The natural history of fibroids

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1 Ultrasound Obstet Gynecol 20; 35: Published online 12 January 20 in Wiley InterScience ( DOI:.02/uog.7482 The natural history of fibroids D. MAVRELOS, J. BEN-NAGI, T. HOLLAND, W. HOO, J. NAFTALIN and D. JURKOVIC Gynaecology Diagnostic and Outpatient Treatment Unit, University College Hospital, London, UK KEYWORDS: benign tumor; fibroid volume; growth; intramural; submucous; subserous; ultrasound ABSTRACT INTRODUCTION Objectives Fibroids are common, hormone-dependent, benign uterine tumors. They can cause significant morbidity and the symptoms depend largely on their size. The aim of this study was to describe the natural history of fibroids and identify factors that may influence their growth. Methods This was a retrospective longitudinal study of premenopausal women who were diagnosed with uterine fibroids on ultrasound examination. All women underwent at least two transvaginal ultrasound scans, which were all performed by a single operator. Fibroids were measured in three perpendicular planes and the mean diameter was calculated. The size and position of every individual fibroid was assessed and recorded on a computerized database. The volume of each fibroid was calculated using the formula for a sphere. Results A total of 122 women were included in the study. Their median age at the initial examination was 40 (range, 27 45) years. Seventy-two (59.0%) were nulliparous and 74 (60.7%) had multiple fibroids. The median interval between the initial and final examination was 21.5 (range, 8 90) months. The median fibroid volume increased by 35.2% per year. Small fibroids (< 20 mm mean diameter) grew significantly faster than larger fibroids (P = 0.007). The median increase in size was significantly higher in cases of intramural fibroids (53.2 (interquartile range (IQR), )%) than in subserous fibroids (25.1 (IQR, )%) and submucous fibroids (22.8 (IQR, 1.7 to 48.3)%) (P = 0.012). Multivariate analysis retained only fibroid size at presentation as an independent predictor of fibroid growth. Conclusion The growth of fibroids in premenopausal women is influenced by the tumor s size at presentation. Copyright 20 ISUOG. Published by John Wiley & Sons, Ltd. Fibroids are the commonest benign uterine tumors and it is estimated that they occur in 20 40% of women during their reproductive years 1,2. They can cause a wide range of clinical symptoms such as heavy menstrual periods, pressure symptoms to surrounding organs and fertility problems 3. As a result, surgery for uterine fibroids is common, and in both the UK and USA fibroids are the primary indication for hysterectomy 4,5. However, in many women uterine fibroids are found incidentally on routine gynecological examination or on pelvic imaging performed for unrelated symptoms. Whether fibroids are symptomatic or not depends primarily on their size and on their position in relation to the uterine cavity 6. Although the definitive management of gynecological symptoms attributable to uterine fibroids is surgical removal, many women decline surgery or prefer to pursue medical management. The natural history of fibroids is poorly understood, which makes it difficult to advise asymptomatic women with fibroids on the risk of developing clinical symptoms in the future. It is well known, however, that fibroids are sensitive to circulating estrogens 7, which will either cause them to grow or to maintain their size. It is less clear whether the growth of fibroids is affected by factors other than ovarian steroid hormones. The aim of this retrospective study was to describe the natural history of uterine fibroids in premenopausal women and to identify demographic and morphological features that may influence their growth rate. METHODS We searched our ultrasound clinic database (PIA Fetal Database, version 3.23, Viewpoint Bildverarbeitung GmbH, Munich, Germany) to identify all women diagnosed with uterine fibroids between July 1997 and July We included only women who had been Correspondence to: Dr D. Jurkovic, Gynaecology Diagnostic and Outpatient Treatment Unit, University College Hospital, 235 Euston Road, London NW1 2BU, UK ( davor.jurkovic@uclh.nhs.uk) Accepted: 25 September 2009 Copyright 20 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

