Post on 04-Jun-2018
A uterine fibroid is a leiomyoma (benign (non-cancerous) tumor from smooth muscle
tissue) that originates from the smooth muscle layer (myometrium) of the uterus.
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.
Other common names are uterine leiomyoma,[1] myoma, fibromyoma,
fibroleiomyoma.
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]
Signs and symptoms[edit]
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 also be the cause of miscarriage,
bleeding, premature labor, or interference with the position of the fetus.
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.[5] 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.[5]
Also larger fibroids may distort or block the fallopian tubes.
Pathophysiology[edit]
An enucleated uterine leiomyoma – external surface on left, cut surface on right.
Leiomyomata 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.
Micrograph of a lipoleiomyoma, a type of leiomyoma. H&E stain.
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.
The appearance of prominent nucleoli with perinucleolar halos should alert the
pathologist to investigate the possibility of the extremely rare hereditary
leiomyomatosis and renal cell cancer syndrome.[6]
Location and classification[edit]
Schematic drawing of various types of uterine fibroids: a=subserosal fibroids,
b=intramural fibroids, c=submucosal fibroid, d=pedunculated submucosal fibroid,
e=fibroid in statu nascendi, f=fibroid of the broad ligament
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 lesions 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.
Extrauterine fibroids of uterine origin, metastatic fibroids[edit]
Fibroids of uterine origin located in other parts of the body, sometimes also called
parasitic myomas have been historically extremely rare, but are now diagnosed with
increasing frequency. They may be related or identical to metastasizing leiomyoma.
They are in most cases still hormone dependent but may cause life threatening
complications when they appear in distant organs. Some sources suggest that a
substantial share of the cases may be late complications of surgeries such as
myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a
morcellator has been associated with a substantially increased risk of this
complication.[7][8][9][10][11]
Pathogenesis[edit]
Fibroids are monoclonal tumors and 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.[12]
Exact aetiology is not clearly understood, but the 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 descent, nulliparity, obesity, polycystic ovary syndrome, diabetes and
hypertension.[13]
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 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 between estrogen and the oxytocin receptor.[14]
It is believed that estrogen and progesterone have a 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 promotes growth by up-
regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and 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 promotes survival through up-regulating Bcl-2 expression and
down-regulating TNF-alpha. Progesterone is believed to counteract growth by
downregulating IGF-1.[15][16][17] Expression of transforming growth interacting
factor (TGIF) is increased in leiomyoma compared with myometrium.[18] TGIF is a
potential repressor of TGF-β pathways in myometrial cells.[18]
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.[19] Most studies found that
polymorphisms in ER and PR gene encodings are not correlated with incidence of
fibroids in Caucasian populations[20][21] 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.[22]
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.[23] PPAR-gamma agonists may also counteract leiomyoma growth by
several other mechanisms of action such as TGF-beta3 expression inhibition.[24]
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.[25][26]
Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in
fibroids, indicating that fibroids can convert circulating androstenedione into
estradiol.[27] Similar mechanism of action has been elucidated in endometriosis and
other endometrial diseases.[28] 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[29]
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.[30]
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.[31] Several factors indicate significant
involvement of extracellular signaling pathways such as ERK1 and ERK2, which in
fibroids are prominently influenced by hormones.[32] Paradoxically and unlike most
other conditions involving significant fibrosis the Cyr61 gene has been found
downregulated in fibroids.[33]
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.[33]
Diagnosis[edit]
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.[34] 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.
•
• A very large (9 cm) fibroid of the uterus which is causing pelvic congestion
syndrome as seen on CT
• A very large (9 cm) fibroid of the uterus which is causing pelvic congestion
syndrome as seen on ultrasound
• A relatively large submucosal leiomyoma; it fills out the major part of the
endometrial cavity
• A small uterine fibroid seen within the wall of the myometrium on a cross
sectional ultrasound view
• Two calcified fibroids (in the uterus)
Coexisting disorders[edit]
Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due
to pressure effects gastrointestinal problems such as constipation and bloatedness
are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may
also present alongside endometriosis, which itself may cause infertility.
Adenomyosis may be mistaken for or coexist with fibroids.
In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the
myometrium can develop.[35]
In extremely rare cases uterine fibroids may present as part or early symptom of the
hereditary leiomyomatosis and renal cell cancer syndrome.
Treatment[edit]
Most fibroids do not require treatment unless they are causing symptoms. After
menopause fibroids shrink and it is unusual for fibroids to cause problems.
