Histology and pathogenesis of uterine leiomyomas (fibroids)
- Elizabeth A Stewart, MD
Elizabeth A Stewart, MD
- Consultant and Professor of Obstetrics and Gynecology
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology
- Mayo Clinic and Mayo Medical School
Uterine leiomyomas (fibroids) are the most common pelvic tumor in women [1,2]. They are benign monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids . The disease is heterogeneous and different fibroids may have different etiologies; many may have multifactorial pathogenesis . Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri and there is evidence of both histological changes in the endometrium and endometrial vasculature in these uteri [5,6].
The pathogenesis of uterine leiomyomas is reviewed here. The diagnosis and management of leiomyomas as well as variants of leiomyomas are discussed separately. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)" and "Overview of treatment of uterine leiomyomas (fibroids)" and "Variants of uterine leiomyomas (fibroids)".)
Uterine leiomyomas are benign monoclonal tumors arising from the smooth muscle cells of the myometrium. They contain a large amount of extracellular matrix (ECM, collagen, proteoglycan, fibronectin) and are surrounded by a thin pseudocapsule of areolar tissue and compressed muscle fibers.
Leiomyomas are benign lesions. However, there is a heterogeneous group of lesions which have some, but not all, characteristics of malignant disease termed leiomyoma variants. Leiomyoma variants are classified as benign or malignant based upon histologic features. Some leiomyoma variants have histologic findings that make it difficult to define them as benign or malignant (eg, smooth muscle tumors of uncertain malignant potential). This is discussed in detail separately. (See "Variants of uterine leiomyomas (fibroids)", section on 'Smooth muscle tumors of uncertain malignant potential'.)
At least two distinct components contribute to leiomyoma development:
- Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981; 36:433.
- Serden SP, Brooks PG. Treatment of abnormal uterine bleeding with the gynecologic resectoscope. J Reprod Med 1991; 36:697.
- Stewart EA. Uterine fibroids. Lancet 2001; 357:293.
- Peddada SD, Laughlin SK, Miner K, et al. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci U S A 2008; 105:19887.
- Stewart EA, Nowak RA. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Hum Reprod Update 1996; 2:295.
- Patterson-Keels LM, Selvaggi SM, Haefner HK, Randolph JF Jr. Morphologic assessment of endometrium overlying submucosal leiomyomas. J Reprod Med 1994; 39:579.
- Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94:435.
- Hashimoto K, Azuma C, Kamiura S, et al. Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene. Gynecol Obstet Invest 1995; 40:204.
- Mashal RD, Fejzo ML, Friedman AJ, et al. Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata. Genes Chromosomes Cancer 1994; 11:1.
- Mehine M, Kaasinen E, Mäkinen N, et al. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 2013; 369:43.
- Linder D, Gartler SM. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science 1965; 150:67.
- Rein MS, Friedman AJ, Barbieri RL, et al. Cytogenetic abnormalities in uterine leiomyomata. Obstet Gynecol 1991; 77:923.
- Stewart EA, Morton CC. The genetics of uterine leiomyomata: what clinicians need to know. Obstet Gynecol 2006; 107:917.
- Van de Ven WJ. Genetic basis of uterine leiomyoma: involvement of high mobility group protein genes. Eur J Obstet Gynecol Reprod Biol 1998; 81:289.
- Mäkinen N, Mehine M, Tolvanen J, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science 2011; 334:252.
- McGuire MM, Yatsenko A, Hoffner L, et al. Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS One 2012; 7:e33251.
- Li S, Chiang TC, Davis GR, et al. Decreased expression of Wnt7a mRNA is inversely associated with the expression of estrogen receptor-alpha in human uterine leiomyoma. J Clin Endocrinol Metab 2001; 86:454.
- Tanwar PS, Lee HJ, Zhang L, et al. Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod 2009; 81:545.
- Ono M, Yin P, Navarro A, et al. Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A 2013; 110:17053.
