Uterine enlargement is common
and most frequently is the result of pregnancy or leiomyomas. Less often,
enlargement is from adenomyosis, hematometra, or an adherent adnexal mass.
Leiomyomas are benign smooth
muscle neoplasms that typically originate from the myometrium. They are often
referred to as uterine myomas, and are incorrectly called fibroids
because the considerable amount of collagen contained in many of them creates a
fibrous consistency. Their incidence among women is generally cited as 20 to 25
percent, but has been shown to be as high as 70 to 80 percent in studies using
histologic or sonographic examination (Buttram, 1981; Cramer, 1990; Day Baird,
2003).
In many women, leiomyomas are
clinically insignificant. Conversely, in some, their number, size, or location
within the uterus can provoke a myriad of symptoms. Taken together, symptoms
caused by these uterine tumors constitute an important segment of gynecologic
practice.
Grossly leiomyomas are round,
pearly white, firm, rubbery tumors that on cut-surface display a whorled
pattern. A typically involved uterus contains 6 to 7 tumors of varying size
(Cramer, 1990). Leiomyomas possess a distinct autonomy from their surrounding
myometrium because of a thin outer connective tissue layer. This clinically
important arrangement allows leiomyomas to be easily "shelled out" of
the uterus during surgery.
Histologically, leiomyomas
contain elongated smooth muscle cells aggregated in bundles that swirl and
intersect at right angles to one another. Mitotic activity, however, is rare
and is a key point in differentiation from leiomyosarcoma (see Chap. 34,
Leiomyosarcoma) (Zaloudek, 2002).
The appearance of leiomyomas
may vary when normal muscle tissue is replaced with various degenerative
substances following hemorrhage and necrosis. This process is collectively
termed degeneration, and these gross changes should be recognized as
normal variants (Fig. 9-1). Degeneration develops frequently in leiomyomas because
of the limited blood supply within these tumors. Leiomyomas have a lower
arterial density compared with the surrounding normal myometrium (Fig. 9-2).
Moreover, there is no intrinsic vascular organization and this disorganization
leaves some tumors vulnerable to hypoperfusion and ischemia (Farrer-Brown,
1970; Forssman, 1976). Acute pain may accompany degeneration.
The appearance of leiomyomas will
vary depending on the degree and type of degeneration present. A. Cystic
degeneration (arrow) seen within this submucous fibroid. B.
Typical histologic architecture of leiomyomas. C. Hyaline degeneration
is identified by abundant pink glassy hyaline that is seen interspersed between
smooth muscle cells. (Courtesy of Dr. Raheela Ashfaq.)
Each leiomyoma is derived from
a single progenitor myocyte. Thus, multiple tumors within the same uterus each
show independent cytogenetic origins (Mashal, 1994; Townsend, 1970). The
primary mutation initiating tumorigenesis is unknown, but identifiable karyotypic
defects are found in about 40 percent of leiomyomas (Rein, 1998; Xing, 1997). A
number of unique defects involving chromosomes 6, 7, 12, and 14 have been
identified to correlate with rates and direction of tumor growth (Brosens,
1998). It is anticipated that further characterization of the specific
functions of these karyotypic changes will help to define the important steps
in leiomyoma development.
Uterine leiomyomas are
estrogen- and progesterone-sensitive tumors (Table 9-1). Consequently, they
develop during the reproductive years and regress in size and incidence after
menopause. This concept is integral in understanding many of the risk factors
associated with leiomyoma development and in formulating treatment plans. Sex
steroid hormones likely mediate their effect by stimulating or inhibiting
transcription and production of cellular growth factors.
Leiomyomas themselves create a
hyperestrogenic environment, which appears requisite for their growth and
maintenance. First, compared with normal myometrium, leiomyomas contain a
greater density of estrogen receptors that results in greater estradiol
binding. Secondly, these tumors convert less estradiol to the weaker estrone
(Englund, 1998; Otubu, 1982; Yamamoto, 1993). A third mechanism described by
Bulun and colleagues (1994) involves higher levels of cytochrome P450 aromatase
in leiomyomas compared with normal myocytes. This specific cytochrome isoform
catalyzes the conversion of androgens to estrogen in a number of tissues.
There are a number of
conditions associated with increased estrogen production that encourage
leiomyoma formation. For example, the increased years of estrogen exposure
found with early menarche and with an increased body mass index (BMI) are each
linked with a greater risk of leiomyomas (Marshall, 1998; Wise, 2005b). Obese
women produce more estrogens from increased adipose conversion of androgens to
estrogen and display decreased hepatic production of sex-hormone binding
globulin (Glass, 1989).
Because pregnancy is a
progesterone-dominant state, it should provide an interlude from chronic
estrogen exposure, and intuitively at least, should discourage leiomyoma
development. In support of this, women giving birth at an early age, those with
higher parity, and those with a more recent pregnancy all display lower
incidences of leiomyoma formation.
In premenopausal women,
estrogen and progesterone hormone treatment probably has no inductive effect on
leiomyoma formation. With few exceptions, oral contraceptive combination pills
either lower or have no effect on this risk (Chiaffarino, 1999; Parazzini,
1992; Ross, 1986).
Most studies evaluating the
effects of hormone replacement therapy, however, show either a stimulatory or
no effect on growth (Polatti, 2000; Reed, 2004). Palomba and associates (2002)
evaluated the relationship between leiomyoma growth and differing doses of
medroxyprogesterone acetate (MPA) in hormone replacement therapy. Because
higher doses of MPA were associated with leiomyoma growth, they recommended
using the lowest possible dose of MPA in these patients.
Finally, smoking alters
estrogen metabolism and lowers physiologically active serum estrogen levels
(Daniel, 1992; Michnovicz, 1986). This may explain why women who smoke
generally have a lower risk for leiomyoma formation (Parazzini, 1992).
The role of progesterone in
leiomyoma growth is less clear, and indeed both stimulatory and inhibitory
effects have been reported. For example, exogenous progestins have been shown
to limit leiomyoma growth in clinical trials (Goldzieher, 1966; Tiltman, 1985).
