1 and XRCC4 are reported to be associated with increased risk of uterine leiomyomata (Hsieh et al., 2008a; Jeon et al., 2005; Yang et al., 2010). Contradictory evidence also exists (Hsieh et al., 2009). Studies suggested that certain cytokine gene polymorphisms, especially for interleukin 4, tumour necrosis factor a and interleukin 1b, may be associated with increased risk for development of uterine leiomyomata (Pietrowski et al., 2009; Sosna et al., 2010). The catechol-O-methyltransferase polymorphism is a risk factor for the development of uterine leiomyomata in different ethnic groups (Al-Hendy and Salama, 2006a; de Oliveira et al., 2008). Other gene polymorphisms reported to be associated with susceptibility include P53 (Denschlag et al., 2005; Hsieh et al., 2007), vascular endothelial growth factor (Hsieh et al., 2008b), matrix metalloproteinases 1 and 9 (Takemura et al., 2006) and hydroxysteroid (17b) dehydrogenase 1 (Cong et al., 2012). Micro-RNA whose expression have been shown to be significantly altered in leiomyomata compared with the myometrium are the let-7 family, miR-17, miR-21, miR-23b,

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miR-29b, miR-34a, miR-26a, miR-18a miR-125b, miR-139, miR-155, miR-206, miR-181a and miR-142–5p. These are believed to target the expression of many genes including ovarian steroid receptors, transforming growth factor b and its receptors and several pro-inflammatory and immune-related genes (Bartel, 2004; Bi et al., 2009). Taken together, current evidence suggests that molecular and genetic markers associated with fibroids differ in different ethnic populations (Pan et al., 2007; Wang et al., 2007; Wei et al., 2006) and that the pathogenetic mechanisms underlying uterine leiomyomata are heterogeneous. It seems likely that this genetic heterogeneity contributes to the dramatic clinical heterogeneity seen in uterine leiomyomata.

Therapy The treatment modalities for uterine leiomyomata include expectant management, medical therapy, uterine artery embolization, high-intensity focused ultrasound (HIFU) and surgery. For decades, myomectomy and hysterectomy have been the one-size-fits-all solution for uterine leiomyomata. Hysterectomy appears to be more cost-effective than uterine artery embolization for management of symptomatic uterine fibroids over a 5-year period (You et al., 2009). However, women having hysterectomies because of myoma-related symptoms have significantly worse scores on SF-36 quality-of-life questionnaires than do women diagnosed with hypertension, heart disease, chronic lung disease or arthritis (Rowe et al., 1999). In addition, a rare complication, parasitic myomata, may be iatrogenically created after laparoscopic surgery, particularly surgery using morcellation techniques (Cucinella et al., 2011; Epstein et al., 2009; Larrain et al., 2010; Sinha et al., 2007; Yanazume et al., 2012). The gynaecological resectoscope was approved by the FDA for the treatment of abnormal uterine bleeding in 1980s. To date, hysteroscopic resection currently represents the standard minimally invasive surgical procedure for treating submucous fibroids. The most widely used system categorizes the myomata into three subtypes according to the proportion of the lesion’s diameter that is within the myometrium, usually as determined by saline infusion sonography or hysteroscopy. The European Society of Gynecological Endoscopy classification of submucous leiymyomata

Table 1 European Society of Gynecological Endoscopy classification of submucous myomata. Type

Characteristics

0

Entirely within endometrial cavity No myometrial extension (pedunculated) <50% myometrial extension (sessile) <90-degree angle between myoma surface to uterine wall 50% myometrial extension (sessile) 90-degree angle between myoma surface to uterine wall