2 Natural history of fibroids 239 examined at least twice by a single expert ultrasound operator (D.J.) with a minimum interval of 8 months between the examinations. Additional inclusion criteria were: age at the time of initial examination, regular menstrual cycles lasting between 21 and 35 days, no use of any form of hormonal contraception or any other medication with a possible effect on ovarian hormone production and no previous surgery for fibroids. We excluded all women who fell pregnant during the interval between examinations and those who developed menstrual irregularities. In our practice we routinely record the indications for examination as well as demographic data and gynecological, obstetric and medical history. All scans are performed in a standardized fashion. First the cervix and uterine corpus are identified in the transverse plane. The uterine corpus is then assessed in a systematic way by examining a series of parallel scanning planes starting from the internal cervical os to the top of the uterine fundus. This facilitates the diagnosis of congenital and acquired uterine anomalies such as fibroids or adenomyosis. Fibroids are defined as distinct, wellcircumscribed heterogeneous lesions arising from the myometrium. Adenomyosis is defined as a cystic or diffuse, heterogeneous myometrial lesion with unclear borders 8. In ambiguous cases Doppler examination is used to assess uterine vascular architecture in order to facilitate the differential diagnosis 8. Each fibroid is examined individually to ascertain its size and position in relation to the uterine cavity. We classified as submucous those fibroids that distorted the endometrial cavity 9 ; fibroids confined mostly to the myometrium were described as intramural, whilst those protruding > 50% through the serosal surface of the uterus were classified as subserous. Each fibroid was measured in three perpendicular planes in the longitudinal and transverse views of the uterus. In women with large fibroids a transabdominal scan was also performed to ensure the accuracy of the measurements. Follow-up examinations were conducted in the same way. We did not routinely perform hydrosonography to assess the position of fibroids. Statistical analysis Only the largest fibroid for each woman was included in our analysis in order to ensure consistency of measurement during follow-up. We used the measurements as recorded in our database at the time of examination to calculate the mean diameter as d mean = (d 1 + d 2 + d 3 )/3. We calculated the volume of the largest fibroid using the formula for the volume of a sphere (V = 1/6 π d 3 ). Percent change in fibroid size (r) was calculated as r = ((V t2 V t1 )/V t1 ) 0% (where V t1 and V t2 are the volumes measured at times t1 and t2), and percentage yearly change in size (r y ) was calculated as r y = (r/interval in months) 12. We defined spontaneous regression as a 5% decrease in volume over 1 year. A database was created to facilitate data entry and retrieval (Excel 2003, Microsoft, Redmond, WA, USA). Data analysis was performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). We categorized women as under 35 years of age or aged 35 years or more to maintain consistency with published work 9. The normal distribution for fibroid volume and yearly percentile growth in fibroid volume was rejected (P = 0.001) and so non-parametric tests were used. The Mann Whitney rank-sum test was used to detect differences between the size at presentation and the final median volume of the largest fibroid as well as differences in fibroid growth rates between different age groups, parous and nulliparous women and women with a single and multiple fibroids. The Kruskal Wallis test was used to detect differences in fibroid growth between different fibroid positions and between different fibroid size classes. Multivariate linear regression analysis was used to detect predictive variables for yearly percentile fibroid growth rate. Variables included in the model were age, parity (categorical: 0; 1), fibroid number (categorical: 1 and > 1), fibroid position (categorical: subserous, intramural and submucous) and fibroid size (categorical: < 20 mm, mm and > 50 mm). RESULTS One hundred and seventy-eight women aged between 25 and 45 years who underwent two or more examinations by a single, expert operator were identified. Reasons for exclusion were: use of hormonal contraception during follow-up (n = 21); interval between the initial scan and follow-up scan was < 8 months (n = 16); became pregnant during follow-up (n = 9); irregular menstrual cycles during follow-up (n = 5); transcervical resection of submucous fibroids (n = 