30/06/2021 Uterine fibroids (leiomyomas): Histology and pathogenesis - UpToDate

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Uterine fibroids (leiomyomas): Histology and

pathogenesis
Authors: Elizabeth A Stewart, MD, Shannon K Laughlin-Tommaso, MD
Section Editor: Robert L Barbieri, MD
Deputy Editor: Alana Chakrabarti, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2021. | This topic last updated: Jan 19, 2021.

INTRODUCTION

Uterine fibroids (leiomyomas) are the most common pelvic neoplasm 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 [3]. The
disease is heterogeneous, and different fibroids within the same uterus may have different
etiologies [4]. 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 histologic 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 "Uterine
fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history" and
"Uterine fibroids (leiomyomas): Treatment overview" and "Uterine fibroids (leiomyomas):
Variants and smooth muscle tumors of uncertain malignant potential".)

HISTOLOGY

Uterine leiomyomas are noncancerous monoclonal neoplasms arising from uterine smooth
muscle cells and fibroblasts [7,8]. They contain a large amount of extracellular matrix
(including collagen, proteoglycan, fibronectin) and are surrounded by a thin pseudocapsule
of areolar tissue and compressed muscle fibers.
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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
and clinical behavior. 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 "Uterine fibroids (leiomyomas): Variants
and smooth muscle tumors of uncertain malignant potential".)

PATHOGENESIS

At least two distinct components contribute to leiomyoma development:

● Transformation of normal myocytes into abnormal myocytes, in most instances through

somatic mutations.

● Growth of abnormal myocytes into clinically apparent neoplasms.

The first process appears to be quite common, in view of the high prevalence of microscopic
myomas [9]. Myometrial and leiomyoma stem cells have been identified that transform and
grow into leiomyomas under the influence of hormones. The subsequent growth of the
neoplasm occurs via clonal expansion from a single cell and will likely be a better target for
new therapeutic interventions [10,11].

GENETICS

Uterine leiomyomas are a common phenotype with differing genotypes. There appear to be
multiple different genetic pathways to phenotypic leiomyomas [12].

Most fibroids arise from somatic mutations with mediator complex subunit 12 (MED12)
being by far the most common group followed by high mobility group AT-hook (HMGA1 and
HMGA2), and collagen type IV, alpha-5 and alpha-6 (COL4A5 and COL4A6) [12-15]. Inherited
mutations in the fumarate hydratase gene (FH) also comprise a major fibroid subgroup with
these individuals and their families at risk of hereditary leiomyomatosis and renal cell
carcinoma syndrome (HLRCC), a rare autosomal dominant syndrome characterized by
cutaneous and uterine leiomyomas and an aggressive form of papillary renal cell cancer.
Patients with HLRCC syndrome appear to be at an increased risk of uterine sarcoma. This is
discussed in detail separately [15,16] (see "Hereditary leiomyomatosis and renal cell cancer
(HLRCC)"). There are also rare cases of somatic FH mutations in fibroids [17].

There is some evidence of genotype/phenotype relationships in fibroids including the fact

that MED12 mutations seem to be associated with fibroids of smaller size [13]. While it has

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been reported that MED12 and FH mutations do not coexist [18], due to the independent
clonal nature of fibroids within the same uterus, multiple genotypes can exist
simultaneously in the same patient, and downstream signaling pathways appear redundant
for all the groups with the exception of the FH group [19].

STEROID HORMONES

Gonadal steroid hormones are an important influence in leiomyoma pathogenesis. While

traditional teaching has always highlighted the role of estrogen, progesterone appears to be
the important hormone [20-22]. Progesterone receptors are upregulated in leiomyomas
compared with normal myometrium, although the truncated PR-A isoform appears to
predominate in both leiomyomas and myometrium [20,23,24].

Estrogens also influence fibroid development. Estrogen receptor alpha appears upregulated
in all leiomyomas, and estrogen receptor beta is sometimes upregulated in various ethnic
groups [25,26]. Myomas also appear to have a modest increase in the type 1 isotype of 17-
beta hydroxysteroid dehydrogenase [27].

Biologically, the enzyme aromatase (coded for by the gene CYP19), which converts
androgens to estrogens, appears to be an important regulator of estrogen response in
leiomyomas. Aromatase is upregulated in leiomyoma cells compared with normal
myometrium [28,29]. The transcription of CYP19 is controlled by a variety of promoters, and
there appear to be differences in the promoter across ethnic and racial groups [30,31]. As an
example, African American patients differentially use the proximal II aromatase promoter
that appears to be correlated with higher expression of CYP19 mRNA [25].

The steroid hormone effect on leiomyomas is also evident in the role of endocrine-disrupting
chemicals in increasing the risk of leiomyomas. One study reported that a 20 to 39 percent
probability of causation of fibroids could be attributed to diphenyl dichloroethene, an
insecticide [32]. Also, early-life exposures such as diethylstilbestrol have been found to be
associated with fibroid incidence in some studies [33,34] but not others [35]; recall bias may
influence results [36,37].

STEM CELLS

Stem cells appear to play a key role in fibroid pathogenesis [38-40]. Stem cells have few
receptors for steroid hormone compared with mature myometrial cells and paracrine
interactions such as from the Wnt/beta-catenin signaling pathway may also play a key role in
fibroid pathogenesis [39,41].

