Figure 1.1
Laparotomic hysterectomy for a giant myomatosic uterus that reaches almost up to the diaphragm
Nowadays, well-designed ultrasound screening studies (Fig. 1.2) are expected to provide the most reliable information on fibroid’s true prevalence [7].
Figure 1.2
A transvaginal ultrasonographic scan showing a uterus with a posterior large fibroid of 9 cm in diameter
Despite paucity of the studies investigating epidemiological factors associated with fibroid onset and growth , not all the risk factors are fully defined and understood yet. Risk factors linked with fibroid formation include age, race, body mass index (BMI), heritage, reproductive factors, sex hormones, obesity, hypertension, and diabetes. Moreover, environmental and lifestyle factors such as diet, caffeine and alcohol consumption, smoking, physical activity, and stress have also been investigated as possible impact factors in fibroid development [1].
In spite of being a benign disease, uterine fibroids represent an immense health burden throughout the world, requiring more research in epidemiology, particularly in terms of modifiable risk factors and these that possibly represent new drugs for fibroid treatment.
Epidemiological studies clearly indicate that risk of fibroid formation is increasing throughout women’s reproductive age, while their frequency decreases with menopause [1, 7]. In line with these observations, clinical reports’ data indicate that incidence of symptomatic fibroids, requiring treatment, is the highest in perimenopausal years [1].
Fibroids are mostly frequent in the black race, indisputably, with up to three times greater incidence in blacks in comparison with whites [7]. Furthermore, black women are affected in younger age, more frequently with multiple fibroids and having more pronounced symptoms than other ethnic groups [1, 6]. Thus, rates of hospitalizations for fibroids are also higher for black women, and they have longer hospital stays and higher medical costs per day [7]. In these, treated by abdominal myomectomy (Fig. 1.3), both blood transfusion and postoperative complication rates are higher [6]. Fibroid growth rates in premenopausal years are also higher in black women, compared to white [7]. In African-Americans, the mean percentage of European ancestry has been documented to be associated with younger age in affected women [1]. Data on fibroid frequency in a younger woman come from reports on early pregnancy screening. Laughlin et al. [8] estimated, by ultrasound, fibroid incidence throughout various ethnic groups in the first trimester of pregnancy as follows: 18% in black women, 10% in Hispanic women, 8% in white women, and 13% in “others,” consisting mostly of Asian women. Possible reasons for this observation might be differences in biosynthesis and/or metabolism of estrogens, receptor-associated factors, and genetic factors. Furthermore, different races exhibit diverse lifestyle habits, including dietary habits, and are documented to be exposed to various levels of stress [1, 9]. Nevertheless, clear causes for the observed ethnic variations are not fully understood yet.
Figure 1.3
A laparotomic myomectomy, with a removal of a large fibroid of 12 cm in diameter
Fibroid formation risk is clearly associated with numerous reproductive factors by both hormonal and non-hormonal mechanisms [7]. These include early age at menarche, less term pregnancies, lower parity, older age in last term pregnancy, and shorter time since last birth, while data on breastfeeding are still contradictory [1, 7]. Pregnancies that did not reach term seem to be unrelated to fibroid risk [7].
Association of both endogenous and exogenous hormones and fibroid development has been widely investigated, with conflicting results in terms of some of these. Fibroids occur exclusively during a woman’s reproductive period, thus confirming their dependence of ovarian steroid hormones. Importance of estrogen and progesterone in fibroid formation and development has been confirmed both by experimental and clinical research [1]. In comparison with normal myometrium, fibroid cells have increased expression of steroid hormone and growth factor receptors, mostly regulated by estrogens [7]. Nevertheless, the exact mechanism on how estrogen and progesterone trigger fibroid formation is still unclear. Epidemiological studies indicated early menarche as one of the risk factors for fibroid onset and growth. Polycystic ovary syndrome is also positively associated with fibroids, indicating elevated levels of luteinizing hormone (LH) and insulin-like growth factor I (IGF-I), insulin resistance, and hyperandrogenism as possible causes for this observation [1].
