UTERINE LEIOMYOMA, LEIOMYOSARCOM

Pressure on adjacent organs. As leiomyomas enlarge, they may produce pressure on surrounding structures. Patients sense a progressive pelvic fullness. The significant manifestations of pressure from leiomyomas include the following:

(i) anterior leiomyomas may cause compression of the bladder with resultant urinary frequency or incontinence; (ii) similarly, posterior leiomyomas that impinge on the rectosigmoid may cause constipation; (iii) intraligamentous lesions may compress the ureter along the pelvis wall, resulting in hydroureter or hydronephrosis.

Pelvic pain is the second most common symptom in uterine leyomyomas. Pain is related to:

(i) compression of organs or nerves from large leiomyomas; (ii) torsion of pedunculated fibroids; or (iii) outgrowing of the blood supply and the development of degenerative changes

The mechanism of abnormal uterine bleeding in women with leiomyoma has not been clearly delineated. Studies provide support for two mechanisms.

(i) intramural leiomyoma deranges the venous drainage from endometrium to parametrium causing congestion and menorrhagia by back-pressure on the endometrium; (ii) leiomyomas produce large amounts of growth factors that promote angiogenesis by inducing endothelial cell proliferation in the tumoral mass and in the uterus in general.

PATHOLOGY. Uterine LMSs present as large solitary tumors. The gross appearance is very helpful in distinguishing them from their benign counterpart:

(i) they tend to produce a relatively large mass (the mean tumor diameter is 6 cm); (ii) they tend to be less circumscribed, softer, less trabeculated or whorled, and more variegated; (iii) areas of necrosis with or without hemorrhage are found in most cases

DEGENERATIVE CHANGES. As leiomyomas enlarge, they outgrow their blood supply. The result is development various types of degenerations which are common in uterine leiomyomas. Larger the leiomyoma, the more likely it is that some forms of degeneration will be present. Clinical signs of uterine leiomyoma degeneration include acute onset of abdominal pain associated sometime with low-grade fever and leukocytosis. Types of changes seen:

1. Hyaline degeneration. Up to 60% of tumors shows this type of degeneration. Hyaline degeneration involves the replacement of smooth muscle cells by homogenous eosinophilic bands or plaques composed of dense accumulations of collagen fibers. 2. Myxoid degeneration. Myxoid degeneration involves the presence of gelatinous intratumoral foci, due to intratumoral accumulation of hyaluronic acid rich mucopolysaccharides. 3. Red degeneration. Red degeneration is a hemorrhagic infarction of the uterine leiomyoma that often occurs during pregnancy. It is due to venous thrombosis, which induces extensive hemorrhagic infarction that involves the entire lesion. Grossly, the tumor has a deep red appearance. 4. Cystic degeneration. Cystic degeneration results from liquefactive or hydropic degeneration in which large pools of watery fluid accumulates in the interstitium. 5. Calcification. Dystrophic calcification may also be observed in uterine leiomyomas. Dystrophic calcification is the end stage of hyaline degeneration.

TUMOR SPREAD AND PROGNOSIS. LMSs are confined to the uterus at presentation in 70-75% of patients. The 5-year survival rate is only 50% with patients whose tumor is confined to the uterus. Surgical removal, if possible, is the best treatment. Despite complete surgical removal and best available treatments, approximately

70% of patients will develop a recurrence within an average of 8 to 16 months after the initial diagnosis. Recurrent uterine LMS is difficult to manage. Chemotherapy and radiation therapy have limited roles in the treatment of these tumors. • Uterine LMS tends to metastasize to the lungs, peritoneum, bones, or liver. Women with uterine LMS that has spread beyond the uterus and cervix have an extremely poor prognosis. Death often occurs within 2 years of diagnosis

Intramural leiomyomas comprise

99% of all leiomyomas. They are often asymptomatic. However, they can be associated with abnormal uterine bleeding and infertility.