2); commenced on gonadotropin-releasing hormone analogs (n = 2); and started on tamoxifen (n = 1). The indications for examination in the 122 women who were included in the final data analysis are presented in Table 1. The median age at the initial scan was 40 (range, 27 45) years and 72 of the women (59.0%) were nulliparous. The median examination interval between the initial and final examination was 21.5 (range, 8 90) months and 74 women (60.7%) had multiple fibroids. Table 1 Indications for examination in the study population (n = 122) Indication for examination n (%) Heavy menstrual periods 43 (35.2) Suspected fibroids on clinical examination 30 (24.6) Pelvic pain 29 (23.8) Suspected ovarian cyst 8 (6.6) Infertility 4 (3.3) Screening for ovarian cancer 2 (1.6) Urinary frequency 2 (1.6) Other 4 (3.3) Total 122 (0.0)

3 240 Mavrelos et al. Women who presented with a suspicion of fibroids on clinical examination or menorrhagia had significantly larger fibroids (median, 13.8 (interquartile range (IQR), ) cm 3 ) than women presenting with pain or other symptoms (median, 1.6 (IQR, ) cm 3 ) (P < 0.001). During the study period the median volume of the largest fibroid increased from 9.9 (IQR, ) cm 3 at the initial examination to 12.0 (IQR, ) cm 3 at the final examination (P < 0.001). This corresponded to a median 35.2 (IQR, )% yearly increase in the volume of the largest fibroid. Fibroid growth rate demonstrated considerable variability, with 26 of 122 (21.3 (95% CI, )%) fibroids showing evidence of spontaneous regression (Figure 1). There was no significant difference in fibroid growth rate between women presenting with menorrhagia or a suspicion of Frequency Figure 1 Distribution of the growth rate of the largest fibroid with the normal distribution superimposed. fibroids on clinical examination compared with women with other initial complaints (P = 0.162). Fibroid volumes and growth rates according to patient and fibroid characteristics are summarized in Table 2. In women 35 years of age the volume of the largest fibroid grew by a median of 69.1 (IQR, )% in 1 year compared to a median of 29.8 (IQR, )% in women > 35 years of age (P = 0.113) (Figure 2a). There was no significant difference in fibroid growth rate between nulliparous and parous women (P = 0.827) or between women with a single and multiple tumors (P = 0.444). Fibroid position was significantly associated with fibroid growth rate. Intramural fibroids grew in volume by a median 53.2 (IQR, )% in 1 year compared with a median of 25.1 (IQR, )% for subserous fibroids and 22.8 (IQR, 1.7 to 48.3)% for submucous fibroids (P = 0.012) (Figure 2b). Fibroid size at presentation was also significantly associated with growth rate. Small fibroids (< 20 mm) and large fibroids (> 50 mm) demonstrated the fastest growth and grew by a median of 51.3 (IQR, )% and 40.7 (IQR, )% in 1 year, respectively. Intermediate fibroids (20 50 mm) demonstrated slower growth and grew by a median 16.8 (IQR, 7.4 to 63.0)% in 1 year (P = 0.007) (Figures 2c and 3). Multivariate analysis demonstrated that fibroid size at presentation is a significant independent predictor for fibroid growth rate (R 2 = 0.074, P = 0.0). The addition of fibroid position to the model does not significantly improve its performance ( R 2 = 0.022, P = 0.234) (Table 3). DISCUSSION Our study showed that in premenopasual women with uterine fibroids, the volume of the largest fibroid increases Table 2 Fibroid volume and growth rate according to patient and fibroid characteristics Volume (cm 3, median (interquartile range)) Patient/fibroid characteristics n At presentation Final Growth rate (% per year, median (interquartile range)) P Age years 26.5 (1.7 to 122.8) 21.2 (4.0 to 213.5) 69.1 (8.3 to 185.1) > 35 years (0.8 to 35.2) 9.2 (2.1 to 62.5) 29.8 (0.0 to 78.7) Parity (1.2 to 83.7) 14.4 (3.0 to 122.4) 27.3 (4.6 to 118.0) (0.9 to 28.3).7 (1.9 to 53.2) 40.1 (0.0 to 2.8) Fibroid number Single (0.5 to 18.1) 3.5 (1.0 to 23.6) 40.1 ( 2.9 to 137.8) Multiple (5.0 to 58.8) 23.1 (6.5 to 126.7) 29.8 (3.8 to 1.2) Fibroid position Submucous (8.8 to 62.8) 23.1 (4.2 to 9.3) 22.8 (1.7 to 48.3) Intramural (0.4 to 5.7) 3.5 (1.1 to 13.5) 53.2 (11.2 to 217.0) Subserous (4.4 to 94.4) 24.4 (5.4 to 137.2) 25.1 (1.1 to 87.1) Fibroid size at presentation < 20 mm (0.2 to 1.2) 1.5 (0.7 to 3.9) 51.3 (9.3 to 2.3) mm (9.9 to 29.5) 23.1 (9.2 to 56.7) 16.8 ( 7.4 to 63.0) > 50 mm (129.0 to 251.5) (192.6 to 368.9) 40.7 (14.1 to 67.0) Data are distributed non-parametrically.