Despite paucity of studies’ relationship between myomas and oral contraceptive (OC) use, epidemiological data on it are still controversial, showing either absent or reduced risk of fibroid formation. Furthermore, there is a question of possible detection bias, as OC users may be undergoing gynecological exams more often than general population. Research conducted in the USA in African-American women failed to document the influence of both ingredients and hormonal strength of OC on fibroid occurrence, while the age of first OC use was associated with a slightly higher risk [1, 7]. The same study documented a lower risk in current users of progestin-only injectable. Data on duration of the OC use are also inconsistent [7]. Clear data on relationship between fibroids and use of levonorgestrel intrauterine contraceptive device are still missing [1]. Hormone replacement therapy after menopause is associated with fibroid growth, both in women using estrogens only and in those using combined therapy [7]. Moreover, exogenous hormones in food, like so-called phytoestrogens and those of artificial origin, possibly also enhance fibroid risk [1]. Fibroid formation risk is also increased in women prenatally exposed to diethylstilbestrol [7].
Some researchers indicated increased fibroid risk in obese women. A tween cohort study from Finland showed increased fibroid risk associated with higher body mass index (BMI), while an Italian study failed to document an association [1]. The possible explanatory mechanism for this observation might be increased levels of circulating estrogens, due to aromatization of androgens in fatty tissue [1]. The contributing factor in such cases is decreased production of sex hormone-binding globulin in the liver of obese women, causing increased bioavailability of both estrogens and androgens [1]. However, most of the circulating estrogens in premenopausal women originate from ovaries. A study from the USA revealed an inverse J-shaped pattern between BMI and fibroid risk, which appeared to be dependent on parity, extent of obesity, and detection bias. The relationship between BMI in obese women and fibroids has been found to be stronger in surgical cases [1].
Investigated lifestyle risks include diet, caffeine and alcohol consumption, smoking, physical activity, and stress. Due to numerous biases and confounding factors, results on dietary factors and fibroid occurrence are inconclusive. Nevertheless, a number of dietary factors have been documented to contribute to the growth of symptomatic fibroids. Food with higher glycemic index increases the fibroid risk, while data on soy food are still under investigation [1]. Fibroid incidence is increased in women having diet rich in red meat and dark meat fish, while it is decreased in those consuming a diet rich in fruit and vegetables [1, 7]. Particularly, intake of citrus fruits is in a strong inverse relationship with fibroid onset risk [1, 10].
Data on micronutrients , such as vitamins A, C, and E, as well as folate intake and fibroid risk, are still limited, while hypovitaminosis D is considered to be an important risk factor for fibroid formation, particularly pronounced in blacks [1, 11]. Experimental data indicate that 1,25-dihidroxyvitamin D inhibits fibroid growth [1, 10]. Fibroid risk is lower in both blacks and whites with sufficient vitamin D levels. Furthermore, fibroid cells express reduced levels of vitamin D receptors in comparison with normal myometrium [11]. Moreover, vitamin D is considered to be a potential regulator of fibroid growth, which requires further investigation as a potential candidate for treatment of uterine fibroids, as vitamin D analogs could represent a potential medical treatment option for fibroids [11]. Carotenoids found in many fruits and vegetables are strong antioxidants, out of which lycopene is the most potent. Experimental studies in animals documented that lycopene-supplemented diets reduce the number and size of fibroids in laboratory animals in a dose-dependent manner, while data from large USA epidemiological studies, both in blacks and whites, showed no associations between carotenoid intake and fibroid risk [1, 7, 10]. Diary consumption is found to be associated with reduced fibroid risk [8]. Data on intake of soy food are still inconclusive [1]. Some animal studies demonstrated an inhibitory effect of green tea extract gallactocatehin gallate on fibroid cell proliferation, but these substance effects require more research [1]. While coffee and caffeine consumption do not seem to influence the fibroid risk, alcohol intake increases it [1].
Given that these risk factors for myoma formation are modifiable, they require more research. Literature data on smoking are inconsistent [1]. Very few studies investigated the association of stress and physical activity and the risk of fibroid formation, and relevant data are mostly lacking. The risk is reduced in women who take physical exercise [1]. Stress has been recently demonstrated to be a potential risk factor as it possibly increases estrogen and progesterone levels [1, 7]. Furthermore, stress influences various health-related habits which possibly promote fibroid formation, both in terms of physical activity and dietary behavior.