- Ono M, Yin P, Navarro A, et al. Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril 2014; 101:1441.
- Varghese BV, Koohestani F, McWilliams M, et al. Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway. Proc Natl Acad Sci U S A 2013; 110:2187.
- Everitt JI, Wolf DC, Howe SR, et al. Rodent model of reproductive tract leiomyomata. Clinical and pathological features. Am J Pathol 1995; 146:1556.
- Crabtree JS, Jelinsky SA, Harris HA, et al. Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway. Cancer Res 2009; 69:6171.
- Wang T, Zhang X, Obijuru L, et al. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer 2007; 46:336.
- Marsh EE, Lin Z, Yin P, et al. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril 2008; 89:1771.
- Zavadil J, Ye H, Liu Z, et al. Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas. PLoS One 2010; 5:e12362.
- Georgieva B, Milev I, Minkov I, et al. Characterization of the uterine leiomyoma microRNAome by deep sequencing. Genomics 2012; 99:275.
- Cirilo PD, Marchi FA, Barros Filho Mde C, et al. An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas. PLoS One 2013; 8:e57901.
- Hodge JC, Morton CC. Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hum Mol Genet 2007; 16 Spec No 1:R7.
- Christacos NC, Quade BJ, Dal Cin P, Morton CC. Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features. Genes Chromosomes Cancer 2006; 45:304.
- Taran FA, Weaver AL, Gostout BS, Stewart EA. Understanding cellular leiomyomas: a case-control study. Am J Obstet Gynecol 2010; 203:109.e1.
- Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer 2011; 10:397.
- Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 1998; 83:1875.
- Okolo SO, Gentry CC, Perrett CW, Maclean AB. Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features. Hum Reprod 2005; 20:2321.
- Van Voorhis BJ, Romitti PA, Jones MP. Family history as a risk factor for development of uterine leiomyomas. Results of a pilot study. J Reprod Med 2002; 47:663.
- Tsibris JC, Segars J, Coppola D, et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril 2002; 78:114.
- Wang H, Mahadevappa M, Yamamoto K, et al. Distinctive proliferative phase differences in gene expression in human myometrium and leiomyomata. Fertil Steril 2003; 80:266.
- Skubitz KM, Skubitz AP. Differential gene expression in uterine leiomyoma. J Lab Clin Med 2003; 141:297.
- Hoffman PJ, Milliken DB, Gregg LC, et al. Molecular characterization of uterine fibroids and its implication for underlying mechanisms of pathogenesis. Fertil Steril 2004; 82:639.
- Andersen J, Barbieri RL. Abnormal gene expression in uterine leiomyomas. J Soc Gynecol Investig 1995; 2:663.
- Cesen-Cummings K, Copland JA, Barrett JC, et al. Pregnancy, parturition, and prostaglandins: defining uterine leiomyomas. Environ Health Perspect 2000; 108 Suppl 5:817.
- Chegini N, Verala J, Luo X, et al. Gene expression profile of leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy. J Soc Gynecol Investig 2003; 10:161.
- Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab 1994; 78:736.
- Folkerd EJ, Newton CJ, Davidson K, et al. Aromatase activity in uterine leiomyomata. J Steroid Biochem 1984; 20:1195.
- Shozu M, Sumitani H, Segawa T, et al. Overexpression of aromatase P450 in leiomyoma tissue is driven primarily through promoter I.4 of the aromatase P450 gene (CYP19). J Clin Endocrinol Metab 2002; 87:2540.
- Imir AG, Lin Z, Yin P, et al. Aromatase expression in uterine leiomyomata is regulated primarily by proximal promoters I.3/II. J Clin Endocrinol Metab 2007; 92:1979.
- Ishikawa H, Reierstad S, Demura M, et al. High aromatase expression in uterine leiomyoma tissues of African-American women. J Clin Endocrinol Metab 2009; 94:1752.
