Multiple benign fibroids.
Large fibroid uterus 20 weeks size on physical exam 0700.
Leiomyoma are the most common tumor in women,[2] and the leading indication for hysterectomy in the United States.[3] They are responsible for one-third of all hospital admissions, with symptoms ranging from pelvic pressure and pain to severe menorrhagia requiring transfusion. Fibroids are larger in African-American women, and occur at a younger age. This racial difference, like most of the racial disparities in medicine, is as yet inexplicable. They are more common in African-America women, and have lifetime prevalence of 80% in African-American women, as compare to 70% in Caucasian women by age 50.[4] A difference of 10% may not seem very discrepant; however, African-American women suffer a disproportionate effect from these tumors, including size at presentation, growth, and symptoms.[5] The health-care costs associated with fibroids are staggering, and the annual cost to treat this condition is estimated to be $5.9 billion–$34.4 billion.[6] In the United States, as more preventive services are covered through the Affordable Care Act (ACA), it is a natural assumption that more fibroid tumors will be diagnosed. The prudent practitioner needs to consider cost-effective and evidenced based treatment.
Fibroids are uncommon in any women before 20 years of age. The prevalence of uterine leiomyoma in women aged more than 35 years is 20%, while the prevalence increases to 51.2%–60.0% in women aged 40–50 years.[7] The incidence is noted to be the same in pre- and postmenopausal women, but the average number and size of the lesions tend to be much more significant in premenopausal women. Multiple studies have shown that despite the number estimated during the preoperative diagnosis of fibroids, the total number of fibroids found in pathological samples is consistently far greater than expected. This calls into question the ability to ever remove all the leiomyoma present on a uterus in the process of a myomectomy.
Genetics
Some characteristics of leiomyoma would seem to indicate that there is a genetic link to the disease. For example, patients with uterine leiomyoma often have a positive family history of uterine leiomyoma, with a particular correlation being noted between first-degree relatives.[8] A small subset of patients has also been noted who seem to exhibit a strong predisposition to developing profusely disseminated leiomyoma in conjunction with renal cell carcinoma. This syndrome is collectively labeled leimyomatosis and renal cell carcinoma syndrome and has been noted to have an autosomal dominant inheritance pattern. Research in this group of patients has led to the discovery of a loss of function mutation in the fumarate hydratase gene that results in loss of suppression of leiomyoma formation.[9, 10] However no specific genetic syndromes have been identified that accounts for the development of uterine fibroids alone, and even in familial settings, their occurrence seems to be multifactorial.
From a cytogenetic perspective, most leiomyoma are chromosomally normal. However, about 40%–50% of leiomyoma show karyotypically detectable chromosomal abnormalities which are most often not random, and specific to that tumor. Recent studies of the molecular genetics of leiomyoma have suggested that the process of chromothripsis (chromosomal breakage and reformation) is the key for the etiology of the fibroid tumor.[11] Additional further research on the topic has yielded the knowledge that location of leiomyoma with reference to the endometrial lining may have a relationship to the presence of cytogenetic abnormalities. One study suggested submucous myomas consistently had fewer cytogenetic abnormalities relative to intramural and subserosal fibroids. The quoted rates were 12%, 35%, and 29%, respectively.[12]
Classifications of fibroids
Leiomyoma are traditionally classified based on their anatomic location relative to the endometrial lining or serosa of the uterus, and the direction of their growth. Subserosal leiomyoma grow out of myocytes that are directly adjacent to the serosal layer of the uterus and often protrude or bulge from the surface of the uterus. Often these may become parasitic, attaching to nearby structures and harvesting from their vascular supply. Intramural leiomyoma are nestled into the myometrium of the uterus. Submucosal leiomyoma, also termed intracavitary leiomyoma, impinge on the endometrial lining of the uterus. Pedunculated fibroids may be located on the serosal layer or be classifiably submucosal; in either case they have a stalk or pedicle as the base from which they protrude. The European Society of Hysteroscopy posits a different classification of leiomyoma, born more out of utility, and based on the percentage of the fibroid located within the myometrium. Type 0 leiomyoma are located entirely within the uterine cavity (intracavitary), type 1 leiomyoma are 50% buried into the myometrium (or 50% extending into the intramural space), and type 2 leiomyoma are less than 50% buried in the myometrium (or greater than 50% extending into the intramural space).[3] This classification system helps to predict the likelihood of successful resection by hysteroscopic methods. Reports indicate as much as 95% success rate retrospectively, in populations where the great majority of leiomyoma were type 2.[13]
History
Treatment of leiomyoma constitutes a significant realm of gynecologic care. In fact, in the years 1998–2005, up to 27% of gynecologic related admissions to hospitals were due to symptoms related to uterine leiomyoma.[14] The clinician must therefore take care to obtain a good history on any patient presenting with symptoms which may be indicative of uterine leiomyomas, as this will guide the workup and help to avoid the use of costly and redundant studies. Additionally, thorough history taking will allow the clinician to discern the urgency of treatment, and appropriately counsel the patient about treatment options.