Arterial hypertension and diabetes mellitus are also investigated in association with fibroid risk by several researches [1]. Several studies documented a positive association between fibroids and arterial hypertension [7]. A study from the Netherlands demonstrated that women with surgically treated uterine fibroids have greater hypertension risk, independent of common risk factors [12]. Moreover, authors suggested that women with fibroids are eligible for hypertension screening. The exact nature of association between high blood pressure and fibroids is not clear, as it is yet unknown if it is caused by detection bias or shared etiology. Data from the USA studies conducted in both blacks and whites found an inverse association between diabetes and fibroid formation, probably due to systemic vascular dysfunction in women with diabetes [1]. On the other hand, hypertension is considered to be a risk factor for fibroid formation [1].
Since the last century, uterine injury caused by either infection or irritation is postulated to be a possible risk factor for fibroid onset [1]. The expression of vascular endothelial growth factor-A , which is important for tumor growth and cell proliferation, is higher in fibroids than in normal endometrium [7]. In line with this are results on the positive association among use of perineal talc and Chagas disease and fibroid risk. Moreover, the relation between pelvic inflammatory disease (PID) episodes and surgically diagnosed fibroids has also been documented [1].
Data on environmental contaminants , such as phthalates, lead, mercury, and cadmium, and risk of fibroid formation are scarce. They could possibly be influential through various mechanisms, including endocrine disruption [7].
Pathogenesis of Uterine Fibroids
Uterine fibroids are thought to be monoclonal uterine mass that occurs via clonal expansion from a single mutated myometrial smooth muscle stem cell [13].
In the recent years, significant progress has been made in our understanding of fibroid tumorigenesis. A current model suggests that a distinct stem/reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP) , is responsible to sustain proliferation and tumor growth [14].
Hormones have been considered as the major promoter of fibroid growth. In addition, several pathogenic factors such as genetics, microRNA, growth factors, cytokines, and chemokines have a role in the fibroid development and growth [15].
The fibroid mechanical properties are another key feature of these benign tumors that may contribute to their growth. Fibroids are in fact stiff tumors characterized by an excessive deposition of disordered extracellular matrix (ECM) components, particularly collagen I, III, and IV, proteoglycans, and fibronectin [15].
Matrix metalloproteinases (MMPs) are implicated in fibroid remodeling with a higher activity of MMP-2 in fibroids than in surrounding myometrium [16].
Fibroids are also surrounded by a thin fibro-neurovascular pseudocapsule, which separates fibroids from normal peripheral myometrium (Fig. 1.4).
Figure 1.4
A uterine fibroid surrounded by a thin fibro-neurovascular structure of a few millimeters, the myoma pseudocapsule, taken with the anatomical forceps; it separates the fibroid from the normal peripheral myometrium
This means that the tumor microenvironment may greatly influence tumor growth and proliferation [17]. Uterine fibroid is a multifactorial and still enigmatic pathology. The genetic background seems to play an important role, with cytogenetic anomalies observed in about 40% of uterine fibroids. Abnormal ECM expression, increased growth factors, cytokine and chemokine concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine fibroids. Estrogens may exert their growth stimulatory effects on such tumors through the action of a complex network of cytokines, growth factors, or apoptosis factors and through different cellular mechanisms [18].
Biochemical and clinical studies also suggested that progesterone, progestin, and progesterone receptors (PR-A and PR-B) might increase proliferative activity in fibroids by enhancing the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNF alpha, Bcl-2 proteins) [19].
Uterine fibroid cells typically show a high expression of cell-cycle regulator and anti-apoptotic proteins. This can trigger tumor growth and make cells resistant to apoptosis [20].
Lora and collaborators demonstrated that the ratio between PR-A and PR-B is similar in normal myometrium and fibroids, while p53 and p21 mRNA and protein levels are increased in fibroids [21].
Matsuo and collaborators showed that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in fibroids compared with normal myometrium [22]. In this study, Bcl-2 protein expression in fibroid cells was upregulated by progesterone but downregulated by estradiol. The same group reported upregulation of expression of proliferating cell nuclear antigen (PCNA) in fibroids by progesterone and estradiol [22].
