Uterine Fibroid

A uterine fibroid (also uterine leiomyoma,[1] myoma, fibromyoma, leiofibromyoma, fibroleiomyoma, and fibroma) (the plural of myoma is myomas or myomata) is a benign (non-cancerous) tumor that originates from the smooth muscle layer (myometrium) and the accompanying connective tissue of the uterus.

Fibroids are the most common benign tumors in females and typically found during the middle and later reproductive years. While most fibroids are asymptomatic, they can grow and cause heavy and painful menstruation, painful sexual intercourse, and urinary frequency and urgency. Some fibroids may interfere with pregnancy although this appears to be very rare.[2]

In the US, symptoms caused by uterine fibroids are a very frequent indication for hysterectomy.[3] Fibroids are often multiple and if the uterus contains too many leiomyomata to count, it is referred to as diffuse uterine leiomyomatosis. The malignant version of a fibroid is extremely uncommon and termed a leiomyosarcoma.

Signs and Symptoms

Fibroids, particularly when small, may be entirely asymptomatic. Symptoms depend on the location of the lesion and its size. Important symptoms include abnormal gynecologic hemorrhage, heavy or painful periods, abdominal discomfort or bloating, painful defecation, back ache, urinary frequency or retention, and in some cases, infertility.[4] There may also be pain during intercourse, depending on the location of the fibroid. During pregnancy they may be the cause of miscarriage, bleeding, premature labor, or interference with the position of the fetus.

The U.S. Department of Health & Human Services states that "Fibroids are almost always benign (not cancerous). Rarely (less than one in 1,000) a cancerous fibroid will occur. This is called leiomyosarcoma. Doctors think that these cancers do not arise from an already-existing fibroid. Having fibroids does not increase the risk of developing a cancerous fibroid. Having fibroids also does not increase a woman's chances of getting other forms of cancer in the uterus."[5]

While fibroids are common, they are not a typical cause for infertility accounting for about 3% of reasons why a woman may not have a child.[6] Typically in such cases a fibroid is located in a submucosal position and it is thought that this location may interfere with the function of the lining and the ability of the embryo to implant.[6] Also larger fibroids may distort or block the fallopian tubes.

Pathophysiology

Leiomyomas grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall.

Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active.

Location

An enucleated uterine leiomyoma – external surface on left, cut surface on right.
large subserosal fibroid

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[3] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:

* Intramural fibroids are located within the wall of the uterus 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.

* Subserosal fibroids are located underneath the mucosal (peritoneal) surface of the uterus and can become very large. They can also grow out in a papillary manner to become pedunculated fibroids. These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma.

* Submucosal fibroids are located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesion in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.

* Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in an intramural location, that is the layer of the muscle of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes.

Pathogenesis

Fibroids are monoclonal tumors, approximately 40 to 50% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein, have been noted in 70 percent of fibroids.[7]

Exact aetiology is not clearly understood, current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African-American descent, nulliparity, obesity, polycystic ovary syndrome, diabetes and hypertension.[8]

Fibroid growth is strongly dependent on estrogen and progesterone. Although both estrogen and progesterone are usually regarded as growth promoting they will also cause growth restriction in some circumstances. Paradoxically fibroids will rarely grow during pregnancy despite very high steroid hormone levels and pregnancy appears to exert a certain protective effect.[2] This protective effect might be partially mediated by an interaction estrogen and the oxytocin receptor.[9]

It is believed that estrogen and progesterone have both mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signalling which controls the expression of the respective nuclear receptors. It is believed that estrogen is growth promoting by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signalling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and the survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.[10][11][12] Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium.[13] TGIF is a potential repressor of TGF-? pathways in myometrial cells.[13]

Whereas in premenopausal fibroids the ER-beta, ER-alpha and progesterone receptors are found overexpressed, in the rare postmenopausal fibroids only ER-beta was found significantly overexpressed.[14] Most studies found that polymorphisms in ER and PR gene encodings are not correlated with incidence of fibroids in Caucasian populations[15][16] however a special ER-alpha genotype was found correlated with incidence and size of fibroids. The higher prevalence of this genotype in black women may also explain the high incidence of fibroids in this group.[17]

Uterine leiomyoma was more sensitive than normal myometrium to PPAR-gamma receptor activation resulting in reduced survival and apoptosis of leiomyoma cells. The mechanism is thought to involve negative cross-talk between ER and PPAR signaling pathways. Several PPAR-gamma ligands were considered as potential treatment.[18] PPAR-gamma agonists may also counteract leiomyoma growth by several other mechanisms of action such as TGF-beta3 expression inhibition.[19]

Hypertension is significantly correlated with fibroids. Although a causal relationships is not at all clear the hypothesis has been formulated that atherosclerotic injury to uterine blood vessels and the resulting inflammatory state may play a role. Furthermore endocrine factors related to blood pressure such as angiotensin II are suspected to cause fibroid proliferation via angiotensin II type 1 receptor.[20][21]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids can convert circulating androstenedione into estradiol.[22] Similar mechanism of action has been elucidated in endometriosis and other endometrial diseases.[23] Aromatase inhibotors are currently considered for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is particularly pronounced in Afro-American women[24]

Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins.[25]

Like keloids, fibroids have disregulated production of extracellular matrix. Recent studies suggest that this production may represent an abnormal response to ischemic and mechanical tissue stress.[26] Several factors indicate significant involvement of extracellular signaling pathways such as ERK1 and ERK2, which in fibroids are prominently influenced by hormones.[27] Paradoxically and unlike most other conditions involving significant fibrosis the Cyr61 gene has been found downregulated in fibroids.[28]

Cyr61 is also known for its role as tumor suppressing factor and in angiogenesis. Hence fibroids are one of the very few tumors with reduced vascular density.[28]

Diagnosis

While a bimanual examination typically can identify the presence of larger fibroids, gynecologic ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus.

Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions there may be evidence of local invasion. A more recent study has suggested that diagnostic capabilities using MRI have improved the ability to detect sarcomatous lesions.[29] Biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.

Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity are hysterosalpingography or sonohysterography.