3.1.9: Uterine Leiomyoma (uLM)
- Page ID
- 94918
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It is a benign neoplasm arising from the uterine smooth muscles, also known as fibroid. Leio (smooth), myo (muscle), oma (tumor). It is the most common neoplasm of the female reproductive system.
3.1.9.2 Pathogenesis
Risk factors for developing fibroids include advanced reproductive age, smoking, contraceptive pill intake, African and Latin American ethnicity, family medical history, obesity, early menarche, arterial hypertension, chronic inflammation, exposure to xenoestrogens in early ontogenesis, sexually transmitted infections, and alcohol. The pathogenetic mechanisms are very complex, considering the interplay of all the previously mentioned factors (Figure 3.1.25)
Figure 3.1.25 An illustration of predisposing factors intricacy and intratumoral heterogeneity complicating the search for key events of uterine leiomyoma (UL) genesis. UL formation is associated with a wide range of predisposing factors: family medical history, African or Latin American ethnicity, gene variants, epigenetic changes, early menarche, exposure to xenoestrogens, obesity, hypertension, vitamin D deficiency, alcohol intake, dietary habits, nulliparity, and advanced reproductive age. During UL growth, each cell acquires a unique set of parameters (cell type, genetic and epigenetic alterations, characteristics of signaling, and microenvironmental components), thus resulting in a pronounced intratumoral heterogeneity and complicating identification of the characteristics of initial UL cell(s).
Image Source: Koltsova, Alla S., Olga A. Efimova, and Anna A. Pendina. “A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity.” International Journal of Molecular Sciences 24, no. 6 (2023): 5752. This work is distributed under a CC BY license. doi.org/10.3390/ijms24065752
Leiomyomas are considered of monoclonal origin (i.e., they arise from a single transformed smooth muscle cell) and later differentiate into other cell types that contribute to the cellular components of fibroids (e.g., fibroblasts and vascular endothelial cells). Several tissue-specific stem cells expressing stem markers (e.g., OCT4, NANOG, and others) have been detected and isolated from uterine leiomyomas. Paracrine signaling and interactions between stem cells and mature smooth muscle cells play a role in leiomyoma formation (Figure 3.1.26)
Figure 3.1.26 Cellular origin of uLM. Specific environmental and genetic changes may cause the transformation of myometrial stem cells into tumor initiating cells, that, through uncontrolled proliferation and reduced apoptosis, may eventually give rise to a uLM tumor
Image Source: Machado-Lopez, Alba, Carlos Simón, and Aymara Mas. “Molecular and Cellular Insights into the Development of Uterine Fibroids.” International Journal of Molecular Sciences 22, no. 16 (2021): 8483. This work is distributed under a CC BY license. doi.org/10.3390/ijms22168483
For further details on leiomyoma pathogenesis and implicated mechanisms, refer to these articles:
- Machado-Lopez A, Simón C, Mas A. "Molecular and Cellular Insights into the Development of Uterine Fibroids." International journal of molecular sciences, 22, No. 16 (Aug 6, 2022):8483. doi: 10.3390/ijms22168483 PMID: 34445194
- Koltsova, Alla S et al. “A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity.” International journal of molecular sciences vol. 24, No. 6 (March 17, 2023):5752. doi:10.3390/ijms24065752 PMID: 34445194
3.1.9.3 Morphology
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Macroscopically
Fibroids are well-circumscribed, rubbery, firm, grey-white, non-encapsulated, spherical tumors. The cut surface is bulging, well demarcated from adjacent myometrium, and exhibits a whorled pattern (Figure 3.1.27). Areas of mucoid change, hemorrhage, necrosis, and calcification could be seen. There are three main types of fibroids with variable locations (Figure 3.1.28):
- Submucosal (bulge into the uterine cavity and covered by the endometrium)
- Intramural (grow within the muscular uterine wall)
- Subserosal (project to the outside of the uterus and covered by the peritoneum)
The latter may be attached to the uterus by a stalk and may attach to surrounding organs where it gets its blood supply from these organs (i.e., parasitic fibroid).
Figure 3.1.27 A well-circumscribed uterine fibroid. The cut surface demonstrates the characteristic whorled pattern.
Image Source: Uthman, Ed. "Leiomyoma from a uterine myomectomy." This work is distributed under a CC BY 2.0 license. Image available from Wikimedia Commons.
Figure 3.1.28 Fibroid Locations.
Image Source: Haggstrom, Mikael. "Fibroid locations." Image adpated from Anja Hirschelmann, Rudy Leon De Wilde. "Plastic and reconstructive uterus operations by minimally invasive surgery? A review on myomectomy". GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW No. 1 (2012). This work is distributed under a CC BY 4.0 license. Image available from Wikimedia Commons.
Histologically, bundles of smooth muscle cells resembling normal myometrium are present (Figure 3.1.29, A). The fascicular pattern/arrangement is responsible for the whorled appearance. Mitotic activity may be observed, but there are usually less than 5 mitoses per 10 high-power fields (HPF). Tumor cellularity is variable, with some tumors being more cellular than others, and areas within the same tumor demonstrate variable cellularity (Figure 3.1.29, B). Areas of degenerative changes, fibrosis, hemorrhage, and calcification could also be detected.
Figure 3.1.29 Leiomyomas typically show smooth muscle in a fascicular pattern (arrows point at fascicles) (A). Leiomyoma, with areas where the cellularity is relatively lower (left) and higher (right) (B). H&E stain.