The most common complaint of women who have symptoms from leiomyoma is abnormal uterine bleeding; thus a careful menstrual and bleeding history is key in the ambulatory gynecologic visit. The most frequent complaints are prolonged menstrual bleeding, heavier menstrual bleeds, and more painful periods. Most women still maintain the cyclic predictability of their menstrual bleeding, but as symptoms worsen this often becomes difficult as bleeding episodes may go on for more than a month, or occur multiple times per month. Menorrhagia is defined as over 80 cc of blood loss per menstrual cycle. Up to 10% of women with menorrhagia and up to 40% of women with more severe menorrhagia have fibroids.[15] It is intuitive that the larger the fibroids and hence the uterine size, the more likely the patient is to be symptomatic. It is a common clinical misperception that submucous fibroids cause more bleeding. Studies suggest that submucous fibroids are more common in women with large fibroid uterus, but it is unclear if the actual submucos fibroids themselves cause more bleeding.[16]
Pelvic pressure is also a common complaint as the leiomyoma increase in size and begin to weigh down the uterus or impinge on other pelvic structures. A significant number of women may also complain of urinary frequency and incontinence as leiomyoma begin to press on the bladder. Additionally, some may complain of chronic constipation or changes in bowel habits. These symptoms are related to the bulk of the fibroids, and usually indicate fairly large tumors. In cases of extremely large leiomyoma, the uterus may become elevated above the pelvic brim. This causes the uterus to be an abdominal organ. These women often report increased sense of abdominal pressure, bloating and increasing abdominal girth. In uteri that extend to above the umbilicus (20-week sized or greater), early satiety may be a symptom as pressure is applied to the greater curvature of the stomach.
It is also important to note that many women with leiomyoma are asymptomatic. They become aware of their fibroids in the process of being evaluated for other complaints, most commonly pelvic pain. The end result is that they tend to attribute their pelvic pain to the presence of fibroids. In reality, pain is a quite uncommon symptom of benign leiomyoma, occurring only in the settings of torsion, prolapse of the fibroid, when there is impingement of the fibroid on other pelvic structures, or when there is degeneration of the fibroid. Degeneration refers to the replacement of the muscle fibers in the tumor by various degenerative substances, and usually occurs after infarction or some other trigger of necrosis. The type of degeneration is based on the substance replacing the muscle fiber and may be fatty, carneous/red, hyaline, calcific, cystic, or myxoid.[17]
A history of recurrent pregnancy loss or infertility may be a sign of leiomyoma, particularly submucosal fibroids. The usual findings in these scenarios are fibroids which are located near and block the corneal openings, or which severely distort the endometrium creating difficulty with sperm transport or causing inflammation or vascular changes which may lead to abnormal placentation and subsequent pregnancy wastage.[18]
Physical exam
The physical exam is just as important, if not more important, than the history. Before ultrasound technology became ubiquitous, the diagnosis of leiomyoma was dependent on the clinician’s exam. The clinician’s assessment of the pelvis is often just as informative as imaging. For asymptomatic patients, the use of imaging is likely to be incidental and only beneficial in documenting the presence, location and size of the leiomyoma for future monitoring. A good bimanual exam is the most essential first step to the physical exam. This should include gauging the size of the uterus in weeks of gestational age or grams, assessment of the positioning of the uterus (midline versus lateral) and the flexion and or version of the uterus. Assessment of the shape and texture of the uterus and assessment of uterine mobility should be undertaken (Table 23-1). The usual findings include and enlarged uterus with irregularities in shape or contour. Additionally, a well-trained clinician will recognize the value of clinical pelvimetry in assessing the patient. Knowing the width and depth of the pelvic inlet and outlet with respect to the fibroid uterus can help guide the counseling regarding options and allow for an informed decision to be made with respect to treatment options.