Symptomatic uterine fibroids can be treated by:
• medication to control symptoms
• medication aimed at shrinking tumours
• ultrasound fibroid destruction
• myomectomy or radio frequency ablation
• hysterectomy
• uterine artery embolization
Medication[edit]
A number of medications are in use to control symptoms caused by fibroids. NSAIDs
can be used to reduce painful menses. Oral contraceptive pills are prescribed to
reduce uterine bleeding and cramps.[5] Anemia may have to be treated with iron
supplementation.
Levonorgestrel intrauterine devices are highly effective in limiting menstrual blood
flow and improving other symptoms. Side effects are typically very moderate
because the levonorgestrel (a progestin) is released in low concentration locally.
There is now substantial evidence that Levongestrel-IUDs provide good symptomatic
relief for women with fibroids.[36] While most Levongestrel-IUD studies
concentrated on treatment of women without fibroids a few reported very good
results specifically for women with fibroids including a substantial regression of
fibroids.[37][38][39]
Danazol is an effective treatment to shrink fibroids and control symptoms. Its use is
limited by unpleasant side effects. Mechanism of action is thought to be
antiestrogenic effects. Recent experience indicates that safety and side effect profile
can be improved by more cautious dosing.[38]
Dostinex in a moderate and well tolerated dosis has been shown in 2 studies to
shrink fibroids effectively. Mechanism of action is unclear.[38][40]
Gonadotropin-releasing hormone analogs cause temporary regression of fibroids by
decreasing estrogen levels. Because of the limitations and side effects of this
medication it is rarely recommended other than for preoperative use to shrink the
size of the fibroids and uterus before surgery. It is typically used for a maximum of 6
months or less because after longer use they could cause osteoporosis and other
typically postmenopausal complications. The main side effects are transient
postmenopausal symptoms. In many cases the fibroids will regrow after cessation of
treatment, however significant benefits may persist for much longer in some cases.
Several variations are possible, such as GnRH agonists with add-back regimens
intended to decrease the adverse effects of estrogen deficiency. Several add-back
regimes are possible, tibolone, raloxifene, progestogens alone, estrogen alone, and
combined estrogens and progestogens.[38]
Ulipristal acetate is a synthetic selective progesterone receptor modulator which has
been tested in small radomized trials with good results for the treatment of
fibroids.[41] Similar to other selective progesterone receptor modulators and
antagonists benign histologic endometrial changes were reported and long term
safety outside of clinical studies has not been established yet.[41][42][43]
Progesterone antagonists such as Mifepristone have been tested, there is evidence
that it relieves some symptoms and improves quality of life but because of adverse
histological changes that have been observed in several trials it can not be currently
recommended outside of research setting.[44][45][46]Selective progesterone
receptor modulators, such as Progenta, have been under investigation.
The selective progesterone receptor modulator Asoprisnil is currently tested with
very promising results as a possible use as a treatment for fibroids - the hope is that
it will provide the advantages of progesterone antangonitst without their adverse
effects.[38]
The long term safety of progesterone antagonists as well as selective progesterone
receptor modulators has yet to be established.[47][48]
Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is
believed to be due partially by lowering systemic estrogen levels and partially by
inhibiting locally overexpressed aromatase in fibroids.[38] Experience from
experimental aromatase inhibitor treatment of endometriosis indicates that
aromatase inhibitors might be particularly useful in combination with a
progestogenic ovulation inhibitor.
Uterine artery embolization[edit]
Uterine artery embolization (UAE): Using interventional radiology techniques, the
interventional radiologist occludes both uterine arteries, thus reducing blood supply
to the fibroid.[49] This intervention is not usually recommended when fertility
should be preserved although subsequent pregnancies are usually possible. A small
catheter (1 mm in diameter) is inserted into the femoral artery at the level of the
groin under local anesthesia. Under imaging guidance, the interventional radiologist
will enter selectively into both uterine arteries and inject small (500 µm) particles
that will block the blood supply to the fibroids. A patient will usually recover from
the procedure within a few days. The UAE procedure should result in limited blood
supply to the fibroids which should prevent them from further growth, heavy
bleeding and possibly shrink them.