I

II

(Table 1) was modified from Wamsteker et al. (1993). In general, submucous myomata (types 0, 1 and 2) up to 4–5 cm in diameter can be removed under hysteroscopic direction by experienced surgeons, whereas larger and multiple myomata are best removed abdominally. Type 2 myomata are more likely to require a multistaged procedure than types 0 and 1 (Fraser et al., 2007; Lasmar et al., 2005; Vercellini et al., 1999). The utility of the levonorgestrel-releasing intrauterine system, tranexamic acid and other medical interventions for heavy menstrual bleeding associated with submucous leiomyomata will remain unclear pending the design and implementation of studies that distinguish between abnormal bleeding associated with submucous myomata and myomata that do not involve the endometrial cavity (Lukes et al., 2010; Magalhaes et al., 2007; Soysal and Soysal, 2005; Zapata et al., 2010). For women with heavy menstrual bleeding who are not interested in future fertility and have selected type 1 and perhaps type 2 submucous myomata, generally 3 cm or less in diameter, endometrial ablation appears to confer a high degree of success, at least in the short term. At the present time, there is inadequate evidence to suggest that one device or technique, such as resectoscopic ablation, is clearly more efficacious than another. Uterine artery embolization was first introduced as a measure to control uterine bleeding and it is associated with improvement of symptoms in above 80% of women (Cooper et al., 2012; Freed and Spies, 2010; Pisco et al., 2009). Although pregnancy is possible after embolization, existing data suggest better reproductive outcomes following myomectomy (Goldberg and Pereira, 2006; Holub et al., 2008; Usadi and Marshburn, 2007; Walker and McDowell, 2006). HIFU provides a noninvasive modality to treat uterine leiomyomata. HIFU ablation of uterine fibroids improves with increased treatment cell size, independent of other significant contributors such as distance of ultrasound propagation or signal intensity of the tumour on T2-weighted MR imaging (Kim et al., 2011). It has been reported that 79.3% of women showed a significant improvement in a follow-up health-related quality-of-life questionnaire (Hindley et al., 2004). Another study carried out in the USA found no major complications after HIFU treatment (Tempany et al., 2003). Recent studies also indicate that HIFU ablation is a safe and effective treatment for fibroids (Dorenberg et al., 2012; Voogt et al., 2011; Wang et al., 2012). Adverse effects associated with HIFU treatment were noted in 563 out of 5526 patients (10.19%). The most frequent adverse effects were burn (2.44%), haematuria (2.88%), nerve injury (3.06%) and severe or prolonged abdominal pain (1.66%) Yu and Luo, 2011). As yet there are no approved medical therapies for the long-term treatment of symptomatic uterine leiomyomata. The only FDA-approved medical therapy is GnRH agonist used preoperatively. However, the use of GnRH agonists is associated with menopausal side effects that limit therapy. Following GnRH agonist treatment, the fibroid will rapidly regrow if not removed surgically. Selective oestrogen-receptor modulators have been shown to induce fibroid regression in post- but not premenopausal women (Palomba et al., 2005), but there is no evidence from a limited number of studies that selective oestrogen-receptor modulators

Heterogeneity of uterine leiomyomata reduce the size of fibroids or improve clinical outcomes (Deng et al., 2012). In a study using selective progesterone-receptor modulators, a multicentre, randomized, controlled, phase-2 clinical trial reported that asoprisnil suppressed uterine bleeding in 28%, 64% and 83% of subjects at 5, 10 and 25 mg, respectively, and reduced leiomyomata and uterine volumes (Chwalisz et al., 2007). To date, the overall clinical data suggest that selective progesterone-receptor modulators have the potential to reduce the number of hysterectomies and other surgical procedures in women with symptomatic leiomyomata. Individualization is of key importance in the treatment decision-making process and should incorporate the woman’s health and quality of life priorities. Individualized treatment should be based on the best available prognosis for each fibroid, which in turn depends increasingly on an understanding of the heterogeneity of fibroids. While considerable research is still required, the ability to scan or blood test a woman and determine whether a small fibroid is of a type that is fast growing and likely to cause significant symptoms such that aggressive treatment should be considered would be a tremendous advance. In some instances, for example those patients with multiple uterine leiomyomata who bear the FH mutation, it is already of importance to make a timely diagnosis so that affected individuals and families can undergo potentially life-saving regular prophylactic screening for renal tumours. Ultimately, most fibroids do not cause symptoms and can be left untreated.

Conclusions Uterine leiomyomata display significant and well-documented heterogeneity in symptoms, diagnostic imaging appearance, pathology, genetic background and therapeutic requirements. Additional research is needed to better understand fibroid heterogeneity as it relates to pathogenesis, molecular targets for potential new therapies, patient symptoms and, ultimately, treatment. To this list should also be added heterogeneity of genetics, lifestyle and individual clinical characteristics of the fibroid. Increasingly, an understanding of uterine leiomyoma heterogeneity will be of importance for clinicians who see patients with this common and costly disease.

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D Zhao, PAW Rogers Declaration: The authors report no financial or commercial conflicts of interest. Received 18 December 2012; refereed 17 March 2013; accepted 2 April 2013.