4 Natural history of fibroids 241 (a) (b) (c) < Age group (years) 0 Submucous Intramural Subserous Fibroid position Size group (cm) > 5.0 Figure 2 Box plots showing yearly change in volume of the largest fibroid (logarithmic scale) by age group (a), fibroid position (b) and fibroid diameter at presentation (c). Median, upper and lower quartiles and range of each group are shown. Change in diameter (% per year) Fibroid diameter at presentation (cm) Figure 3 Scatter plot of change in diameter against fibroid diameter at presentation., Linear plot (R 2 = 0.01, P = 0.245);, cubic curve (R 2 = 0.18, P = 0.001). by a median of 35% per year. We found that the growth rate of fibroids shows considerable variability and, in contrast to traditional teaching, that up to one fifth of fibroids in premenopausal women may spontaneously regress. To date there are very few studies in the literature on the natural history of fibroids. Recently Peddada et al. 9,ina study of 262 fibroids in 72 women examined using magnetic resonance imaging (MRI), reported that the median growth rate for fibroids was 9% in 6 months and that the growth rate of individual fibroids was slower in women with multiple tumors. They also found that 7% of the fibroids in the study decreased in volume by more than 20% in 6 months and described these fibroids as regressing. In our dataset only 3% of the fibroids showed similar behavior. However, in our study approximately 40% of the participants had a single tumor, in contrast to those in the study of Peddada et al., more than 90% of whom had multiple fibroids. This difference in population and the Table 3 Results of multivariate analysis of the prediction of fibroid growth including fibroid size at presentation only (Step 1), and with the addition of fibroid position (Step 2) Beta t P R 2 Step 1 (Constant) Size at presentation mm > 50 mm Step 2 (Constant) Size at presentation mm > 50 mm Fibroid position Submucous Intramural Dependent variable: yearly fibroid growth, Step 1 R 2 = 0.074, R 2 = for Step 2 (P = 0.234). fact that we restricted our analysis to the largest fibroid in each woman may account for the differences in growth rate and proportion of regressing fibroids between the studies. We found only one other ultrasound study of the natural history of fibroids in the literature that of DeWaay et al., who in 2002 reported an average 1.2 cm increase in diameter per 2.5 years 6. However this study was based on a very small sample, 18 fibroids, and the change in mean fibroid diameter over the examination interval did not reach statistical significance. Our results suggest that a fibroid s size at the initial scan can be used to assess its potential to grow in the future. We found that fibroids measuring less than 20 mm andmorethan50mmindiameteratpresentationhave a growth rate up to three times higher than fibroids measuring mm in diameter. This is in contrast to the findings of Peddada et al. 9, who did not detect a significant difference in the growth rate between different sized fibroids. A limitation of their study, however, was that they only included women with at least one fibroid over 50 mm and that they could not measure accurately fibroids less than 15 mm in diameter. This may have led them to underestimate the effect of size on growth rate.

