Classification

Leiomyomas are a heterogeneous disease process. Multiple methods have been proposed to classify fibroids that would account for both clinical significance and epidemiologic uniformity. The most commonly used system of classification, classifies fibroids in comparison to the uterine layers: submucosal, intramural, and subserosal [16]. Submucosal, refers to the region that is below the endothelium, the term is actually a misnomer as the uterus does not contain any mucosal tissue, the term “subendothelial” would be more accurate [17]. Intramural fibroids are those that do not distort the endometrial cavity and <50% protrusion into the serosal surface. Subserosal are then defined as those with >50% protrusion into the serosal surface [18]. Classification for submucosal fibroids has been further subdivided to allow for greater clinical significance. The ESHRE/ESGE classification system further subdivides submucosal fibroids into three categories. Type 0 are >90% within the uterine cavity and are also called pedunculated or intra‐cavitary. Type I are sessile submucosal fibroids that are >50% in the cavity, and type II are <50% in the cavity [19]. A more detailed classification system known as the STEP W system, that includes fibroid size, location, and depth of invasion has been proposed with the goal of more accurately predicting the success of treatment [20, 21]. This new system has not gained widespread acceptance. There is currently no widely used or universally accepted classification system that takes into account location, size, and number of fibroids.

Etiology

The etiology of fibroids is not well understood, and rather than a single disease process, there appear to be at least two types of fibroids: genetic or common (sporadic) fibroids. The best characterized cause of genetic fibroids in both North America and Europe, are those due to hereditary leiomyomatosis and renal cell carcinoma (HLRCC). These cellular fibroids are associated with fumarate hydratase gene mutations and more severe disease [22–24]. For fibroids not related to HLRCC, a genetic predisposition seems likely, as there is high racial correlation and first degree relatives of women with fibroids have a 2.5 times greater risk of developing fibroids themselves [25]. Genetic studies of fibroid tissue have shown mutations that increase the HOX gene, catechol‐o‐methyltransferase (COMT) expression, and lower retinoic acid [26–28]. Karyotype studies of the tumors themselves show that up to 40% of fibroids have at least one anomaly [29]. It should also be noted that as fibroids are monoclonal neoplasms, and within one uterus, each may have a different genotype.

Fibroids are hormonally responsive, sensitive to both estrogen and progesterone, and thus different physiologic states that effect or change the hormonal milieu may affect fibroid growth [12]. Early menarche, nulliparity, and elevated BMI are associated with higher levels of estrogen and are also associated with increased risk of fibroid disease [5, 30]. Fibroids express much higher levels of aromatase within them, creating a microenvironment with supra‐physiologic estrogen levels; the levels of fibroid aromatase compared to normal myometrium are 38‐fold higher in white women and 83‐fold higher in black women [31]. Estrogen has traditionally been viewed as the primary cause of fibroid proliferation and growth, however it is now clear that without progesterone, estrogens do not cause fibroid growth or even maintenance of fibroid size [32]. Furthermore, lack of estrogen in the presence of progesterone does not lead to fibroid regression. Progesterone antagonists cause shrinkage of fibroid tissue [33–35].

The inciting event for fibroid development may be related to inflammatory and hyperplastic processes. It appears that seedling fibroids develop in areas of myometrial hyperplasia (MMH) and disordered collagen, and afterword become neoplastic [36, 37]. Myometrial smooth muscle cells (MSMCs) can react in different ways to inflammation, and fibroids cells, which communicate via autocrine and paracrine pathways, contain all markers of inflammation including cyclo‐oxygenase and lipo‐oxygenase [38]. Fibroids have fewer progenitor/stem cells [39] and lower levels of anti‐fibrotic factors such as vitamin D3 [40]. It has been suggested that certain risk factors for fibroids may be the source of the inciting inflammation or irritation of MSMC. Hypertension, more specifically diastolic hypertension increases the risk by 24% of symptomatic fibroids, this correlation was also incremental or graded in that for every 10 mmHg increase in BP there was an 8–10% increase in risk of fibroids [41]. It is postulated that this relationship arises from myometrial injury or cytokine release due to hypertension. Studies have linked fibroids to infections of smooth muscle such as Chagas’ disease [42].

Fibroids are very dynamic and it has become apparent that every fibroid behaves differently. A recent longitudinal study that followed fibroid growth with serial MRIs reported there was an overall growth of 9% over a six month period for fibroids. However fibroid growth patterns could be further classified: 34% were rapidly growing (>20% increase in size over 6 m) and 7% were spontaneously regressing (> decrease in size over 6 m). Interestingly, even individual fibroids in the same patient behaved independently, showing that factors other than circulating hormone levels drive fibroid growth. Additionally, the study found that in white women over age 45, growth slowed to 2%; however this was not the case for black women at the same age, had an average fibroid growth rate of 15% in six months [13]. Studies assessing fibroid growth and regression relating to pregnancy found that pregnancy eliminated 36% of fibroids and 72% had >50% fibroid regression [34]. In summary, while fibroids tend to grow over time, within one uterus each may behave differently, and some will shrink, especially post‐partum.