Similarly, epidemiologic studies link depot medroxyprogesterone use with a
lower incidence of leiomyoma development (Lumbiganon, 1996). In contrast, other
studies report a stimulatory influence of progestins on leiomyoma growth. For
example, the antiprogestin, mifepristone (RU486), induces atrophy in most
leiomyomas (Murphy, 1993). Moreover, in women treated with
gonadotropin-releasing hormone (GnRH) agonists, leiomyomas typically decrease
in size. However, if progestins are given simultaneously with agonists, there
may be increased leiomyoma growth (Carr, 1993; Friedman, 1994).
During the reproductive years,
the incidence of this tumor increases with age. In a study by Day Baird and
colleagues (2003), the cumulative incidence by age 50 years was nearly 70
percent in Caucasians and over 80 percent in African-American women. Sporadic
case reports such as the one by Bekker and colleagues (2004) document their
rarity in teenagers. After menopause, leiomyomas generally shrink in size, and
new tumor development is uncommon. Thus, it seems that most risk or protective
factors depend on circumstances that chronically alter estrogen or progesterone
levels or both.
Leiomyomas are more common in
African-American women compared with Caucasian, Asian, or Hispanic women. Few
studies have been done to ascertain these ethnic differences (Amant, 2003;
Woods, 1996). Heredity likely plays a role in susceptibility to the initial
mutation involved with leiomyoma development. Family and twin studies have
shown the risk of leiomyoma formation to be approximately two times greater in
women with affected first-degree relatives (Sato, 2002; Vikhlyaeva, 1995).
Leiomyomas are classified based
on their location and direction of growth (Fig. 9-3). Subserosal leiomyomas
originate from myocytes adjacent to the uterine serosa, and their growth is
directed outward. When these are attached only by a stalk to their progenitor
myometrium, they are called pedunculated leiomyomas. Parasitic
leiomyomas are subserosal variants that attach themselves to nearby pelvic
structures from which they derive vascular support, and then may or may not
detach from the parent myometrium. Intramural leiomyomas are those with
growth centered within the uterine walls. Finally, submucous leiomyomas
are proximate to the endometrium and grow toward and bulge into the endometrial
cavity. Only about 0.4 percent of leiomyomas develop in the cervix (Tiltman,
1998). Leiomyomas have also been found less commonly in the ovary, fallopian
tube, broad ligament, vagina, and vulva.
Leiomyomas can be described as
submucous, subserosal, intramural, or pedunculated. The borders of most
leiomyomas overlap these distinct regions.
Extrauterine smooth muscle
tumors, which are benign yet infiltrative, may develop in women with concurrent
uterine leiomyomas. This condition is termed leiomyomatosis, and its
categorization is described below. In such cases, the diagnosis of malignant
metastasis from a leiomyosarcoma must be excluded.
Intravenous leiomyomatosis
is a rare, benign smooth muscle tumor that invades and extends serpiginously
into the uterine and other pelvic veins, vena cava, and even cardiac chambers.
Although histologically benign, the tumor can be fatal as a consequence of
venous obstruction or cardiac involvement (Fang, 2007; Uchida, 2004).
Benign metastasizing
leiomyomas derive from morphologically benign uterine leiomyomas which
disseminate hematogenously. Lesions have been found in the lungs,
gastrointestinal tract, spine, and brain (Alessi, 2003). Classically, these are
found in women who have a recent or distant history of pelvic surgery
(Zaloudek, 2002).
Disseminated peritoneal
leiomyomatosis appears as multiple small nodules on the peritoneal surfaces
of the abdominal cavity or the abdominal organs or both. They are usually found
in women of reproductive age, and 70 percent are associated with pregnancy or
combination oral contraceptives (Robboy, 2000).
Treatments for these three
benign conditions involve hysterectomy with oophorectomy, tumor debulking, and
more recently, use of GnRH agonists, aromatase inhibitors, and selective
estrogen receptor modulators (Bodner, 2002; Rivera, 2004; Sobiczewski, 2004).
Most women with leiomyomas are
asymptomatic. However, symptomatic patients typically complain of bleeding,
pain, pressure sensation, or infertility. In general, the larger the leiomyoma,
the greater the likelihood of symptoms (Cramer, 1990).
This is the most common symptom
and usually presents as menorrhagia (Olufowobi, 2004). The pathophysiology
underlying this bleeding may relate to dilatation of venules. Bulky tumors are
thought to exert pressure and impinge on the uterine venous system, which
causes venular dilatation within the myometrium and endometrium (Figs. 9-4 and
9-5). Accordingly, intramural and subserosal tumors have been shown to have the
same propensity to cause menorrhagia as submucous ones (Wegienka, 2003).
Dysregulation of local
vasoactive growth factors are also thought to promote vasodilatation. When
engorged venules are disrupted at the time of menstrual sloughing, bleeding
from the markedly dilated venules overwhelms usual hemostatic mechanisms
(Stewart, 1996).
A sufficiently enlarged uterus
can cause pressure sensation, urinary frequency, incontinence, and constipation.
Rarely, leiomyomas extend laterally to compress the ureter and lead to
obstruction and hydronephrosis. Although dysmenorrhea is common, in a
population-based cross-sectional study, Lippman and co-workers (2003) reported
that women with leiomyomas more frequently had dyspareunia or noncyclical
pelvic pain than dysmenorrhea.
Although the mechanisms are not
clear, leiomyomas can be associated with infertility. It is estimated that 2 to
3 percent of infertility cases are due solely to leiomyomas (Buttram, 1981;
Kupesic, 2002). Their putative effects include occlusion of tubal ostia and
disruption of the normal uterine contractions that propel sperm or ova.
Distortion of the endometrial cavity may diminish implantation and sperm
transport. Importantly, leiomyomas are associated with endometrial inflammation
and vascular changes that may disrupt implantation (American Society for
Reproductive Medicine, 2004a; Brosens, 2003; Farhi, 1995).
There is a stronger association
of subfertility with submucous leiomyomas than with tumors located elsewhere.
Improved pregnancy rates following hysteroscopic resection have provided most
of the indirect evidence for this link (Vercellini, 1999). In one study, Garcia
and Tureck (1984) reported pregnancy rates approaching 50 percent following
myomectomy in women with submucous leiomyomas as their sole source of
infertility.