| Uterine flexion | Shape/texture | Uterine mobility |
|---|---|---|
| Anteflexed | Elongated | Fixed |
| Anteverted | Wide | Freely mobile |
| Retroflexed | Heterogonous | |
| Retroverted | Globular |
Workup
When leiomyoma are suspected, a comprehensive differential diagnosis should be considered. In addition to fibroids, the following diagnosis should be entertained; uterine polys, endometrial hyperplasia or cancer, cervicitis, cervical dysplasia or cancer, anovulation, thyroid dysfunction, or perimenopausal bleeding. A basic workup should start with a blood count to discern the presence or absence of anemia. Additional lab tests ordered must be tailored to demonstrated symptoms. An endometrial sampling may also be indicated and should be performed liberally, especially if the heavy bleeding occurs in women with risk factors for endometrial hyperplasia such as obesity, chronic anovulation, and metabolic syndrome.
Pelvic ultrasound is generally the first imaging modality employed in women who complain of any pelvic symptoms. The utility of ultrasound in diagnosing uterine fibroids is limited and should be used in conjunction with interpretation of clinical presentation and the physical exam. The main utility is in deciphering the location of uterine leiomyoma and qualifying their appearance, especially in women who present with acute pain syndromes. Fever and elevated white blood cell counts may be indicative of a degenerating leiomyoma.[19] Each class of degenerating leiomyoma has a distinctive echogenicity pattern on ultrasound, with cystic and calciferous degenerations being the most sonographically distinctive. Calcifications have been noted to be hyperechoic and may be stippled throughout the body of the tumor, or rim the edges. Both cystic and myxoid degeneration may take on the appearance of multiple hypoechoic areas scattered throughout the body of the tumor.[20]
Saline infused sonohysterography may be employed as a diagnostic technique in any woman who presents with abnormal bleeding. This will help to define the texture and shape of the uterine cavity, elucidating polyps, submucosal leiomyoma, synechiae, or congenital malformations of the uterine cavity such as the presence of septa or multiple horns.[21] This method of evaluation may be performed concurrently with an endometrial biopsy to help rule out malignancy, particularly in obese patients and those over the age of 35, or with a Hysterosalpingogram to rule out tubal occlusion in women who present with complaints of infertility.
Computed tomography (CT) imaging is often the initial modality used to work up abdominal pain and indeed is how many uterine fibroids are brought initially to the attention of the gynecologist. However, the ability to differentiate the source of what is almost always reported as a “pelvic mass” is by ultrasound follow-up or magnetic resonance imaging (MRI). MRI has been shown to be more specific in terms of pinpointing the size, number, and location of leiomyoma when compared to other imaging modalities, especially in obese patients.[22] It is particularly important in differentiating changes in tissue texture that can help to define the origin of a mass as ovarian, versus, uterine, versus gastrointestinal and may help point the clinician in the direction of other diagnoses such as adenomyosis.