Wang and collaborators showed that protein and mRNA expression of bFGF and T-cadherin in uterine fibroid were present with significantly higher expression than that in adjacent normal myometrium and control normal myometrium. In addition, T-cadherin correlated well with bFGF. There was a relationship between T-cadherin and color Doppler flow imaging (CDFI) [23].
Data from genomic and proteomic studies demonstrated that many of the differences in fibroid’s gene expression observed in the two ethnic groups might be attributed to differences in myometrial gene expression, as well as differences in fibroids vs. myometrium. Moreover, functional analysis of microarray and proteomic data revealed that many of the observed differences may be attributed to molecules with a role as transcriptional, translational, and signal transduction mediators, cell cycle and EMC regulators, cell-cell adhesion, and metabolic regulators. The current approach to diagnosis and treatment should evolve in the future and consider women with a greater genomic risk.
Somatic mutations involving the gene encoding the mediator complex subunit 12 (MED12) and the gene encoding the high-mobility group AT-hook 2 (HMGA2) are known to be associated to fibroids.
Mäkinen and collaborators [24] found that approximately 70% of fibroids contained heterozygous somatic mutations that affect MED12, a gene located on the X chromosome. Authors described that all mutations resided in exon 2 (codon 44), suggesting that aberrant function of this region of MED12 contributes to tumorigenesis. Moreover, they also performed a pathway analysis, comparing eight tumors positive for MED12 mutations with their respective normal tissues. Three pathways were found to be substantially altered in the tumors, namely, focal adhesion, extracellular matrix receptor interaction, and Wnt signaling pathways. This suggests that MED12 mutations contribute to tumor development by altering specific cellular pathways [25].
MED12 belongs to a family of evolutionarily conserved transcriptional factors (mediator) that promote the assembly, activation, and regeneration of transcription complexes on core promoters during the initiation and reinitiation phases of transcription [26].
In detail, this gene codifies for a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. It is a subunit of the “kinase” module of the mediator complex, which also contains MED13, CYCLIN C, and Cyclin-dependent kinase 8 (CDK8).
It was also observed that activation of ERK signaling by MED12 suppression may confer resistance to tyrosine kinase inhibitors including crizotinib, gefitinib, vemurafenib, selumetinib, and sorafenib, thus providing a link between suppression of MED12 and drug resistance [27].
As demonstrated by Mäkinen and collaborators, MED12 mutations alone are sufficient for driving tumor development. Authors analyzed whole exome sequencing data of 27 uterine fibroids (12 MED12 mutation-negative and 15 MED12 mutation-positive) and their paired normal myometrium. They searched for genes, which would be recurrently mutated. No such genes were identified in MED12 mutation-negative uterine fibroids as well as MED12 mutation-positive fibroids. These results highlight the unique role of MED12 mutations in genesis of uterine fibroids [28].
Although fibroids are believed to be chromosomally rather stable, cytogenetic rearrangements have been detected in 40–50% of fibroids. Studies found translocation between chromosomes 12 and 14, trisomy 12, translocation between chromosomes 6 and 10, and deletion of chromosomes 3 and 7, with multiple candidate genes [27].
Several signaling pathways are activated in uterine fibroids. The role of the wingless-type (Wnt) pathway in supporting tumor initiation of fibroids is well demonstrated. The Wnt pathway could mediate molecular and cellular mechanisms involved in tumor initiation. Wnt acts as a paracrine signal from estrogen/progesterone receptor-rich mature cells to activate the canonical β-catenin pathway in fibroid stem cells to stimulate self-renewal and proliferation, eventually leading to tumor growth [29].
Other studies have demonstrated a central role for the phosphoinositide 3-kinase–protein kinase B/AKT (PI3K/AKT) pathway leading to the activation of mammalian target of rapamycin (mTOR) in the pathogenesis of fibroids [30].
Histopathological Aspects of Uterine Fibroids
As abovementioned, uterine fibroid is a benign tumor that originates from the uterine smooth muscle and grossly appears as round, well-circumscribed (but not encapsulated), solid nodules (Fig. 1.5) that are white or tan and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size, from a few millimeters to over 20 cm in diameter, felt by the patient herself through the abdominal wall.