A retrospective cohort study showed that UAE has much fewer serious adverse
effects than hysterectomy (odds ratio 0.25) and similar rates of satisfaction. In this
study, 86% of women treated with UAE would recommend the treatment to a friend
compared to 70% of those treated by hysterectomy.[50]
Uterine artery ligation[edit]
Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries are
minimally invasive methods to limit blood supply of the uterus by a small surgery
that can be performed transvaginally or laparoscopically. The principal mechanism of
action may be similar like in UAE but is easier to perform and fewer side effects are
expected.[51][52][53] UAE currently appears much more effective than this method
in direct comparison.[54]
Radio frequency ablation[edit]
Radiofrequency ablation is one of the newest minimally invasive treatments for
fibroids.[55] In this technique the fibroid is shrunk by inserting a needle-like device
into the fibroid through the abdomen and heating it with radio-frequency (RF)
electrical energy to cause necrosis of cells. The treatment is a potential option for
women who have fibroids, have completed child-bearing and want to avoid a
hysterectomy.
Myomectomy[edit]
After treatment of an intramural fibroid by laparoscopic surgery
Myomectomy is a surgery to remove one or more fibroids. It is usually
recommended when more conservative treatment options fail for women who want
fertility preserving surgery or who want to retain the uterus.[56]
There are three types of myomectomy:
• In a hysteroscopic myomectomy (also called transcervical resection), the fibroid
can be removed by either the use of a resectoscope, an endoscopic
instrument inserted through the vagina and cervix that can use high-
frequency electrical energy to cut tissue, or a similar device.
• A laparoscopic myomectomy is done through a small incision near the navel. The
physician uses a laparoscope and surgical instruments to remove the fibroids.
Studies have suggested that laparoscopic myomectomy leads to lower
morbidity rates and faster recovery than does laparotomic myomectomy.[57]
• A laparotomic myomectomy (also known as an open or abdominal myomectomy)
is the most invasive surgical procedure to remove fibroids. The physician
makes an incision in the abdominal wall and removes the fibroids from the
uterus.
Hysterectomy[edit]
Hysterectomy was the classical method of treating fibroids. Although it is now
recommended only as last option, fibroids are still the leading cause of
hysterectomies in the US.
Endometrial ablation[edit]
Endometrial ablation can be used if the fibroids are only within the uterus and not
intramural and relatively small. High failure and recurrence rates are expected in the
presence of larger or intramural fibroids.
Magnetic resonance guided focused ultrasound[edit]
Magnetic Resonance guided Focused Ultrasound, is a non-invasive intervention
(requiring no incision) that uses high intensity focused ultrasound waves to destroy
tissue in combination with magnetic resonance imaging (MRI), which guides and
monitors the treatment. During the procedure, delivery of focused ultrasound
energy is guided and controlled using MR thermal imaging.[58] Patients who have
symptomatic fibroids, who desire a non-invasive treatment option and who do not
have contraindictions for MRI are candidates for MRgFUS. About 60% of patients
qualify. It is an outpatient procedure and takes one to three hours depending on the
size of the fibroids. It is safe and about 75% effective.[59] Symptomatic
improvement is sustained for two plus years.[60] Need for additional treatment
varies from 16-20% and is largely dependent on the amount of fibroid that can be
safely ablated; the higher the ablated volume, the lower the re-treatment rate.[61]
In comparison to available treatment options, the cost effectiveness of MRgFUS in
the U.S. and U.K. has been found to be reasonable and comparable to alternative
treatments (hysterectomy, pharmacotherapy, uterine artery embolization).[62][63]
There are currently no randomized trial between MRgFUS and UAE. A multi-center
trial is underway to investigate the efficacy of MRgFUS vs. UAE.
Genetic associations[edit]
An association with fatty acid synthase has been reported.[66]
Familial leiomyomata[edit]
A syndrome (Reed’s syndrome) of cutaneous and uterine leiomyomata and renal cell
cancer has been reported.[67][68][69] This is associated with a mutation in the
fumarate hydratase which is located on the long arm of chromosome 1 (1q42.3-43).
Inheritance is autosomal dominant.
This syndrome is described in greater detail on the page Hereditary leiomyomatosis
and renal cell cancer.
Prognosis[edit]
About 1 out of 1000 lesions[5] are or become malignant, typically as a
leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after
menopause.[5] There is no consensus among pathologists regarding the
transformation of leiomyoma into a sarcoma. Most pathologists believe that a
Leiomyosarcoma is a de novo disease[citation needed
].
Metastasis[edit]
There are a number of rare conditions in which fibroids metastasize. They still grow
in a benign fashion, but can be dangerous depending on their location.[77]
• In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a
vessel but there is no risk of recurrence.
• In Intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as
their source. Cardiac involvement can be fatal.
• In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such
as the lungs and lymph nodes. The source is not entirely clear. Pulmonary
involvement can be fatal.
In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the
peritoneal and omental surfaces, with uterine fibroids as their source. This can
simulate a malignant tumor but behaves benignly.