- Kasai T, Shozu M, Murakami K, et al. Increased expression of type I 17beta-hydroxysteroid dehydrogenase enhances in situ production of estradiol in uterine leiomyoma. J Clin Endocrinol Metab 2004; 89:5661.
- Brandon DD, Erickson TE, Keenan EJ, et al. Estrogen receptor gene expression in human uterine leiomyomata. J Clin Endocrinol Metab 1995; 80:1876.
- Brandon DD, Bethea CL, Strawn EY, et al. Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas. Am J Obstet Gynecol 1993; 169:78.
- Stewart EA, Austin DJ, Jain P, et al. RU486 suppresses prolactin production in explant cultures of leiomyoma and myometrium. Fertil Steril 1996; 65:1119.
- Ishikawa H, Ishi K, Serna VA, et al. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology 2010; 151:2433.
- Matsuo H, Maruo T, Samoto T. Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone. J Clin Endocrinol Metab 1997; 82:293.
- Yin P, Lin Z, Cheng YH, et al. Progesterone receptor regulates Bcl-2 gene expression through direct binding to its promoter region in uterine leiomyoma cells. J Clin Endocrinol Metab 2007; 92:4459.
- Yin H, Lo JH, Kim JY, et al. Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids. Mol Endocrinol 2013; 27:726.
- Chang HL, Senaratne TN, Zhang L, et al. Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium. Reprod Sci 2010; 17:158.
- Ono M, Qiang W, Serna VA, et al. Role of stem cells in human uterine leiomyoma growth. PLoS One 2012; 7:e36935.
- Sampson, JA. The blood supply of uterine myomata. Surg Gynecol Obstet 1912; 14:215.
- Stewart EA, Nowak RA. New concepts in the treatment of uterine leiomyomas. Obstet Gynecol 1998; 92:624.
- Faerstein E, Szklo M, Rosenshein NB. Risk factors for uterine leiomyoma: a practice-based case-control study. II. Atherogenic risk factors and potential sources of uterine irritation. Am J Epidemiol 2001; 153:11.
- Mangrulkar RS, Ono M, Ishikawa M, et al. Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium. Biol Reprod 1995; 53:636.
- Anania CA, Stewart EA, Quade BJ, et al. Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding. Mol Hum Reprod 1997; 3:685.
- Lee BS, Stewart EA, Sahakian M, Nowak RA. Interferon-alpha is a potent inhibitor of basic fibroblast growth factor-stimulated cell proliferation in human uterine cells. Am J Reprod Immunol 1998; 40:19.
- Stewart EA, Friedman AJ, Peck K, Nowak RA. Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab 1994; 79:900.
- Catherino WH, Leppert PC, Stenmark MH, et al. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids. Genes Chromosomes Cancer 2004; 40:204.
- Leppert PC, Baginski T, Prupas C, et al. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril 2004; 82 Suppl 3:1182.
- Rogers R, Norian J, Malik M, et al. Mechanical homeostasis is altered in uterine leiomyoma. Am J Obstet Gynecol 2008; 198:474.e1.
- Dou Q, Zhao Y, Tarnuzzer RW, et al. Suppression of transforming growth factor-beta (TGF beta) and TGF beta receptor messenger ribonucleic acid and protein expression in leiomyomata in women receiving gonadotropin-releasing hormone agonist therapy. J Clin Endocrinol Metab 1996; 81:3222.
- Chegini N, Tang XM, Ma C. Regulation of transforming growth factor-beta1 expression by granulocyte macrophage-colony-stimulating factor in leiomyoma and myometrial smooth muscle cells. J Clin Endocrinol Metab 1999; 84:4138.
- Kothapalli R, Buyuksal I, Wu SQ, et al. Detection of ebaf, a novel human gene of the transforming growth factor beta superfamily association of gene expression with endometrial bleeding. J Clin Invest 1997; 99:2342.