Ethnicity and leiomyoma

African American women have 3 times greater risk of having uterine leiomyomas than Caucasian women. African American women also have myomas present at a younger age, and have more numerous, larger and more symptomatic myomas.

DIAGNOSIS Leiomyomas.

Pelvic examination can identify large subserosal and intramural leiomyomas based on findings of a bulky, large, irregular, or firm uterus. Transabdominal ultrasonography cannot detect myomas smaller than 1 cm. Transvaginal approaches allow for detailed high-resolution images and can detect even myomas of 0.5 cm-diameter. However, subserosal leiomyomas remain outside the field of view in this modality. MRI is the best diagnostic technique that enables accurate classification of individual masses as submucosal, intramural or subserosal. Hysteroscopic evaluation of leiomyomas is particularly useful in women with submucosal tumors. The advantages of this technique include surgical intervention at the time of hysteroscopic evaluation.

Submucosal leiomyomas.

These tumors account for only 5% of uterine leiomyomas, and they are most commonly symptomatic. They tend to be associated with dysmenorrhea and menorrhagia. In rare instances, submucosal leiomyoma may become pedunculated and protrude into the cervical canal or vagina.

Subserosal leiomyomas.

These tumors are usually asymptomatic. However, pedunculated subserosal leiomyomas may undergo torsion, which results in infarction of the tumor accompanied by pain.

Most individuals with uterine leiomyomas are asymptomatic. Only a small fraction of patients with leiomyomas presents with clinical symptoms. The clinical presentation is variable, depending on the size, location and number of tumors. The four major symptoms of leiomyomas are

abnormal uterine bleeding, pressure on adjacent organs, pain, and infertility.

Age. Leiomyomas are associated with the

active reproductive period. The age range of women with uterine leiomyomas is 20-55 years, with a mean age of 42 years. This shows that uterine leiomyomas are dependent on ovarian hormones: they are diagnosed only after menarche, and they tend to decline after menopause. Large uterine leiomyomas are common by the time women reach their 40s. • Postmenopausal women have a 70-90% reduced risk of uterine leiomyomas which could be due to tumor regression in the absence of hormonal stimulus following the menopause. But some leiomyomas persist after menopause

Microscopically, LMSs show intersecting fascicles of spindle cells which are elongated, with eosinophilic fibrillary cytoplasm and elongated blunt-ended nuclei. • The distinction between benign and malignant uterine smooth muscle cell tumors is established by the assessment of three histological features -

cytological atypia, tumor cell necrosis, and mitotic activity. ◦ Nuclear pleomorphism, enlarged nuclei and hyperchromatism observed at low-power magnification are indicators of significant cytological atypia. ◦ Tumor cell necrosis is defined as an abrupt transition between viable and necrotic tumor without an interposed zone of granulation tissue or hyalinized collagen. A perivascular distribution of viable tumor is also characteristic of tumor cell necrosis. ◦ Uterine LMSs have a high mitotic activity, which exceeds 10 mitoses per 10 high power microscopic fields (>10MF/10HPF).

Exercise. Former college athletes have 40% lower prevalence of leiomyomas compared with non-athletes. It is not clear whether this difference represents the

effects of exercise or the effects of relative leanness.

Obesity is associated with an increased incidence of uterine leiomyoma. Obese individuals are characterized by a significant increase of

estrogen level, due to conversion of circulating adrenal androgens to estrone by excess adipose tissue. All circulating estrogens postmenopausally are derived from the metabolism of circulating androgens.