Diagnosis

While clinical history and physical exam are always crucial to the assessment of fibroids, imaging studies are key for proper diagnosis and treatment. Fibroids can be evaluated with many different imaging modalities, each with its own sensitivity, convenience, and cost. The most widely used and generally readily accessible method is ultrasound. This method is limited by its inability to fully assess a fibroids relationship to endometrium, distinguish adenomyosis from myometrial contractions from fibroids, and ovarian or adnexal masses from pedunculated fibroids. Saline infusion sonograms, with or without 3D technology, are able to articulate the endometrial surfaces and more clearly define the nature of submucosal fibroids. Hysterosalpingograms are only able to indirectly characterize the endometrial cavity, but have the advantage of showing tubal status or patency, which may be effected by fibroids or other sources. MRI is now the method of choice as it is able to delineate a fibroid’s proximity to other tissues including endometrium, bowel, and bladder. MRI is also able to distinguish adenomyosis, atypical cellular fibroids, sarcoma, and degenerating fibroids [43]. Historically, CT scans were used to assess the relationship of fibroids to surrounding organs or vessels; this modality is rarely used if MRI ultrasound is available. Surgical pathology remains the only method to definitively diagnose fibroids (see Figure 7.1, which shows ultrasound).

Evidence‐based approach to clinical management

Uterine fibroids can present with a multitude of clinical scenarios that stem from their differences in size, location, and number. The management of fibroids is thus based on the clinical signs and symptoms with which they present.

Vaginal bleeding is the most common complaint associated with fibroids. It is clear that fibroids are the source of abnormal uterine bleeding for many women, however no study has been able to correlate with it specific fibroid characteristics and predict with accuracy which fibroids will cause bleeding [10]. Submucosal and large fibroids >5 cm both increase the risk for abnormal bleeding [44]. The major cause of this bleeding is abnormal endometrium in the area around the fibroid. Other potential sources include the increased endometrial surface area [45], local endometrial atrophy [46], and global changes in the endometrium related to altered expression of the HOX gene [47]. Consistent with these findings is the increasing likelihood of global endometrial changes and glandular atrophy observed with large fibroids beginning at 4 cm, with 100% correlation by 8 cm [48]. Even those fibroids that do not physically distort the endometrial cavity but are within 5 mm of the cavity are likely to cause endometrial changes [46].

Pressure or pain from the fibroids is also a common presenting complaint. It is not uncommon for fibroids to grow to well over 20 cm in height or 10 cm in width. Additionally they can be found abutting the bladder anteriorly and the rectum posteriorly. Fibroids can cause urinary frequency, incontinence, and even renal failure by compressing the ureters. Posterior fibroids can cause constipation, obstruction, and diarrhea. As fibroids age, they may become calcified and hard, exhibiting greater pressure on their surrounding tissue. A degenerating or twisting pedunculated fibroid can cause sudden onset and severe pain [49]. Women with fibroids were twice as likely to report severe non‐cyclic pelvic pain (95% CI 0.9–7.6), although only a trend as the difference detected was not statistically significant [50, 51]. Of women undergoing hysterectomy for fibroid disease, black women are more likely to have severe pelvic pain, 59% vs. 40% for white women [52]. Cyclic pain or dysmenorrhea is not associated with fibroids [50, 51].

Dyspareunia is strongly associated with fibroids as patients with known fibroids were 40% more likely to have mild and 80% more likely to have severe dyspareunia when compared to their non‐fibroid counterparts (95% CI 0.9–8.3), although again, only a trend but not statistically significant [50]. Anterior fibroids were more likely to cause deep dyspareunia than those in other locations [53].

Evidence‐based pregnancy outcomes related to fibroids

Fibroids can affect pregnancy from preconception to the post‐partum period (see Tables 7.1 and 7.2). They can cause infertility by obstructing fallopian tubes and impaired gamete transport [54]. As stated above fibroids cause both focal and global changes in the endometrium, altering its physiologic receptivity and its physical shape. Besides being hormonally sensitive, fibroids are also hormone generating. They can change the local hormone milieu and create a hyper‐estrogenic environment, which can be inhospitable to an embryo; this is aside from the changes in HOX gene expression [55]. The clinical role of fibroids, and the characteristics of those fibroids that effect pregnancy rates and outcomes has been extensively studied. However, many studies lacked appropriate control groups or uniform study methods and thus the results are often contradictory [55]. Recently there have been a series of meta‐analyses that summarize the evidence. In 2001, a meta‐analysis concluded that women with fibroids had a relative risk (RR) of 1.7 for a spontaneous abortion after clinical pregnancy, the study also showed these patients had decreased RR, 0.7, for live births. These risks could have been secondary to the significantly worse prognosis for submucosal fibroids that had a RR of 0.36 for clinical pregnancy and 0.32 for live birth when compared to their normal counterparts [56]. To elucidate and further classify the risk, a more recent meta‐analysis was performed that showed intramural fibroids decreased pregnancy rates, RR 0.8, and increased spontaneous abortion rates, RR 1.7 [57]. Both of these meta‐analyses contained data from assisted reproductive technology (ART) cycles and spontaneous pregnancies. An Italian study focusing on women undergoing ART reported that the odds ratio for women with submucosal fibroids was 0.3 for both clinical pregnancy and live birth. For women with intramural fibroids the odds ratios were 0.8 for clinical pregnancy and 0.7 for live birth, respectively, when compared to the unaffected controls. The study also confirmed earlier evidence that subserosal fibroids were not correlated with decreased ART success rates [58]. The reduced pregnancy rates of women with intramural fibroids can be further divided by size. Those women with intramural fibroids that are greater than 4 cm had pregnancy rates of 12%, while those with smaller fibroids had pregnancy rates of 30%, similar to the general population [59].