The relationship between
subfertility and intramural and subserosal leiomyomas that do not distort the
endometrial cavity is more tenuous. A number of investigators have reported
equally good in vitro fertilization success rates in women with and without
leiomyomas that did not distort the endometrial cavity (Farhi, 1995; Oliveira,
2004). Others, however, have reported adverse fertility effects from even
intramural and subserosal leiomyomas (Hart, 2001; Marchionni, 2004).
Both uterine leiomyoma and
spontaneous miscarriage are common, and an association between these has not
been shown convincingly. Indirect evidence comes from studies that cite
significantly lower abortion rates following resection (Campo, 2003;
Vercellini, 1999).
Less than 0. 5 percent of women
with leiomyomas develop myomatous erythrocytosis syndrome. This may
result from excessive erythropoietin production by the kidneys or by the
leiomyomas themselves (Kohama, 2000; Yokoyama, 2003). In either case, red cell
mass returns to normal following hysterectomy.
Leiomyomas occasionally may
cause pseudo-Meigs syndrome. Traditionally, Meigs syndrome consists of
ascites and pleural effusions that accompany benign ovarian fibromas. However,
any pelvic tumor including large, cystic leiomyomas or other benign ovarian
cysts can cause this. The presumed etiology stems from discordancy between the
arterial supply to and the venous and lymphatic drainage from leiomyomas.
Resolution of ascites and hydrothorax follows hysterectomy.
Leiomyomas are often detected
by pelvic examination with findings of uterine enlargement, irregular contour,
or both. In reproductive-aged women, uterine enlargement should prompt
determination of a urine or serum 
-hCG level.
-hCG level.
Sonography is initially done to
define pelvic anatomy. The sonographic appearances of leiomyomas vary from
hypo- to hyperechoic, depending on the ratio of smooth muscle to connective
tissue and whether there is degeneration. Calcification and cystic degeneration
create the most sonographically distinctive changes (Fig. 9-6). Calcifications
appear hyperechoic and commonly rim the tumor or are randomly scattered (Kurtz,
1979). Cystic or myxoid degeneration typically fills the leiomyoma with
multiple, smooth-walled, round, irregularly sized but generally small
hypoechoic areas.
Leiomyomas have characteristic
vascular patterns that can be identified by color flow Doppler. A peripheral
rim of vascularity from which a few vessels arise to penetrate into the center
of the tumor is traditionally seen. Doppler imaging can be used to
differentiate an extrauterine leiomyoma from other pelvic masses or a submucous
leiomyoma from an endometrial polyp or adenomyosis (see Chap. 8, Transvaginal
Color Doppler Sonography) (Fleischer, 2003).
Magnetic resonance (MR) imaging
may be required when imaging is limited by body habitus or distorted anatomy.
This tool allows more accurate assessment of the size, number, and location of
leiomyomas, which may help identify appropriate patients for alternatives to hysterectomy,
such as myomectomy or uterine artery embolization (see Fig. 2-25) (Zawin,
1990).
Regardless of their size,
asymptomatic leiomyomas usually can be managed expectantly by annual pelvic
examination (American College of Obstetricians and Gynecologists 2001). If
assessment of the adnexa is hindered by uterine size or contour, some may
choose to add annual sonographic surveillance (Guarnaccia, 2001).
In the past, most preferred
surgical removal of a large, asymptomatic leiomyomatous uterus because of
concerns regarding increased operative morbidity and cancer risks. These have
been disproven, and thus otherwise asymptomatic women with large leiomyomas can
also be managed expectantly (Parker, 1994; Stovall, 1994). In addition, most
infertile women with uterine leiomyomata are management expectantly. For those
with symptomatic tumors, surgery should be timed closely to planned pregnancy,
if possible, to limit the risk of leiomyoma recurrence.
In some women with symptomatic
leiomyomas, medical therapy may be preferred (Table 9-2). In addition, because
leiomyomas typically regress postmenopausally, some women choose medical
treatment to relieve symptoms in anticipation of menopause. In others, medical
therapy, such as GnRH agonists, are used as a preoperative adjunct to surgery.
Women with dysmenorrhea have
higher endometrial levels of prostaglandins F2 and E2 than asymptomatic
women (Willman, 1976; Ylikorkala, 1978). Accordingly, treatment of dysmenorrhea
and menorrhagia associated with leiomyomas is based on the role of
prostaglandins as mediators of these symptoms. A number of NSAIDs have proved
effective for dysmenorrhea, yet there is not one considered to be superior
(Table 10-2). Prostaglandins are also associated with menorrhagia (see Chap. 8,
Nonsteroidal Anti-Inflammatory Drugs) (Willman, 1976). That said, benefits of
NSAIDs for leiomyoma-related bleeding are less clear. The few studies done have
had conflicting results (Anteby, 1985; Makarainen, 1996; Ylikorkala, 1986).
Available data do not support their use as sole agents for leiomyoma-related
menorrhagia.
and E2 than asymptomatic
women (Willman, 1976; Ylikorkala, 1978). Accordingly, treatment of dysmenorrhea
and menorrhagia associated with leiomyomas is based on the role of
prostaglandins as mediators of these symptoms. A number of NSAIDs have proved
effective for dysmenorrhea, yet there is not one considered to be superior
(Table 10-2). Prostaglandins are also associated with menorrhagia (see Chap. 8,
Nonsteroidal Anti-Inflammatory Drugs) (Willman, 1976). That said, benefits of
NSAIDs for leiomyoma-related bleeding are less clear. The few studies done have
had conflicting results (Anteby, 1985; Makarainen, 1996; Ylikorkala, 1986).
Available data do not support their use as sole agents for leiomyoma-related
menorrhagia.
Both combination oral
contraceptive pills (COCs) and progestins have been used to induce endometrial
atrophy and decrease prostaglandin production in women with leiomyomas.
Friedman and Thomas (1995) studied 87 women with leiomyomas and reported that
those taking low-dose COCs had significantly shorter menses and no evidence of
uterine enlargement. Orsini and colleagues (2002) reported similar results.