PATHOLOGY Uterine Leiomyomas.

firm, spherical, and well circumscribed, although there is no true capsule. Their cut surface is gray white with a characteristic trabeculated or whorled appearance. The size of uterine leiomyomas is variable, ranging from microscopic to large tumors that fill the abdomen. One of the most striking features is the very sharp line of demarcation between the tumor and the surrounding myometrium. This forms a plane of cleavage that enables the leiomyoma to be shelled out at myomectomy. In about two-thirds of women with uterine leiomyoma, multiple myomas are present. • Leiomyomas are composed predominantly of fascicles of uniform smooth muscle cells separated by variable amounts of fibrous connective tissue. The neoplastic smooth muscle cells are markedly elongated, have eosinophilic cytoplasm and elongated cigar-shaped nuclei that show blunt ends. Nuclei are uniform and mitoses are very infrequent (<5 mitotic figures per 10 high-power microscopic fields) (<5MF/10HPF). • Uterine leiomyomas stain positively for the following immunohistochemistry markers: estrogen and progesterone receptors, smooth muscle actin, desmin, and caldesmon. They stain negatively for CD10.

Polycystic ovary syndrome is associated with 65% higher incidence of uterine leiomyomas. This correlation is due to the

hyperestrogenic status, which is typical in this condition

Smoking. Current smoking is associated with 20% - 50% lower risk for uterine leiomyomas. The inverse correlation between smoking and fibroids has been commonly attributed to the fact that smoking

induces enzymes of estrogen metabolism.

It has been shown that MED12 and HMGA2 aberrations are mutually exclusive, suggesting that these represent the two major initiators of leiomyoma formation. On the other hand, both estradiol and progesterone are critical for

leiomyoma growth: in fact, they are considered as promoters of leiomyoma growth. • Estrogen acts primarily by increasing cell responsiveness to progesterone. At the fibroid level, the number of progesterone receptors is elevated. There is growing evidence that biding of progesterone to its receptors directly activates signaling systems that promote proliferation and survival of leiomyomas. Progesterone, through its receptor, activates the MAPK and PI3K/AKT signaling pathways. Also, progesterone increases the expression of growth factor signaling pathways (EGF, IGF-I, TGF-β3).

• The recent molecular studies have shown that basic fibroblast growth factor (bFGF) and parathyroid hormone-related protein (PTHrP) are markedly expressed in

leiomyomas compared to normal myometrium. Overexpression of these mediators results in the development of venular ectasia at the periphery of leiomyomas and especially in the endometrium. With ecstatic venules, the hemostatic actions of the platelet and fibrin plug are overwhelmed by the increased diameter of the vessels which causes the excessively heavy menses clinically seen in many women with uterine leiomyoma.

Abnormal uterine bleeding is the most frequent manifestation of symptomatic leiomyomas. The most common types of uterine leiomyoma associated with heavy bleeding are intramural or submucosal leiomyomas. This bleeding may manifest as

menorrhagia (excessive > 80 mL bleeding during the menstrual periods) or metrorrhagia (intermenstrual bleeding or excessive bleeding occurring at completely irregular intervals). Both result in iron-deficiency anemia.

Glucose-6-phosphate dehydrogenase isoenzyme analysis has found that uterine leiomyomas are

monoclonal proliferations. If multiple tumors in the same uterus are found, each is clonally distinct.

The clinical symptoms of LMS are nonspecific and not significantly different from those of leiomyoma. Patients present with abnormal vaginal bleeding, palpable pelvic mass, and pelvic pain. • Preoperative distinction between the two tumors may be difficult. Nevertheless, malignancy should be suspected if the patient is a

postmenopausal woman not on hormonal replacement therapy or if rapid increase in the size of the uterus occurs after menopause.

Pregnancy-related complications. Up to 4% of pregnancies are affected by leiomyomas. About 20% of leiomyomas increase in size during the pregnancy. Complications attributed to leiomyomas include

recurrent miscarriage, antepartum hemorrhage, placental disturbances including placental insufficiency and placental abruption, increased risk of preterm labor and delivery, and acute degenerative changes of the tumor secondary to decreased perfusion or torsion.