Image Source: Haggstrom, Mikael. "Histopathology of a leiomyoma in a postmenopausal uterus". Intermediate magnification. Own work. (October 2020). This work is distributed under a CCO license. Image available from Wikimedia Commons.
3.1.9.4 Clinical Features and Treatment
Common presentations include abnormal uterine bleeding, pelvic pain, dyspareunia, pressure effects on the bladder or rectum, and infertility. Anemia results from excessive bleeding. Other consequences include spontaneous abortions, pre-term delivery, and Caesarean sections. Imaging techniques such as transabdominal or transvaginal ultrasound are the most commonly used diagnostic modalities. MRI may be used to delineate the number, size, and location of fibroids in certain cases, and hysteroscopy may be useful to distinguish between sub-endometrial fibroids and large endometrial polyps.
Surgical treatment includes hysterectomy or myomectomy depending on the size, number, and extent of fibroids and the patient’s wishes about fertility. Myomectomy (i.e., surgical removal of fibroids) is performed by Hysteroscopy or laparoscopy. The latter is the standard surgical option in women who do not wish to retain fertility.
Non-surgical interventional treatments include uterine artery embolization (UAE) and high-frequency MR-guided focused ultrasound surgery. Medical management of fibroids using gonadotropin-releasing hormone (GnRH) analogs is indicated for symptomatic treatment of pain and bleeding. Other therapeutics, such as selective progesterone receptor modulators (SPRMs), effectively control heavy menstrual bleeding and correct anemia by reducing fibroids' size. Estrogen levels remain at around mid-follicular levels, and, as a consequence, menopausal symptoms and bone loss are not encountered regularly.20
Glossary terms
- Arterial
- related to or flowing in an artery
- Calcification
- process by which organic tissue becomes hardened by the physiologic deposit of calcium salts
- Dyspareunia
- genital pain before, during, or after intercourse
- Embolization
- action of deliberately blocking the flow of blood in a particular blood vessel by putting material into the blood
- Endothelial
- layer of epithelium that lines the heart, blood vessels (ENDOTHELIUM, VASCULAR), lymph vessels (ENDOTHELIUM, LYMPHATIC), and the serous cavities of the body
- Fascicular
- of, related to, or consisting of fasciculi (seldner bundle of anatomical fibers, nerve fibers)
- Fibroblasts
- most abundant cell type in connective tissue, secretes protein fibers and matrix into the extracellular space
- Fibroid
- benign tumor derived from smooth muscle tissue
- Hemorrhage
- excessive bleeding
- Hypertension
- blood pressure goes below the homeostatic set point when standing
- Hysterectomy
- surgery to remove the uterus and, sometimes, the cervix
- Hysteroscopy
- endoscopic examination of the uterus
- Inflammation
- basic innate immune response characterized by heat, redness, pain, and swelling
- Laparoscopy
- procedure that uses a laparoscope, inserted through the abdominal wall, to examine the inside of the abdomen
- Leiomyoma
- benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the UTERUS and the GASTROINTESTINAL TRACT but can occur in the SKIN and SUBCUTANEOUS TISSUE, probably arising from the smooth muscle of small blood vessels in these tissues
- Menarche
- first menstruation in a pubertal female
- Mitotic
- of, related to, involving or occurring by cellular mitosis
- Monoclonal
- produce by, being, composed of, or caused by cells derived from a single cell
- Mucoid
- resembling mucus
- Myomectomy
- surgical removal of a LEIOMYOMA of the UTERUS
- Myometrium
- smooth muscle layer of uterus that allows for uterine contractions during labor and expulsion of menstrual blood
- Necrosis
- accidental death of cells and tissues
- Ontogenesis
- development of course of development of an organism
- Paracine
- cellular signaling in which a factor secreted by a cell affects other cells in the local environment
- Pathogenic
- causing or capable of causing disease
- Transabdominal
- passing through or performed by passing through the abdomen of the abdominal wall
- Transvaginal
- passing through or performed by way of the vagina
- Whorled
- having or arranged in whorls (arrangement of similar anatomical parts in a circule aruond a point or on an axis)
- Xenoestrogens
- foreign synthetic chemicals that mimic natural estrogens and can bind to estrogen receptors in the body
Footnotes
- Koltsova, Alla S., Olga A. Efimova, and Anna A. Pendina. “A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity.” International Journal of Molecular Sciences 24, no. 6 (2023): 5752. This work is distributed under a CC BY license. doi.org/10.3390/ijms24065752
- Koltsova, Efimova, and Pendina, 2023.
- Machado-Lopez, Alba, Carlos Simón, and Aymara Mas. “Molecular and Cellular Insights into the Development of Uterine Fibroids.” International Journal of Molecular Sciences 22, no. 16 (2021): 8483. This work is distributed under a CC BY license. doi.org/10.3390/ijms22168483
Image Acknowledgements
- Koltsova, Alla S., Olga A. Efimova, and Anna A. Pendina. “A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity.” International Journal of Molecular Sciences 24, no. 6 (2023): 5752. This work is distributed under a CC BY license. doi.org/10.3390/ijms24065752
- Machado-Lopez, Alba, Carlos Simón, and Aymara Mas. “Molecular and Cellular Insights into the Development of Uterine Fibroids.” International Journal of Molecular Sciences 22, no. 16 (2021): 8483. This work is distributed under a CC BY license. doi.org/10.3390/ijms22168483