	Submucosal	Intramural	Large (>4–5 cm)	Small (<4–5 cm)	Subserosal
Pregnancy rate	a	b		Depends on location	–
Live birth rate	a	b	–	–	–

Decreased risk.

Decreased risk, by more than 50%.

– No significant difference.

^a Risk is removed if the fibroid is removed and returns are not significantly different from counterparts without fibroids.

^b Risk does not change with removal of these fibroids.

	Submucosal	Intramural	Large (>4–5 cm)	Small (<4–5 cm)
Preterm labor	No clear evidence a	No clear evidence a		–
Cesarean section		No clear evidence a	Evidence contradict: No dif vs.	–
Post‐partum hemorrhage	No clear evidence a	No clear evidence a	OR 1.8	–

Increased risk.

Increased risk, more than 200%.

– No significant difference.

^a Studies are small, inconclusive, or contradictory.

After clinical pregnancy is established there are further risks associated with fibroids (see Table 7.2). Although it was commonly believed that fibroids were risk factors for many adverse obstetrical outcomes, there were few data to confirm these suspicions. As high‐quality obstetric ultrasound became more frequently used, the data have consistently shown adverse outcomes associated with fibroids. Early studies showed that women with even one fibroid were about twice as likely to have cesarean section, 23% vs. 12% [60]. The study did not mention the indication for the cesarean sections, but it could have been impacted by an almost fourfold increased risk of malpresentation associated with submucosal fibroids [61]. More recent studies have confirmed a similarly increased risk of cesarean section in women with fibroids, but have also found a 1.5–2.5 fold increased risk of preterm delivery, almost sevenfold increase risk of preterm premature rupture of membranes (PPROM), 4.5 fold increased risk of short cervix, and increased risk of post‐partum hemorrhage with a greater than 10‐fold increased risk of receiving a blood transfusion [62–64]. Early evidence showed that the location of the fibroid with relation to the placenta was paramount in determining risk in pregnancy, while overall size played a less significant role [65]. More recent studies have confirmed that the risk of preterm labor is increased when the placenta is directly overlying the fibroid, or if there are multiple fibroids evident [61]. During pregnancy as many as 20% of women with known fibroids will have clinical evidence of fibroid degeneration, 50% of which will be confirmed with ultrasound [66]. Fortunately, for those women with fibroids that are able to conceive, carry the fetus to term and deliver, there is a high rate of fibroid resolution or shrinkage post‐partum secondary to myometrial remodeling, hormonal flux, and uterine involution [12, 34].

Quantitative measures of fibroid disease

The ability to accurately qualify and quantify in an objective, replicable, and analytical system the symptoms of fibroid disease is crucial to any accurate and therefore meaningful epidemiologic, diagnostic, or therapeutic analysis or study. Many systems have been used and most focus on just one aspect of the disease.

For vaginal bleeding alkaline hematin (AH) is the gold standard. Alkaline hematin has been used as marker or quantitative correlate of hemoglobin since the 1940s. A method of extracting the substance from sanitary napkins for measuring menstrual blood loss has been in use in the US since the 1970s. This method is limited by the use of only specific sanitary napkins from which the alkaline hematin can be removed and specific labs with the capabilities of measuring the alkaline hematin. This method is prohibitively laborious and expensive. Thus, the pictorial blood loss assessment chart (PBAC) was created to simplify, using pictures, the assessment of menstrual blood loss. The PBAC system takes into account the degree to which each item of a sanitary napkin is soiled with blood as well as the total number of pads or tampons used. The system has an 80% sensitivity and specificity as a diagnostic test for menorrhagia, using alkaline hematin as the control. Since its advent in 1990, it has been used frequently as a qualitative and quantitative marker of menorrhagia, however alkaline hematin remains the gold standard [67].

To assess the bulk symptoms of fibroids The Medical Outcomes Study Short‐Form 36 (SF‐36) Health Survey was often applied. This 36‐item self‐administered questionnaire assesses eight categories of pain: physical function, physical role limitations, vitality, general health perceptions, bodily pain, social function, emotional role limitations, and mental health. The SF‐36 has been used extensively as an indicator of health‐related quality of life, and its reliability and validity are well documented [68]. Although the SF‐36 had been well validated and extensively used in many disciplines including gynecology, it was not designed to assess for the specific somatic complaints and pain that can be related to fibroids.

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