Pathophysiology Uterine fibroid

1 pathophysiology

1.1 location , classification

1.1.1 extrauterine fibroids of uterine origin, metastatic fibroids


1.2 pathogenesis

pathophysiology

an enucleated uterine leiomyoma – external surface on left, cut surface on right.

fibroids type of uterine leiomyoma. fibroids grossly appear round, circumscribed (but not encapsulated), solid nodules white or tan, , show whorled appearance on histological section. size varies, microscopic lesions of considerable size. typically lesions size of grapefruit or bigger felt patient herself through abdominal wall.

micrograph of lipoleiomyoma, type of leiomyoma. h&e stain.

microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, cigar-shaped nucleus) , form bundles different directions (whorled). these cells uniform in size , shape, scarce mitoses. there 3 benign variants: bizarre (atypical); cellular; , mitotically active.

the appearance of prominent nucleoli perinucleolar halos should alert pathologist investigate possibility of extremely rare hereditary leiomyomatosis , renal cell cancer (reed) syndrome.

location , classification

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 broad ligament

growth , location main factors determine if fibroid leads symptoms , problems. small lesion can symptomatic if located within uterine cavity while large lesion on outside of uterus may go unnoticed. different locations classified follows:

intramural fibroids located within muscular wall of uterus , common type. unless large, may asymptomatic. intramural fibroids begin small nodules in muscular wall of uterus. time, intramural fibroids may expand inwards, causing distortion , elongation of uterine cavity.
subserosal fibroids located on surface of uterus. can grow outward surface , remain attached small piece of tissue , called pedunculated fibroids. these pedunculated growths can detach uterus become parasitic leiomyoma.
submucosal fibroids located in muscle beneath endometrium of uterus , distort uterine cavity; small lesions in location may lead bleeding , infertility. pedunculated lesion within cavity termed intracavitary fibroid , can passed through cervix.
cervical fibroids located in wall of cervix (neck of uterus). rarely, fibroids found in supporting structures (round ligament, broad ligament, or uterosacral ligament) of uterus contain smooth muscle tissue.

fibroids may single or multiple. fibroids start in muscular wall of uterus. further growth, lesions may develop towards outside of uterus or towards internal cavity. secondary changes may develop within fibroids hemorrhage, necrosis, calcification, , cystic changes. tend calcify after menopause.

if uterus contains many count, referred diffuse uterine leiomyomatosis.

extrauterine fibroids of uterine origin, metastatic fibroids

fibroids of uterine origin located in other parts of body, called parasitic myomas have been historically extremely rare, diagnosed increasing frequency. may related or identical metastasizing leiomyoma.

they in cases still hormone dependent may cause life-threatening complications when appear in distant organs. sources suggest substantial share of cases may late complications of surgeries such myomectomy or hysterectomy. particularly laparoscopic myomectomy using morcellator has been associated substantially increased risk of complication.

there number of rare conditions in fibroids metastasize. still grow in benign fashion, can dangerous depending on location.

in leiomyoma vascular invasion, ordinary-appearing fibroid invades vessel there no risk of recurrence.
in intravenous leiomyomatosis, leiomyomata grow in veins uterine fibroids source. involvement of heart can fatal.
in benign metastasizing leiomyoma, leiomyomata grow in more distant sites such lungs , lymph nodes. source not entirely clear. pulmonary involvement can fatal.
in disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on peritoneal , omental surfaces, uterine fibroids source. can simulate malignant tumor behaves benignly.

pathogenesis

multiple uterine leiomyoma



large subserosal fibroid



multiple uterine leiomyoma calcification

fibroids monoclonal tumors , approximately 40 50% show karyotypically detectable chromosomal abnormalities. when multiple fibroids present have unrelated genetic defects. specific mutations of med12 protein have been noted in 70 percent of fibroids.

the exact cause of fibroids not understood, current working hypothesis genetic predispositions, prenatal hormone exposure , effects of hormones, growth factors , xenoestrogens cause fibroid growth. known risk factors african descent, obesity, polycystic ovary syndrome, diabetes, hypertension, , never having given birth.

it believed estrogen , progesterone have mitogenic effect on leiomyoma cells , act influencing (directly , indirectly) large number of growth factors, cytokines , apoptotic factors other hormones. furthermore, actions of estrogen , progesterone modulated cross-talk between estrogen, progesterone , prolactin signaling controls expression of respective nuclear receptors. believed estrogen promotes growth up-regulating igf-1, egfr, tgf-beta1, tgf-beta3 , pdgf, , promotes aberrant survival of leiomyoma cells down-regulating p53, increasing expression of anti-apoptotic factor pcp4 , antagonizing ppar-gamma signaling. progesterone thought promote growth of leiomyoma through up-regulating egf, tgf-beta1 , tgf-beta3, , promotes survival through up-regulating bcl-2 expression , down-regulating tnf-alpha. progesterone believed counteract growth downregulating igf-1. expression of transforming growth interacting factor (tgif) increased in leiomyoma compared myometrium. tgif potential repressor of tgf-β pathways in myometrial cells.

aromatase , 17beta-hydroxysteroid dehydrogenase aberrantly expressed in fibroids, indicating fibroids can convert circulating androstenedione estradiol. similar mechanism of action has been elucidated in endometriosis , other endometrial diseases. aromatase inhibitors considered treatment, @ doses inhibit estrogen production in fibroid while not largely affecting ovarian production of estrogen (and systemic levels of it). aromatase overexpression particularly pronounced in african-american women.

genetic , hereditary causes being considered , several epidemiologic findings indicate considerable genetic influence onset cases. first degree relatives have 2.5-fold risk, , 6-fold risk when considering onset cases. monozygotic twins have double concordance rate hysterectomy compared dizygotic twins.

expansion of uterine fibroids occurs slow rate of cell proliferation combined production of copious amounts of extracellular matrix.

a small population of cells in uterine fibroid have properties of stem cells or progenitor cells, , contribute ovarian steroid-dependent growth of fibroids. these stem-progenitor cells deficient in estrogen receptor α , progesterone receptor , instead rely on substantially higher levels of these receptors in surrounding differentiated cells mediate estrogen , progesterone actions via paracrine signaling.