Treatment
As the growth of leiomyoma is dependent on estrogen and progesterone production, many treatment modalities focus on hormonal agents to offer symptom relief. Continuous estrogen exposure is believed to be the most important underlying risk factor in the development of leiomyoma, with most growth occurring in the reproductive years and cessation of growth with regression of ovarian estrogen secretion. This chapter will confine discussion of treatment options to nonsurgical approaches.
Oral contraceptive pills (OCPs) and nonsteroidal anti-inflammatory agents (NSAIDs) are often offered as first-line therapy for the treatment of fibroids. Data is mixed on the efficiency of either of these therapeutic agents in terms of treatment of leiomyoma. OCPs do an excellent job in control of irregular menses; however, there is no clear data on their efficacy in the treatment of fibroids. NSAIDs are useful in the treatment of menorrhagia, but the evidence suggests they are less effective on the treatment of menorrhagia associated with fibroids. A small randomized controlled trial (RCT), which only included 25 patients total (11 of whom had fibroids), demonstrated that in the presence of fibroids, NSAIDs were not efficacious on the treatment of menorrhagia.[23] As evidence for the benefit of either of these two agents is limited, one must utilize these agents with caution if the therapeutic intent is symptom reduction from leiomyoma.
Gonadotropin-releasing hormone analogues (GnRH agonists) have been proven with several RCTs to reduce both the size and the total volume of the leiomyoma.[24] This medication works by suppressing gonadotropin release, thus suppressing ovarian release of estrogen and progesterone. This therapy can cause a decrease in the patient’s bleeding symptoms, which in turn will correct anemia. The biggest drawback to this therapy is the hormonal withdrawn symptoms. Side effects such as bone loss, hot flushes, vaginal dryness, and mood changes can cause this agent to be discontinued. These side effects restrict the use for a maximum six-month course. Add back hormones, most commonly in the form of a low dose OCP, can be utilized to control symptom relief. This therapy is especially useful in perimenopausal women, as it can shrink the size of her leiomyoma and control some symptoms until natural menopause occurs. These tumors naturally shrink postmenopausal, when the patient’s endogenous ovarian steroid production of hormones declines.
The progesterone intrauterine device (IUD) has an indication for the treatment of menorrhagia. Its efficacy in reducing bleeding while providing contraception makes this agent a good therapeutic choice for women.[25] A comprehensive systematic review article concluded that the progesterone IUD will reduce the amount of menorrhagia in women with fibroids. However, expulsion rates may be higher in women with large fibroids or women whose fibroids may distort the uterus.[26, 27] Counseling the patient to recognize signs of IUD dislodgment or use of a postinsertion IUD may help mitigate this complication. Additional care must be taken upon insertion into a uterus with a distorted cavity to avoid uterine perforation.
Mifepristone, or RU-486, is classified as selective progesterone receptor modulators (SPRM), or anti-progesterone on the uterus. This agent has been studied in the treatment of fibroids, and has shown to have clinical efficacy rates similar to the GnRH agonists.[28, 29] These agents reduce the size of the fibroids, but not the actual uterine volume. In addition they reduce bleeding symptoms associated with fibroids and increase the hemoglobin levels in women taking this medication. Widespread use has been somewhat limited by high rates of side effects, including elevation in liver function tests and stimulation of the endometrial lining. Additionally, commercial availability is limited and often necessitates a compounding pharmacy dosing for the treatment of fibroids. This fact alone has limited the widespread use of this agent.
Another commercially available SPRM is very promising. Ulipristal acetate is available as post-coital contraception; it works by blocking the progesterone receptor, thereby delaying or inhibiting ovulation. In leiomyoma cell culture, these agents have actual proapoptotic effects. Additionally, they thin the endometrial lining, which induces amenorrhea. These actions have created an agent that appears to be efficacious and well tolerated in the treatment of fibroid tumors.[30, 31] They are currently under consideration for approval for label use in the treatment of fibroid tumors. These agents are as efficacious in treatment of bleeding and induction of amenorrhea as Lupron but are better tolerated (Table 23-2).
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