Uterine leiomyoma (also known as myoma, fibromyoma) is a benign tumor of the

smooth muscle cells of the myometrium, colloquially known as "fibroid". EPIDEMIOLOGY. Uterine leiomyoma is the most common gynecologic tumor. It has been postulated that uterine leiomyomas occur in over 70% of women by the onset of menopause. They are estimated to be clinically apparent in 25% of women of reproductive age and cause symptoms severe enough in approximately 25% of women with uterine leiomyomas to require treatment. • The age distribution peaks in the 35-45 years age range, with a mean age of 42 years. Uterine leiomyomas are seldom seen before the menarche. They undergo involution after menopause. • Uterine leiomyomas occur 3 times as often among African American women as Caucasian women. The reasons for this difference are not known. Rates of uterine leiomyomas among Hispanic and Asian women are like those among Caucasians.

Approximately 40% of uterine leiomyomas have chromosomal abnormalities. The chromosomal anomaly most commonly identified in uterine leiomyomas is the

t(12;14)(q14-15:q23-24) translocation. The chromosomal region 12q14-15 encodes for HMGA2 protein. This protein contains structural DNA-binding domains and acts as a transcriptional regulating factor. The fusion partner of HMGA2 in uterine leiomyomas with t(12;14) translocation is RAD51L1, a DNA repair gene. The t(12;14) fusion gene causes high levels of HMGA2 protein overexpression in uterine tissue. HMGA2 gene is silenced in normal adult tissues. The overexpression of HMGA2 in tissues is commonly associated with both malignant and benign tumor formation.

Most uterine leiomyomas involve what part of the uterine corpus

the myometrium of the uterine corpus. According to their anatomical location, leiomyomas are classified as submucosal (projecting into the endometrial cavity), intramural (within the substance of the myometrium), or subserosal (beneath the serosa). This classification is of clinical significance because symptoms and treatment vary among these subtypes of leiomyomas.

DEFINITION. Uterine leiomyosarcoma (LMS) is a rare malignant tumor arising from

the smooth muscle cells of the myometrium. LMSs are thought to develop independently from uterine leiomyomas.

Infertility. The relationship between uterine leiomyomas and subfertility is difficult to establish. Fibroids are known to occur more frequently in women with fertility problems, they are thought to be responsible for 2-3% of cases of infertility. Uterine leiomyoma has been demonstrated to cause high-frequency uterine peristalsis during the

time period of the implantation window (luteal phase day 5-9), which affects the embryo implantation in a negative manner, perhaps by expelling embryos from the uterine cavity

Studies have registered a protective effect of pregnancy on the development of

uterine leiomyoma with high parity (three or more deliveries) decreasing the risk of fibroids up to 5-fold. The explanation of these findings is that pregnancy reduces the time of exposure to unopposed estrogens, whereas nulliparity may be associated with anovulatory cycles characterized by long term unopposed estrogen.

The MED12 gene on chromosome Xq13.1 is mutated at high frequency (70%) in

uterine leiomyomas. The MED12 gene encodes a protein called mediator complex subunit 12, which is involved in transcriptional regulation of the RNA polymerase II complex. The most common MED12 abnormality in leiomyomas is a point mutation (Gly44Asp) predicted to substitute glycine with aspartic amino acid. This MED12 mutation cause leiomyomas via a gain of function that drives genomic instability

TP53 is the most commonly mutated gene in About 32% of the

uterine leiomyosarcomas harbor mutations of the TP53 gene. Most of them are missense mutations that are known to alter the protein structure and inhibit its tumor suppressor function. • Mutations of the ATRX gene have been identified in 26% of cases. ATRX gene encodes a transcriptional regulator that contains an ATPase/helicase domain; it is thus a member of the SWI/SNF2 family of chromatin remodeling proteins. ATRX mediates chromatin remodeling and plays an important role in DNA methylation and gene expression. • ATRX plays a key role in maintaining genomic stability as well, through its deposition of H3.3 at telomeres. These interactions are important for maintaining silencing at these sites. Loss of ATRX expression has been associated with ALT (alternative lengthening of telomeres) pathway. Some malignancies use the ALT pathway and not activation of the telomerase to counteract the telomere attrition occurring through cell division. • MED12 gene is mutated in 9% of cases. This suggests that a small fraction of leiomyosarcomas may develop from existing leiomyomas.