There are conflicting results
from trials of the levonorgestrel-releasing intrauterine device (Mirena,
Berlex, Wayne, NJ) to treat leiomyoma-related menorrhagia. Although, Grigorieva
and co-workers (2003) reported reduced blood loss and improved hematocrits in
these women, Mercorio and associates (2003) did not confirm these findings.
Because of unpredictable
effects of progestins on leiomyoma growth with the potential to worsen
symptoms, the American Society for Reproductive Medicine (2004a) does not
recommend either progestins or combination COCs for leiomyoma-related symptoms.
Both danazol and gestrinone
have been found to shrink leiomyoma volume and improve bleeding symptoms
(Coutinho, 1989; De Leo, 1999). Unfortunately, their prominent side effects,
which include acne and hirsutism, preclude their use as first-line agents (see
Chap. 10, Androgens).
These compounds are synthetic
derivatives of the GnRH decapeptide. Amino-acid substitution makes them
resistant to degradation, thereby increasing their half-life and resulting in
prolonged receptor binding. They are inactive if taken orally, but
intramuscular, subcutaneous, and intranasal preparations are available. A
number of GnRH agonists that have been studied in clinical trials are shown in
Table 9-3. There is no evidence to support the superiority of one of these
regimens over the others for leiomyoma treatment (Chavez, 2001).
These drugs shrink leiomyomas
by targeting the growth effects of estrogen and progesterone. They initially
stimulate receptors on pituitary gonadotropes to cause a supraphysiologic
release of both luteinizing hormone (LH) and follicle-stimulating hormone
(FSH). Also called a flare, this phase typically lasts 1 week. With
their long-term action, however, agonists downregulate receptors in
gonadotropes, thus creating desensitization to further GnRH stimulation.
Correspondingly, decreased gonadotropin secretion leads to suppressed estrogen
and progesterone levels 1 to 2 weeks after initial GnRH agonist administration
(Broekmans, 1996). Another possible mechanism is that leiomyomas themselves may
contain GnRH receptors, and agonists may directly decrease leiomyoma size
(Chegini, 1996; Parker, 2007; Wiznitzer, 1988).
Results with GnRH agonist
treatment include dramatic decreases in uterine and leiomyoma volume. Most
women experience a mean decrease in uterine volume of 40 to 50 percent, with
most shrinkage occurring during the first 3 months of therapy. Clinical
benefits of reduced leiomyoma volumes include pain relief and diminished
menorrhagia, usually amenorrhea. During this time, anemic women are given oral
iron therapy to repair red cell mass and increase iron stores (Filicori, 1983;
Friedman, 1990). Most recommend treatment for a total of 3 to 6 months.
Following their discontinuance, normal menses resume in 4 to 10 weeks.
Unfortunately, leiomyomas then regrow and uterine volumes regain pretreatment
sizes within 3 to 4 months (Friedman, 1990). Despite regrowth, Schlaff and
co-workers (1989) reported symptom relief for about 1 year in half of women
given GnRH agonists.
GnRH agonists have significant
costs, risks, and side effects. Side effects result from a profound drop in
serum estrogen levels and include vasomotor symptoms, libido changes, and
vaginal epithelium dryness and accompanying dyspareunia. Importantly, 6 months of
agonist therapy can result in a 6 percent loss in trabecular bone, not all of
which may be recouped following discontinuation (Scharla, 1990). As a result,
these agents are not recommended for use longer than 6 months.
To obviate the severity of
these side effects, several medications have been added to GnRH agonist
treatment. The goal of this "add-back therapy" is to counter side
effects without mitigating the effects on uterine and leiomyoma volume
decrease. Mizutani and co-workers (1998) found that GnRH agonists suppress
leiomyoma cell proliferation and induce cell apoptosis at the fourth week of
GnRH agonist therapy. They proposed that add-back therapy be withheld until
after this time threshold. Because of these and other observations, add-back therapy
is typically begun 1 to 3 months following GnRH agonist initiation.
Add-back therapy traditionally
includes estrogen combined with a progestin. A regimen of medroxyprogesterone
acetate (MPA) 10 mg (days 16 to 25 of each cycle), combined with equine estrogen
0.625 mg (days 1 to 25), or a continuous daily regimen of MPA 2.5 mg and equine
estrogen 0.625 mg may be used.
Add-back therapy with selective
estrogen receptor modulators (SERMs), such as tibolone and raloxifene, has also
been shown to prevent bone loss. Advantages of SERMs include the ability to
begin them concurrently with GnRH agonist treatment without negating the
agonist effects of leiomyoma shrinkage. Unfortunately, a high percentage of
women complain of vasomotor symptoms while taking SERMs (Palomba, 1998, 2004).
Because of the limitations of
GnRH agonist therapy, the American College of Obstetricians and Gynecologists
(2001) currently recommends it only as a temporizing agent in women nearing
menopause or as surgical pretreatment in selected women.
Preoperatively, GnRH agonists
offer several advantages. Their use decreases menorrhagia and may allow
correction of anemia. Decreased uterine size as a result of treatment may allow
a less-complicated or extensive surgical procedure. For example, hysterectomy
or myomectomy may be performed through a smaller laparotomy incision or by
vaginal hysterectomy, laparoscopy, or hysteroscopy (Crosignani, 1996;
Mencaglia, 1993; Stovall, 1994). A fuller discussion of preoperative GnRH
agonist use can be found in Section 41-18, Myomectomy.
Synthetically derived GnRH
antagonists have also been studied for treatment of leiomyomas. Although their
profound hypoestrogenic effects are similar to those of GnRH agonists, they
avoid the initial gonadotropin flare and have a more rapid action. Studies have
evaluated cetrorelix and also Nal-glu, so named because of its glutamatic acid
structural substitution of the original GnRH structure. Daily subcutaneous
injections induce leiomyoma shrinkage comparable with GnRH agonists
(Gonzalez-Barcena, 1997; Kettel, 1993). A depot form of cetrorelix, however,
did not provide adequate or consistent suppression of estrogen production or
leiomyoma growth (Felberbaum, 1998).
Mifepristone, also known as
RU486, is the most widely available antiprogestin for treatment of leiomyomas.
It has proved effective in decreasing leiomyoma volume and clinical symptoms.