Figure 1.5
The fibromatosis of the uterus transversally incised after its removal, showing an inner uterine fibroid appearing as round, well-circumscribed white solid nodules
Growth and location are the main factors that determine if a fibroid leads to symptoms and problems, so in uterine fibroids placing is very important to evaluate its clinical or surgical treatment.
As the traditional reported classification of fibroids, these tumors can be subserous, intramural, submucosal, or cervical.
Intramural fibroids are located within the wall of the uterus (Fig. 1.6) and are the most common type; unless large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity (Fig. 1.7).
Figure 1.6
A transvaginal ultrasonographic scan showing an antevert uterus, with a uterine body intramural fibroid of 2 cm
Figure 1.7
A transvaginal ultrasonographic scan showing a uterus with a fundal fibroid of 5 cm in diameter, causing distortion of the uterine cavity
Subserosal fibroids are located underneath the peritoneal surface of the uterus (Fig. 1.8) and can become very large. They can also grow out in a papillary manner to become pedunculated fibroids (Fig. 1.9).
Figure 1.8
A transvaginal ultrasonographic scan showing a uterus with a posterior subserosal uterine body fibroid of 2.5 cm in diameter, located underneath the peritoneal surface of the uterus
Figure 1.9
A laparotomic myomectomy of a fundal mitotically active pedunculated fibroid of 10 cm in diameter; fibroma expresses a highly irregular surface, is of mixed consistency (soft and hard), and grew up in the patient in less than a year
These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma (Fig. 1.10).
Figure 1.10
A rare image, taken during transversal suprapubic laparotomy, of parasitic uterine fibroid of 4 cm in diameter, grew up in the rectus abdominis muscle. The patient was operated with two previous myomectomies, after which he suffered pain and a palpable mass in the abdomen area
Submucosal fibroids are located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility (Fig. 1.11).
Figure 1.11
A hysteroscopic image of a small submucosal G0 fibroid; these fibroids, even small of diameter, may lead to bleeding and infertility
A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix (Fig. 1.12).
Figure 1.12
An intracavitary fibroid passed through the uterine cervix and expelled into the vagina
Cervical fibroids are located in the wall of the cervix (neck of the uterus) (Fig. 1.13).
Figure 1.13
A transvaginal cervical myomectomy, with a removal of a cervical fibroid of 7 cm in diameter located in the anterior wall of the cervix
Sometimes, fibroids are found in the supporting uterine structures (round ligament, broad ligament, uterosacral ligament) that also contain smooth muscle tissue.
To best standardize the fibroid location in the uterus, FIGO used the leiomyoma subclassification system of Wamsteker et al. of 1993 [31]. The system that includes the tertiary classification of leiomyomas categorizes the submucosal group and adds categorizations for intramural, subserosal, and transmural lesions. Intracavitary lesions are attached to the endometrium by a narrow stalk and are classified as type 0, whereas types 1 and 2 require a portion of the lesion to be intramural—with type 1 being less than 50% and type 2 at least 50%. The type 3 lesions are totally extracavitary but about the endometrium. Type 4 lesions are intramural leiomyomas that are entirely within the myometrium, with no extension to the endometrial surface or to the serosa. Subserosal (types 5–7) leiomyomas represent the mirror image of the submucosal leiomyomas—with type 5 being at least 50% intramural, type 6 being less than 50% intramural, and type 7 being attached to the serosa by a stalk. The classification of lesions that are transmural would be categorized by their relationship to both the endometrial and the serosal surfaces.
Discussing on histological characteristics, uterine fibroids can be single or multiple and induce symptoms depending on the size and location. Most fibroids start in the muscular wall of the uterus and, with further growth, some lesions may develop toward the outside of the uterus or toward the internal cavity. They can become large and interfere with pregnancy or cause inflammatory complications. Macroscopically they have a cutting tense-elastic surface (Fig. 1.14).
Figure 1.14
A collection of removed fibroid of different diameter by laparotomic myomectomy. Macroscopically they have a cutting tense-elastic surface
Microscopically the tumor is formed by smooth muscle cells separated by a more or less plentiful quantity of vascular connective tissue (Fig. 1.15). Malignant transformation of these tumors is a rare event, quite exceptional. In general, it appears that uterine leiomyosarcomas do not arise from benign leiomyomas, with rare exceptions [32].