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VASCULAR ABNORMALITIES

Abnormalities in uterine blood vessels and angiogenic growth factors appear to play a role
in the pathobiology of myoma formation. The myomatous uterus has increased numbers of
arterioles and venules, as well as venular ectasia (dilation) [42]. Molecular alterations leading
to increased vessel number or abnormal function are the likely mechanisms for these
abnormalities, although the venous changes were originally thought to be induced by
physical compression of the vascular structures by bulky myomas [5].

It is possible that myoma formation is a response to injury, much like an atherosclerotic

plaque that forms in response to hypoxia of arterial muscle [43]. Hypoxia of myometrial cells
during menstruation may promote transformation of normal myocytes to abnormal
myocytes and subsequently to leiomyomas. The fact that atherogenic risk factors appear to
be more common in patients with leiomyomas supports this hypothesis [44].

The effect of vascular factors is also demonstrated at a molecular level. The angiogenic
growth factor fibroblast growth factor-2 (also called basic fibroblast growth factor) and its
receptor appear significantly altered in the leiomyomatous uterus [45-47].

FIBROTIC FACTORS

Leiomyomas can be viewed as a fibrotic process with abnormalities of the extracellular

matrix at many levels. There is upregulation of the mRNA and protein for major extracellular
matrix (ECM) components, particularly type I and III collagen [48]. Decreased expression of
the collagen-binding protein dermatopontin is seen both in leiomyomas and in keloid scars,
possibly suggesting a link between both of these abnormalities in Black patients [49];
however, no association was found between keloids and fibroids in the prospective Study of
Environment, Life-style & Fibroids cohort [50]. There is also increasing information that the
morphologic arrangement of extracellular components is abnormal in myomas and that the
increased stiffness of these ECM alterations leads to altered gene expression through solid-
state signaling [51,52].

Fibrotic growth factors are also dysregulated in leiomyomas. Transforming growth factor-
beta (TGF-beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are
involved in other fibrotic processes, may also contribute to the pathophysiology of
leiomyomas. When obtained from the secretory phase of the menstrual cycle, leiomyomas
appear to have higher levels of TGF-beta and TGF-beta receptor mRNA and protein than
myometrium [53]. In addition, there is a substantial reduction in TGF-beta levels in the
leiomyomas of patients treated with a gonadotropin-releasing hormone agonist to diminish
the size of their tumors prior to surgical extirpation [53]. The association between vitamin D

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deficiency and uterine fibroids may be mediated in part by the effect of vitamin D on the
TGF-beta pathways [54].

GM-CSF may differentially stimulate leiomyomas and normal myometrium both on its own
and through an increase in expression of TGF-beta [55]. A TGF-beta homologue, endometrial
bleeding-associated factor (EBAF, now called LEFTY-A), which is normally expressed in the
endometrium only in the luteal phase of the menstrual cycle, is expressed throughout the
cycle in patients with abnormal uterine bleeding of various etiologies, including leiomyomas
[56].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Beyond the Basics topic (see "Patient education: Uterine fibroids (Beyond the Basics)")

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Uterine fibroids
(leiomyomas)".)

SUMMARY

● Uterine fibroids (leiomyomas) are noncancerous monoclonal neoplasms arising from the
smooth muscle cells of the myometrium. (See 'Introduction' above.)

● Two distinct components contribute to leiomyoma development: transformation of

normal myocytes into abnormal myocytes and growth of abnormal myocytes into

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clinically apparent tumors. Multiple factors likely play a role in both this transformation
and growth acceleration for leiomyomas. (See 'Pathogenesis' above.)

● Uterine leiomyomas are a common phenotype with many underlying genotypes. Both
somatic and inherited mutations account for the majority of uterine fibroids, with the
most common mutations occurring in the MED12, HMGA1 and HMGA2, FH, collagen type
IV, alpha-5 (COL4A5) and collagen type IV alpha-6 (COL4A6) genes. (See 'Genetics' above.)

● Steroid hormone factors that influence leiomyoma development include upregulation of

aromatase, estrogen, and progesterone receptors as well as a potential role of
gonadotropins. Stem cells appear to also play a key role in fibroid pathogenesis. (See
'Steroid hormones' above and 'Stem cells' above.)

● The myomatous uterus has increased numbers of arterioles and venules, as well as
venular ectasia (dilation). In addition, the angiogenic growth factor fibroblast growth
factor-2 and its receptor appear significantly altered in the leiomyomatous uterus. (See
'Vascular abnormalities' above.)

● Leiomyomas can be viewed as a fibrotic process with abnormalities of the extracellular

matrix at many levels. (See 'Fibrotic factors' above.)

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Topic 5431 Version 27.0

Contributor Disclosures
Elizabeth A Stewart, MD Grant/Research/Clinical Trial Support: NIH Grants [Uterine fibroids].
Consultant/Advisory Boards: Bayer Health Care [Uterine fibroids]; Myovant [Uterine fibroids]; AbbVie
[Uterine fibroids]; ObsEva [Uterine fibroids]. Other Financial Interest: Peer View [CME course]; PER
[CME course]; Massachusetts Medical Society [Honorarium]. Shannon K Laughlin-Tommaso,
MD Grant/Research/Clinical Trial Support: Bayer [Fibroids]. Robert L Barbieri, MD Nothing to
disclose Alana Chakrabarti, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

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