Progesterone binds to either
progesterone receptor A or B (PR-A, PR-B). Mifepristone exerts its effects
mainly through PR-A, which is found in leiomyomas in greater amounts than PR-B
(Viville, 1997). Mifepristone diminishes leiomyoma volume by approximately
half. Various doses have been used and include 5, 10, 25, or 50 mg given orally
daily during 12 weeks (Eisinger, 2003; Murphy, 1993). In their review,
Steinauer and colleagues (2004) found that although there was not a consistent
correlation between increasing mifepristone dose and leiomyoma response,
increasing duration of treatment did correlate with tumor shrinkage during 3-
to 6-month trials. They also reported that mifepristone was effective in
improving symptoms. Of those treated, 91 percent developed amenorrhea, 75
percent reported improved pain relief, and 70 percent had fewer pressure symptoms.
In a comparison of leuprolide acetate treatment and mifepristone therapy,
Reinsch and associates (1994) showed comparable decreases in uterine volume,
yet mifepristone was better tolerated.
Mifepristone therapy, however,
has several drawbacks. Approximately 40 percent of treated women complain of
vasomotor symptoms. Antiprogestational effects expose the endometrium to
unopposed estrogen, and Eisinger and associates (2003) found simple hyperplasia
in 28 percent of 36 women sampled. Serum levels of hepatic transaminases become
elevated in about 4 percent of women, but these return to normal after
discontinuation in virtually all (Steinauer, 2004). Despite its
antiglucocorticoid potential, increased serum cortisol levels are unusual with
mifepristone, and if elevated they revert to normal after discontinuation
(Reinsch, 1994).
This is an angiographic
interventional procedure that delivers polyvinyl alcohol (PVA) microspheres or
other particulate emboli into both uterine arteries. Uterine blood flow is
therefore obstructed, producing ischemia and necrosis. Because vessels serving
leiomyomas have a larger caliber, these microspheres are preferentially
directed to the tumors, sparing the surrounding myometrium.
An angiographic catheter is
placed in either femoral artery and advanced under fluoroscopic guidance to
selectively catheterize both uterine arteries (Fig. 9-8). Failure to embolize
both uterine arteries allows existing collateral circulation between the two
uterine arteries to sustain leiomyoma blood flow and is associated with a
significantly poorer outcome.
As a result of leiomyoma
necrosis, there typically are significant postprocedural symptoms—the postembolization
syndrome. This usually lasts 2 to 7 days, and it is classically marked by
pelvic pain and cramping, nausea and vomiting, low-grade fever, and malaise.
Intensity of these symptoms varies, and pain management strategies include
oral, intravenous, epidural, or patient-controlled analgesia regimens
(Hovsepian, 2004).
Embolization is effective for
leiomyoma-related symptoms. Pron and associates (2003) followed 538 women after
UAE and found a clinical success rate of 80 percent for bleeding and pain and
91 percent for patient satisfaction. In addition, for most, UAE is associated
with shorter hospital stays and quicker postoperative recovery than
hysterectomy. However, rates of readmission and further treatment for bleeding
are higher with UAE (Edwards, 2007; Hehenkamp, 2005; Pinto, 2003). Long-term
data following UAE are limited. Broder and co-workers (2002) re-evaluated a
group of these women 5 years postprocedure and reported that 27 percent had
required further invasive treatment(s) for their leiomyomas. The American
College of Obstetricians and Gynecologists (2004) currently recommends UAE for
short-term relief of bleeding or pressure symptoms.
There are a number of
complications associated with UAE. Leiomyoma tissue passage is common and
likely is seen only with leiomyomas that have contact with the endometrial
surface. Necrotic tissue that passes into the vagina usually can be removed in
the office. Those that do not pass spontaneously or that remain firmly attached
to the uterine wall may require dilatation and evacuation (Spies, 2002).
Transient amenorrhea, which lasts at most a few menstrual cycles, is also
commonly seen following UAE and is not typically associated with increased FSH
levels or menopausal symptoms. Permanent amenorrhea, however, develops
occasionally. Rarely, serious complications occur following embolization and
include necrosis of surrounding tissues such as the uterus, adnexa, bladder,
and soft tissues.
A number of complications have
been identified in women during pregnancy subsequent to UAE. Goldberg and
colleagues (2004) reported increased risks for preterm delivery and
malpresentation in women who were treated by UAE when compared with pregnancies
that followed laparoscopic myomectomy. Increased incidence of abnormal
placentation has also been identified (Pron, 2005). Due to lack of long-term
outcome data, women who desire future childbearing are not currently considered
candidates for UAE (American College of Obstetricians and Gynecologists, 2004).
As discussed in Chapter 2,
preliminary studies indicate that magnetic resonance imaging–guided focused
ultrasound (MRI-FUS) therapy is a safe and feasible, minimally invasive
alternative for leiomyoma treatment (Chen, 2005; Fennessy, 2007; Stewart, 2003,
2006). It may provide short-term symptom relief with the advantage of a quicker
recovery and few major adverse events. However, little information is available
on the costs and comparisons with other treatments such as UAE.
Bleeding and pain symptoms may
improve in many women using medical treatment or UAE. However, for many,
surgical treatments for leiomyomas are necessary and include hysterectomy,
myomectomy, and myolysis.
Removal of the uterus is the
definitive and most common surgical treatment for leiomyomas. Hysterectomy for
leiomyoma can be performed vaginally, abdominally, or laparoscopically. Between
1994 and 1999, more than 3.5 million hysterectomies were performed in the
United States, and almost a third were performed for the diagnosis of uterine
leiomyoma (Keshavarz, 2002). In a study of 418 women undergoing hysterectomy
for benign gynecologic conditions, Carlson and co-workers (1994) found
hysterectomy for women with symptomatic leiomyomas resulted in satisfaction
rates greater than 90 percent. There were marked improvements in pelvic pain,
urinary symptoms, fatigue, psychological symptoms, and sexual dysfunction.
Removal of the ovaries is not
required, and the decision to perform oophorectomy at the time of hysterectomy
is made based on the usual factors (see Section 41-19, Hysterectomy). Other considerations
prior to hysterectomy include uterine size and preoperative hematocrit. In some
cases, preoperative GnRH agonist use may provide advantages.
Resection of tumors is an
option for symptomatic women who desire future childbearing or for those who
decline hysterectomy. This can be performed laparoscopically,
hysteroscopically, or via laparotomy incision and are described in Section
41-18, Myomectomy.
Myomectomy usually improves
pain, infertility, or bleeding. For example, menorrhagia improves in
approximately 70 to 80 percent of patients (Buttram, 1981; Olufowobi, 2004).
Historically, hysterectomy has
been recommended for women not seeking pregnancy. Many believed that
myomectomy, compared with hysterectomy, carried a greater risk for
perioperative morbidity. As experience accrued, myomectomy has been shown to be
effective and to carry perioperative risks comparable with hysterectomy. In a
number of reports, blood loss, intraoperative injuries, and febrile morbidity
were similar (Iverson, 1996; Sawin, 2000).
Disadvantageously,
postoperative intra-abdominal adhesions and leiomyoma recurrence are more
common after myomectomy compared with hysterectomy (Stricker, 1994). Recurrence
rates following myomectomy range from 40 to 50 percent (Acien, 1996; Fedele,
1995). New leiomyoma development, however, appears diminished in women who
become pregnant following myomectomy, perhaps because of protective effects of
increasing parity (Candiani, 1991).
Laparoscopic leiomyoma
resection may be performed with successful outcomes (Hurst, 2005; Mais, 1996).
In one study, Seracchioli and co-workers (2000) reviewed results of 131 women
following myomectomy for at least one large leiomyoma. They reported equivalent
pregnancy rates with fewer transfusions, shorter hospital stays, and less
febrile morbidity in women undergoing laparoscopic resection compared with
laparotomy. Moreover, laparoscopic myomectomy appears to incite less adhesion formation
than with laparotomy (Bulletti, 1996; Dubuisson, 2000; Takeuchi, 2002).
Limitations to a laparoscopic
approach, however, include uterine size and laparoscopic surgical skills,
especially suturing techniques. Most advocate a one- or two-layer suture
closure of leiomyoma beds following enucleation (Seinera, 1997). In addition,
several investigators have recommended limiting resection to those tumors less
than 8 to 10 cm because of increased hemorrhage and operating time with larger
tumors (Dubuisson, 2001; Takeuchi, 2003).
There are risks associated with
laparoscopic myomectomy. Excision sites have been associated with
uteroperitoneal fistula or with uterine rupture during subsequent pregnancy
(Nezhat, 1996). At times, laparoscopic technique requires conversion to
laparotomy due to bleeding or difficult tumor enucleation. It is unclear
whether laparoscopic myomectomy is associated with greater risk of recurrence.
Rossetti and co-workers (2001) found equivalent rates of leiomyoma recurrence
with laparotomy or laparoscopic myomectomy, whereas Nezhat and colleagues
(1998) found higher rates following laparoscopy.
Resection of submucous
leiomyomas through a hysteroscope has long-term effectiveness of 60 to 90
percent for the treatment of menorrhagia (Derman, 1991; Emanuel, 1999; Hallez,
1995). Hysteroscopic leiomyoma resection also improves fertility rates,
especially when tumors are the sole cause of infertility (Fernandez, 2001;
Vercellini, 1999). In their review, Donnez and Jadoul (2002) calculated an
overall pregnancy rate of 45 percent following hysteroscopic tumor resection in
women with leiomyoma as their sole identified source of infertility.
There are several tissue
destructive modalities that ablate the endometrium and they are discussed in
detail in Section 41-36, Endometrial Ablation Procedures. These techniques are
effective for women with dysfunctional uterine bleeding, but when used as a
sole technique for leiomyoma-related bleeding, the failure rate approaches 40
percent (Goldfarb, 1999; Yin, 1998). In some cases, ablation is used as an
adjunct to hysteroscopic leiomyoma resection in women with menorrhagia.
A number of techniques are
available to induce leiomyoma necrosis and shrinkage and include mono- or
bipolar cautery, laser vaporization, or cryotherapy. All of these techniques
are used laparoscopically and consume a great deal of operating room time,
incite variable degrees of necrosis within the leiomyoma and surrounding normal
myometrium, and produce significant postoperative pain. Data regarding
long-term symptom relief, recurrence rates, and effects on fertility and
pregnancy are lacking. Until clinical trials are done, these are currently
considered experimental.
Ovarian masses are a common
finding in general gynecology. Of these, neoplasms constitute a significant
number, and most are benign. Ovarian neoplasms can be distinguished
histologically and are grouped as surface epithelial tumors, germ cell
tumors, and sex cord-stromal tumors depending on their cell type of
origin (see Fig. 36-1). The types and particular characteristics of these
tumors are discussed in Chapters 35 and 36.
Despite continuous improvement
in diagnostic methods, it is often impossible to clinically differentiate
between benign and malignant conditions. Thus, management must balance concerns
of performing an operation for an innocent lesion with the risk of not removing
an ovarian malignancy.
Most benign and malignant
ovarian masses are predominantly cystic. The incidence of ovarian cysts varies
only slightly with patient demographics and ranges from 5 to 15 percent (Dorum,
2005; Millar, 1993; Porcu, 1994).
Histologically, they are often
divided into those derived from neoplastic growth, ovarian cystic neoplasms,
and those created by disruption of normal ovulation, functional ovarian
cysts. Differentiation of these is not always clinically apparent using
either imaging tools or tumor markers. Accordingly, ovarian cysts are often
managed as a single composite clinical entity.
These cysts often require
excision because of symptoms or the possibility of cancer, and consequently
their economic impact is significant. In their review of indications for
hospitalization in the United States, Velebil and colleagues (1995) reported
that approximately 200,000 women are admitted annually for benign ovarian
cysts, comprising a third of admissions for gynecologic disease.
The exact mechanisms leading to
cyst formation are unclear. Angiogenesis is an essential component of both the
follicular and luteal phases of the ovarian cycle. It also participates in
various pathologic ovarian processes, including follicular cyst formation,
polycystic ovarian syndrome, ovarian hyperstimulation syndrome, and benign and
malignant ovarian neoplasms. There is evidence that vascular endothelial growth
factor serves as a major mediator of angiogenesis, and it factors into the
development of ovarian neoplasms (Abulafia, 2000; Fasciani, 2001; Yamanoto, 1997).
Most women with ovarian cysts
are asymptomatic. If symptoms develop, pain and vague pressure sensations are
common. Cyclic pain with menstruation may indicate endometriosis and an
associated endometrioma (see Chap. 10, Patient Symptoms). Intermittent pain may
reflect early torsion, whereas acute severe pain may indicate torsion with
resulting ovarian ischemia (Ovarian Remnant Syndrome). Other causes of acute
pain include cyst rupture or tubo-ovarian abscess (see Chap. 3, Chronic Pelvic
Inflammatory Disease). In contrast, vague pressure or achiness may be the only
symptom and can result from stretching of the ovarian capsule. In advanced
ovarian malignancies, women complain of increased abdominal girth and early
satiety from ascites or an enlarged ovary.
In some women, evidence of
hormonal disruption may be found. For example, excess estrogen production from
granulosa cell stimulation may disrupt normal menstruation or initiate bleeding
in prepubertal or postmenopausal patients (see Chap. 36, Clinical Findings).
Similarly, virilization may result from increased androgens produced by theca
cell stimulation.
Many ovarian cysts are
asymptomatic and found incidentally on routine pelvic examination or during
imaging studies for another indication. Findings may vary, but typically masses
are mobile, cystic, nontender, and found lateral to the uterus.
In the evaluation of adnexal
pathology, serologic -hCG testing provides valuable information.
Detection of serum -hCG may indicate ectopic pregnancy or a
corpus luteum of pregnancy. Less commonly, -hCG can also serve as a tumor marker in
defining ovarian neoplasm.
-hCG testing provides valuable information.
Detection of serum -hCG may indicate ectopic pregnancy or a
corpus luteum of pregnancy. Less commonly, -hCG can also serve as a tumor marker in
defining ovarian neoplasm.
Tumor markers are typically
proteins that are produced by tumor cells or by the body in response to tumor
cells. Several such markers have been used to identify ovarian malignancies.
Cancer antigen 125 (CA125) is
an antigenic determinant on a high-molecular-weight glycoprotein. As a tumor
marker, serum levels are often elevated in women with epithelial ovarian cancer
(Menon, 1999). Unfortunately, CA125 is not a tumor-specific antigen, and it is
elevated in up to 1 percent of healthy controls. It may also be elevated in
women with nonmalignant disease such as leiomyomas, endometriosis, and
salpingitis. Despite these limitations, serum CA125 determinations may be
helpful and are often used in the evaluation of ovarian cysts.
Serum alpha-fetoprotein (AFP)
levels may be elevated in those rare patients with an endodermal sinus tumor or
embryonal cell carcinoma. Increased serum levels of -hCG may indicate an ovarian choriocarcinoma,
a mixed germ cell tumor, or embryonal cell carcinoma. Lactate dehydrogenase
levels may be increased in those with dysgerminoma, whereas elevated
carcinoembryonic antigen and cancer antigen 19-9 (CA 19-9) levels arise from
secretions of mucinous epithelial ovarian carcinomas (Campo, 1999). A more
detailed discussion of these tumor markers is found in Chapters 36, Laboratory
Testing.
-hCG may indicate an ovarian choriocarcinoma,
a mixed germ cell tumor, or embryonal cell carcinoma. Lactate dehydrogenase
levels may be increased in those with dysgerminoma, whereas elevated
carcinoembryonic antigen and cancer antigen 19-9 (CA 19-9) levels arise from
secretions of mucinous epithelial ovarian carcinomas (Campo, 1999). A more
detailed discussion of these tumor markers is found in Chapters 36, Laboratory
Testing.
Both transvaginal sonography
(TVS) and transabdominal sonography (TAS) are excellent methods, and cyst size
is the main determinant in selecting between the two. For lesions confined to
the true pelvis, TVS has superior resolution, whereas TAS is more useful for
large tumors (Marret, 2001). Characteristic findings for specific types of
ovarian cysts have been described and have also been defined to discriminate
malignant from benign lesions (Table 9-4) (Granberg, 1989; Minaretzis, 1994;
Okugawa, 2001).
Traditional gray-scale
sonography may also be augmented with color flow Doppler. Transvaginal color
Doppler sonography (TV-CDS) may add information regarding the nature of the
lesion, its malignant potential, and the presence of torsion (Emoto, 1997;
Rosado, 1992; Wu, 1994). For assessing simple ovarian cysts and the risk of
malignancy, however, TV-CDS typically adds no significant advantage compared
with conventional TVS (Vuento, 1995).
Use of MR imaging for ovarian
cyst evaluation has been investigated. Although its added value compared with
sonography is limited in most clinical settings, MR imaging may add information
in situations in which anatomy or patient habitus complicates sonographic
imaging (Outwater, 1996).
Most ovarian cysts are
functional, and most spontaneously regress within 6 months of identification.
High-dose oral contraceptive pills have been used by some to hasten cyst
resolution, however, Turan and associates (1994) found no additional benefit to
this adjunctive therapy.
For postmenopausal women with a
simple ovarian cyst, expectant management may also be reasonable. A
number of investigators have confirmed the safety of this approach when several
criteria are met: (1) sonographic evidence of a thin-walled, unilocular cyst;
(2) cyst diameter less than 5 cm; (3) no cyst enlargement during surveillance;
and (4) normal serum CA125 levels (Menon, 1999; Nardo, 2003).
Despite efforts by
investigators to classify lesions by radiologic and serologic means, there is
considerable morphologic similarity among cyst types as well as between those
that are malignant and benign. Accordingly, for many cases, surgical excision
of the cyst serves as the definitive diagnostic tool.
The decision for one surgical
technique in preference over the other is dictated by lesion size, age, and
intraoperative findings. For example, in premenopausal women, smaller lesions
generally require only cystectomy with preservation of reproductive function.
Larger lesions may necessitate oophorectomy because of the difficulty with cyst
enucleation without rupture and the greater risk of malignancy in these larger
cysts. However, in postmenopausal women, oophorectomy is preferred because the
risk for cancer is higher and benefits to ovarian salvage are limited (Okugawa,
2001).
Clinical findings of malignancy
at the time of surgery will dictate further actions. Multiple small lesions
studding the peritoneal surface, ascites, and exophytic growths extending from
the ovarian capsule should prompt appropriate clinical staging and treatment
for ovarian cancer as discussed in Chapter 35, Management of Early-Stage
Ovarian Cancer.
The surgical approach for cyst
excision is also dictated by clinical factors. Laparoscopy has many advantages,
but it generally has been underused for management of ovarian cysts. Concerns
of increased rates of cyst rupture with the risk for tumor spill and malignant
seeding have caused many to avoid this modality. That said, several
investigators have documented the safety of laparoscopic cystectomy and
oophorectomy (Lin, 1995; Mais, 1995; Yuen, 1997).
For small or moderately sized
cysts, laparotomy incisions can usually be minimized. As a result, most who
undergo mini-laparotomy can be discharged the day of surgery (Berger, 1994;
Flynn, 1999). Although mini-laparotomy typically offers shorter operative
times, lower rates of cyst rupture, and greater cost savings compared with
laparoscopy or laparotomy, this approach can limit lysis of adhesions and
inspection of peritoneal surfaces for signs of ovarian malignancy.
Women with a greater potential
for malignancy are best managed by laparotomy, as it provides a surgical field
large enough for oophorectomy or cyst enucleation without tumor rupture or
spill and for surgical staging if malignancy is found.
Historically, there has been
hesitation to aspirate ovarian cysts because of possible intraperitoneal
seeding by early stage ovarian cancer. Moreover, nondiagnostic, false-positive,
and false-negative results are common (Dejmek, 2003; Martinez-Onsurbe, 2001;
Moran, 1993). For these reasons, very few indications exist for this procedure.
Ovarian cysts frequently
require surgical treatment. Most of these lesions are benign and typically are
removed by general gynecologists. When malignancy is present, however, formal
cancer staging should accompany excision. Studies support that optimal surgical
resection and proper staging performed by gynecologic oncologists during the
primary operation for ovarian cancers are major factors in long-term survival.
Thus, women with pelvic masses and preoperative findings suspicious for
malignancy are generally referred. The American College of Obstetricians and
Gynecologists and Society of Gynecologic Oncologists (2002) have presented
guidelines regarding clinical criteria that should prompt referral to a
gynecologic oncologist (Table 9-5). If one or more criteria from this list or
other suspicious findings are identified, referral should follow (Im, 2005).
Of the different type of
ovarian cysts, functional ovarian cysts are common. They originate from
follicles and are created by hormonal dysfunction related to ovulation. They
are subcategorized as either follicular cysts or corpus luteum cysts
based on both their pathogenesis and histologic qualities. They are not
neoplasms and derive mass from accumulation of intrafollicular fluids rather
than cellular proliferation. Hormonal dysfunction prior to ovulation results in
expansion of the follicular antrum with serous fluid and formation of a
follicular cyst. In contrast, following ovulation excessive hemorrhage may fill
the corpus luteum, creating corpus luteum cysts. Although these cysts generally
have similar symptoms and management, they differ in the potential hormones
produced as well as histologic appearance.
Several epidemiologic studies
have linked smoking with functional cyst development (Holt, 2005; Wyshak,
1988). Although the exact mechanism(s) by which cigarette smoking exerts its
effect is not known, changes in gonadotropin secretion and ovarian function are
suspected (Michnovicz, 1986; Zumoff, 1990).
High-dose oral hormonal
contraceptives suppress ovarian activity and protect against cyst development
(Ory, 1974). Subsequent studies, however, have shown only modest protective
effects from low-dose monophasic or low-dose triphasic contraceptives
(Chiaffarino, 1998; Holt, 2003).
By contrast, there is an
increased incidence of follicular cysts reported with many progestin-only
contraceptives. Recall that continuous, low-dose progestins do not completely
suppress ovarian function (see Chap. 5, Oral Progestins). As a result, dominant
follicles may develop in response to gonadotropin secretion, yet the normal
ovulatory process is frequently disrupted. Follicles fail to rupture and
follicular cysts develop. In clinical studies, cystic masses were found on
bimanual pelvic examination in 2 to 9 percent of women using the progestin-only
implants (Brache, 2002). Similarly, levonorgestrel-containing intrauterine
devices have been associated with the development of functional ovarian cysts
(Inki, 2002).
One intriguing observation is
that bilateral tubal ligation has been associated with an increased risk of
these cysts (de Alba, 2000; Holt, 2003). The mechanism for this is unclear.
Women treated with tamoxifen
for breast cancer—either pre- or postmenopausal—have an increased risk for
ovarian cyst formation. Most studies report rates of 15 to 30 percent compared
with 7 percent cited for the general postmenopausal population (Cohen, 2003;
Mourits, 1999). Premenopausal women are disparately affected, and from 30 to 80
percent of women in this age group develop cysts (Mourits, 1999; Shushan,
1996).
Most of these are believed to
be functional cysts, but the exact mechanism by which tamoxifen stimulates
their formation is unknown. Fortunately, the majority of these cysts resolve
with time whether tamoxifen treatment is continued or discontinued (Lindahl,
1997; Shushan, 1996). If small simple cysts are found, these women should
undergo sonographic surveillance. However, if clinical signs of malignancy are
present (see Table 9-5), then surgical exploration is indicated and tamoxifen
use is discontinued.
Functional cysts are managed
similarly to other cystic ovarian lesions. Consequently, sonography is the
imaging tool of choice for evaluation. Typically, follicular cysts are
completely rounded anechoic lesions with thin, regular walls (Fig. 9-10).
Conversely, corpus luteum cysts
are termed "great imitators" because of their varied sonographic
characteristics (Fig. 9-11). Immediately following hemorrhage into its cavity,
the cyst generally appears echogenic and mimics a solid mass. With evolution of
the clot, a lacy reticular pattern develops. As the clot hemolyzes, a distinct
line often forms between the serum and retracting clot. With further
retraction, the clot may appear as an intramural nodule. Imaging with
transvaginal color Doppler typically displays a brightly colored ring because
of their increased surrounding vascularity (Swire, 2004; Yoffe, 1991). This ring
of fire is also common to ectopic pregnancies (see Fig. 7-7).
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