5 242 Mavrelos et al. Our results suggest that fibroids do not continue growing at a constant rate indefinitely, that is that fibroid growth is not linear despite a stable hormonal environment. It may be the case that fibroids start by growing quickly, and then growth slows once the tumor reaches a certain size. The maximum size might be determined by non-hormonal factors such as availability of blood supply to support fibroid growth. Interestingly, recent cytogenetic studies have demonstrated an association between fibroid mean diameter and fibroid karyotype. Rein et al. 11 and Hennig et al. 12 demonstrated, in histopathological specimens, that fibroids with a chromosome 12;14 translocation had significantly larger mean diameters (8 9 cm) than fibroids with chromosome 7 deletions (3 5 cm). Fibroids with a mosaic pattern were of intermediate diameter compared to abnormal non-mosaic fibroids, while those with apparently normal karyotype were the smallest in both studies. In addition to our finding about fibroid size at presentation, we also found that fibroids in different locations have significantly different growth rates. Intramural fibroids demonstrated the fastest growth followed by subserous and submucous fibroids. However, the myometrium is relatively thin and fibroids over mm are inevitably classified as subserous or submucous. Indeed in our study intramural fibroids were significantly smaller than subserous and submucous fibroids. The results of our multivariate analysis confirm that, while fibroid size independently influences growth rate, the association between position and growth rate is a reflection of the effect of size on growth rate rather than an independent effect of fibroid position. Women with fibroid-related symptoms (menorrhagia, clinically palpable tumor) had significantly higher median fibroid volume at presentation than women who presented for other reasons. Others have reported that fibroid size plays a pivotal role in fibroid symptomatology 13 and our results are in agreement with this. The prevalence of fibroids increases with age 5 and some have speculated that this increase in prevalence is due to accelerated fibroid growth in later life secondary to hormonal changes. Our results did not confirm this theory and if anything suggest that women over 35 tend to have slower fibroid growth rates, although this relationship did not reach statistical significance. A similar decline in fibroid growth rates with age in Caucasian women was recently reported by Peddada et al. 9 (who, as mentioned above, used MRI for their measurements). It is possible that the reported increased prevalence of fibroids in later life is due to a prolonged period of sustained growth rather than a tendency of fibroids to grow faster in older women. The heterogeneity in fibroid growth rate makes it difficult to make firm predictions about the behavior of individual fibroids. Indeed, a minority of fibroids in our study demonstrated evidence of spontaneous regression, which is an unexpected finding in premenopausal women. Until now fibroid regression had been assumed to occur only after the menopause secondary to the reduction in circulating ovarian steroids. DeWaay et al. 6 suggested that this regression is secondary to women being in the perimenopause, but our study included only women with regular menses, so this is an unlikely explanation. We also excluded any women on exogenous hormonal treatment, so we can speculate that individual fibroids may have regressed secondarily to local effects, such as a change in vascularity. Clearly further investigation into the characteristics of regressing fibroids is necessary. We conclude that fibroid growth is highly variable and women s age as well as tumor size at presentation can give an indication as to the likely course of the tumor s future development. Importantly, fibroids can regress spontaneously, even in premenopausal women, and therefore interventions should be planned only after a period of observation to establish tumor behavior in individual cases. REFERENCES 1. Ryan GL, Syrop CH, Van Voorhis BJ. Role, epidemiology, and natural history of benign uterine mass lesions. Clin Obstet Gynecol 2005; 48: Wallach EE, Vlahos NF. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 2004; 4: Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007; 87: Vessey MP, Villard-Mackintosh L, McPherson K, Coulter A, Yeates D. The epidemiology of hysterectomy: findings in a large cohort study. Br J Obstet Gynaecol 1992; 99: Marshall LM, Spiegelman D, Barbieri RL, Goldman MB, Manson JE, Colditz GA, Willett WC, Hunter DJ. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997; 90: DeWaay DJ, Syrop CH, Nygaard IE, Davis WA, Van Voorhis BJ. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002; 0: Blake RE. Leiomyomata uteri: hormonal and molecular determinants of growth. J Natl Med Assoc 2007; 99: Dueholm M. Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract Res Clin Obstet Gynaecol 2006; 20: Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, Semelka RC, Kowalik A, Armao D, Davis B, Baird DD. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci USA 2008; 5: Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 2003; 111: Rein MS, Powell WL, Walters FC, Weremowicz S, Cantor RM, Barbieri RL, Morton CC. Cytogenetic abnormalities in uterine myomas are associated with myoma size. Mol Hum Reprod 1998; 4: Hennig Y, Deichert U, Bonk U, Thode B, Bartnitzke S, Bullerdiek J. Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells. Mol Hum Reprod 1999; 5: Wegienka G, Baird DD, Hertz-Picciotto I, Harlow SD, Steege JF, Hill MC, Schectman JM, Hartmann KE. Self-reported heavy bleeding associated with uterine leiomyomata. Obstet Gynecol 2003; 1: