Published online: 2020-10-20

108

Pathology and Pathogenesis of Adenomyosis

Maria Facadio Antero, MD1 Ayse Ayhan, MD, PhD2 James Segars, MD1 Ie-Ming Shih, MD, PhD1,2

1 Department of Gynecology and Obstetrics, Johns Hopkins University Address for correspondence Ie-Ming Shih, MD, PhD, Department of
School of Medicine, Baltimore, Maryland Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550
2 Department of Pathology, Johns Hopkins University School of Orleans Street, CRB2, RM305, Baltimore, MD (e-mail: ishih@jhmi.edu).
Medicine, Baltimore, Maryland

Semin Reprod Med 2020;38:108–118

Abstract Adenomyosis represents a unique pathophysiological condition in which normal-

appearing endometrial mucosa resides within myometrium and is thus protected
from menstrual shedding. The resulting ectopic presence of endometrial tissue
composed of glands and stroma is thought to affect normal contractile function
and peristalsis of uterine smooth muscle, causing menometrorrhagia, infertility, and

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adverse obstetric outcomes. Since the first description of adenomyosis more than
150 years ago, pathologists have studied this lesion by examining tissue specimens,
and have proposed multiple explanations to account for its pathogenesis. However, as
compared with endometriosis, progress of adenomyosis research has been, at best,
incremental mainly due to the lack of standardized protocols in sampling tissue and a
lack of consensus diagnostic criteria in pathology practice. Despite these limitations,
recent advances in revealing the detailed anatomy and biology of eutopic endometri-
um offer an unprecedented opportunity to study this common but relatively under-
Keywords studied disorder. Here, we briefly summarize the pathological aspects of adenomyosis
► adenomyosis from an historical background, and discuss conventional morphology and recent
► endometriosis tissue-based molecular studies with a special emphasis on elucidating its tissue of
► pathology origin from a pathologist’s perspective. We also discuss unmet needs in pathology
► pathogenesis studies that would be important for advancing adenomyosis research.

Maintaining tissue specification and cohesiveness are cardi-
nal features in multicellular organisms, and this evolution-
endowed tenet requires that adult tissues of the same type
stay together. Breaking this rule has serious consequences for
the organism as exemplified by tumor invasion and metas-
tasis. An exception applies to two related benign and com-
mon gynecologic disorders, adenomyosis and endometriosis,
in which normal-appearing endometrium resides in myo-
metrium and in peritoneal tissue, respectively (►Fig. 1).1
Thus, the pathologies of adenomyosis and endometriosis are
unique among human nonmalignant diseases. Because of
their anatomic locations and the unique microenvironments,
the ectopic endometrial tissues may or may not observe the
ovarian hormonal cycles and can have molecular changes
that are distinct from eutopic endometrium despite their
similar morphological appearance.
Adenomyosis is a major gynecologic disorder causing chronic
pelvic pain, dysmenorrhea, dyspareunia, infertility, and adverse
obstetric outcomes.2,3 It has been estimated that adenomyosis
affects 10 to 80% of premenopausal women, and its prevalence is
even higher in women with infertility and chronic pelvic pain.4,5
Like endometriosis, adenomyosis imposes a substantial socio-
economic burden from increased medical care and loss of work
productivity, without mentioning the compromised quality of
life.6,7 Here, we provide a succinct summary of our current
understanding of adenomyosis from a pathology perspective.
We discuss how the term “adenomyosis” has evolved from a
historical background, the histopathological features, the chal-
lenge in its classification, and current concepts pertaining to
development of adenomyosis. We also propose critical tasks
that are fundamentally important for accelerating progress,
both biological and translational, in adenomyosis research.

Issue Theme Adenomyosis and
Endometriosis; Guest Editors, Linda C.
Giudice, MD, PhD, MSc, Lisa M.
Halvorson, MD, Elizabeth A. Stewart, MD,
and Luk Rombauts, PhD, FRANZCOG, MD
Copyright © 2020 by Thieme Medical DOI https://doi.org/
Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1718922.
New York, NY 10001, USA. ISSN 1526-8004.
Tel: +1(212) 760-0888.
 Pathology and Pathogenesis of Adenomyosis Antero et al. 109

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Fig. 1 The ectopic endometrium and eutopic endometrium. The diseases related to ectopic endometrium include adenomyosis, deep
infiltrating endometriosis, peritoneal endometriosis, and ovarian endometriotic cyst (endometrioma). The insets illustrate the similar histology
of eutopic endometrium (top) and ectopic lesions (bottom), containing both glandular epithelium and stroma. (Modified from Wang et al1; [©
IM Shih, Johns Hopkins University].)

A Historical Perspective
First, let us wind back the clock to 1860 when Karl von
Rokitansky initially described endometrial glands embedded
in the uterine myometrium.8 He named this condition
“cystosarcoma adenoids uterinum,” reflecting the essence
of adenomyosis—glandular and sometimes cystic structures
forming tumor-like lesions in uteri. Chiari9 also observed a
similar lesion which he called “salpingitis isthmica nodosa
(SIN)” around the fallopian tube musculature and believed
that it was a variant of adenomyosis. Subsequently, other
investigators in the late 19th century attempted to explain
the possible mechanisms for the establishment of adeno-
myosis. Meyer10 was the first to propose the theory of
“epithelial heterotopy,” an analogy to wound healing, where
epithelial cells would invade inflammatory tissue that was
damaged. He developed this theory after finding endometrial
glands in the suture lines of a patient who had undergone a
prior uterine ventrofixation secondary to pelvic pain. He
thought that these glands were derived from either embry-
onic or “well-differentiated” cells.
Cullen, who established gynecologic pathology as a sub-
specialty of pathology at the Johns Hopkins Hospital, pio-
neered a systematic and comprehensive description of what
we know today as adenomyosis. He suggested a mechanism in
which endometrial glands and stroma in endometrium could
invade the underlying myometrium, as, in some cases, a direct
connection between uterine cavity and the heterotopic glands
could be seen.11 Another important contribution by Cullen was
that he attributed the pathology of adenomyosis to clinical
phenotypes including lengthened menstrual periods and pel-
vic pain. He further proposed that hysterectomy was the
preferred treatment, as unlike a well-circumscribed leio-
myoma it was often hard to dissect out adenomyomas because
their “growth was so interwoven with the normal muscle.”12
Cullen’s theory of mucosal invasion faced challenges for many
years, as other contemporary theories argued that displace-
ment of mesonephric elements together with idiopathic stro-
mal hyperplasia were responsible for adenomyosis.13,14 It was
not until the 1920s that the endometrial origin of adenomyosis
was widely accepted. This acceptance coincided with Samp-
son’s theory of retrograde menstruation to explain how men-
struated endometrial tissue caused endometriosis,15 and
helped to clarify that adenomyosis and endometriosis were
two different disease entities, although both lesions were
thought to originate from uterine endometrium.
Finally, the term “adenomyosis uteri” was introduced in
1925 by Frankl,16 who described the mucosal invasion of the
myometrium. He explained that the term was chosen so that
it remained clear that the condition was not caused by an
inflammatory process as had been previously proposed. He
also further differentiated adenomyomas from adenomyosis,

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110 Pathology and Pathogenesis of Adenomyosis Antero et al.

stating that the former originated independently within the

uterus, and the latter was diffuse with a direct connection
with the endometrium. It was only in 1972 that the current
histological definition of adenomyosis was put forth by Bird
et al17 positing that adenomyosis was characterized by the
“… benign invasion of endometrium into myometrium,
producing a diffusely enlarged uterus which microscopically
exhibits ectopic, nonneoplastic, endometrial glands and
stroma surrounded by hypertrophic and hyperplastic myo-
metrium.” The modern histological definition was thus born.

Pathology of Adenomyosis and Correlation

with Imaging Results
Grossly, the uterus may appear slightly enlarged and globular
due to myometrial hypertrophy in severe cases of adenomyosis
(►Fig. 2a),18–20 but in general, the involved uteri preserve the
overall contour, and are rarely bigger than a 12-week size gravid

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uterus.17,21,22 The cut surface of adenomyotic foci is character-
ized by hyperfasciculated and trabeculated areas of myome-
trium, which correspond with myometrial hypertrophy
(►Fig. 2b). On gross appearance, adenomyosis, unlike leio-
myoma, does not manifest a well-demarcated border (►Fig. 2c,
d). The adenomyotic foci may appear grossly indistinct or as a
white-gray mass with areas of brown-staining secondary to
hemolyzed blood and hemosiderin deposits.23 Blood-filled
cysts can also be occasionally observed.24 In some cases, uterine
adenomyosis can form localized nodules that grossly mimic
leiomyomas. These focal adenomyotic nodules are known as
adenomyomas, and are composed of smooth muscle surround-
ing endometrial glands and stroma. Upon gross examination,
adenomyomas, unlike leiomyomas, are unencapsulated, and
the hypertrophied myometrium is often mixed with the sur-
rounding normal myometrium (►Fig. 2c, d).
Microscopically, adenomyosis consists of irregularly
shaped islands of endometrial glands and stroma within
the myometrium. They are always multiple, and we believe
that the discrete islands, especially those are adjacent to each
other on cross tissue sections, are not separated but rather
are interconnected, which can be seen if a series of sequential
sections are examined or a three-dimensional reconstruc-
tion can be generated. Thus, the architecture of adenomyosis
is distinct from that of the functional endometrium, in which
the glands are solitary, nonbranching, and longitudinally
arranged (►Fig. 2e, f ). In fact, the glands and stroma of
adenomyotic foci architecturally resemble the basalis layer
in eutopic endometrium, where a complex horizontally
connected glandular structure is normally formed.25 The
gland-to-stroma ratio varies widely among adenomyoma
foci, and some may have attenuated or undetectable stromal
components,26 which may reflect sampling issue in which
the tangential cut surface does not contain the neighboring
stroma. The adenomyotic endometrium may retain its pro-
liferative potential, which could contribute to endometrial
regrowth and failure after endometrial ablation.27 Glands
can vary in shape and size, with 5% of them forming cystic
structures filled with cellular debris and hemosiderin-laden
macrophages (►Fig. 2g).28 The stromal components of
Fig. 2 Gross and microscopic features of adenomyosis. (a) The involved
uterus appears slightly enlarged and globular. (b) A bivalved surface from a
hysterectomy specimen shows multiple foci of adenomyosis with petechia-
like areas (yellow arrows) in myometrium. The smooth muscle appears
hypertrophied and disarrayed. (c, d) Comparison of gross appearance of
adenomyosis (AD) and leiomyoma (LM). Formalin fixed cross-section in C
and hematoxylin and eosin (H&E) stained section in D. (e) Microscopic
features showing presence of glandular epithelium and stroma surrounded
by hypertrophic smooth muscle cells. (H&E stain 20 magnification). (f)
Higher magnification view to show the resemblance of epithelial and
stromal components of adenomyosis to eutopic endometrium (H&E stain
40 magnification). (g) Ectopic endometrial tissue showing foci of hem-
orrhage with histiocytes and hemosiderin-laden macrophages (red arrow)
(H&E stain 20 magnification). (h) Marked decidualization with small
inactive glands in adenomyosis seen after exogenous progestin therapy.
(H&E stain 20 magnification).
adenomyosis present a monotonous appearance, and are
usually inactive and nonmitotic. Secretory changes, includ-
ing stromal decidualization, have been observed during
gestation and exogenous progestin therapy (►Fig. 2h).
Adenomyosis is never found in a leiomyoma.
In normal uteri, the junction between endometrium and
myometrium is not always well demarcated, and an irregular
border with focal extension of endometrial tissue into superfi-
cial myometrium is not uncommon. As such, tangential sec-
tions can reveal seemingly detached foci of glands and stroma
beneath endometrium, and these foci may be mistakenly
diagnosed as superficial adenomyosis, further confounding

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 Pathology and Pathogenesis of Adenomyosis Antero et al. 111

clinicopathological studies of adenomyosis. Tissue biomarkers
that help distinguish true adenomyosis from endometrial
extensions from the irregular border would be useful. Along
this line, upregulation of the biomarker STING (stimulator of
interferon gene) has recently been reported to distinguish
epithelial cells of adenomyosis from eutopic endometrium.29
The endometrial–myometrial junctional zone located be-
tween the endometrium and the inner myometrium has
received much attention in adenomyosis research because
this zone is often thickened and exhibits architectural changes
that may lead to abnormal uterine peristalsis.30,31 Architec-
tural changes include loss of nerve fibers and smooth muscle
hypertrophy.32 At the ultrastructural level, these myocytes
associated with adenomyosis show abnormal nuclear and
mitochondrial shapes, abundant myelin bodies and interme-
diate filament aggregates, extensive endoplasmic reticulum,
and increased expression of oxytocin receptors.33,34 Although
these findings and their biological significance requires vali-
microvessels than adjacent normal endometrium or eutopic
endometrium of disease-free women.37
The aforementioned pathologic features of adenomyosis
can explain many of the commonly observed findings
reported in ultrasound or MRI studies. Subendometrial
echogenic linear striations, nodules, and/or asymmetrical
myometrial bulkiness may be related to muscular hypertro-
phy in different regions in reaction to the presence of ectopic
endometrium. Moreover, hyperechoic islands and subendo-
metrial cysts can be a result of focal cystic dilatation of the
fluid-filled glands in adenomyosis. Thus, the irregular endo-
metrial–myometrial junction may reflect the complex and
convoluted connection between endometrium and the un-
derlying adenomyosis. In color Doppler sonography, a gen-
eral increase in vascularity and in numbers of tortuous
vessels penetrating myometrium is likely associated with
enhanced angiogenesis. Thickening of the junctional zone,
visualized as a hypoechoic halo beneath the endometrial

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dation, the morphological abnormalities in the junctional zone
in adenomyosis may play a role in hyperperistalsis. It is not
certain whether hyper- or dysperistalsis facilitates invasion of
endometrial glands into the myometrium,35 or whether the
presence of abundant ectopic endometrial tissues in myome-
trium interferes with or triggers peristalsis.
Adenomyotic lesions also have a higher angiogenic po-
tential, as evidenced by an increased level of vascular endo-
thelial growth factor (VEGF) and hypoxia-inducible factor-1α
(HIF-1α) compared with paired eutopic endometrium and
with endometrium from disease-free women.36 Further-
more, although verification will be required, it appears
that ectopic endometrium contains a greater density of
layer (usually greater than 12 mm), is suggestive of an
adenomyosis. However, it is challenging to correlate such
thickening with adenomyosis-associated histopathological
findings.
Unusual Pathology and Related Gynecologic
Conditions
Hyperplastic changes with or without atypia are not
unusual in adenomyosis, and can often be detected in
the corresponding eutopic endometrium. However, malig-
nant transformation of adenomyosis is a rare event occur-
ring mostly in postmenopausal women (►Fig. 3).38,39

Fig. 3 Atypical hyperplasia and low-grade endometrioid carcinoma arising from adenomyosis. (a) Foci of atypical hyperplasia within a
preexisting adenomyosis lesion. (b) An incipient low-grade endometrioid carcinoma arising from adenomyosis with cancerous tissue coexisting
with ectopic benign glandular tissue (hematoxylin and eosin stain 20 magnification).

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112 Pathology and Pathogenesis of Adenomyosis Antero et al.
Endometrioid carcinoma is the most common histological
type of malignant transformation of adenomyosis, but
serous carcinoma, clear cell carcinoma, and poorly differen-
tiated carcinoma may also be seen.40 Pathologic findings
that suggest malignant transformation of adenomyosis
include the presence of cancerous tissue and ectopic endo-
metrial tissue in the same lesion, diagnosis of adenomyosis,
transformation evidence between benign and malignant
gland structures, and exclusion of other sources of tumor
invasion or metastasis.41 In addition to epithelial cells,
stromal cells in adenomyosis can also undergo neoplastic
transformation to form intramural adenosarcoma, but this
is exceedingly rare.
Other unusual subtypes of adenomyosis have been
described. As mentioned earlier, adenomyomas are a nod-
ular form of adenomyosis involving myometrium focally,
which distinguishes it from the diffuse appearance of
conventional adenomyosis. Both adenomyomas and diffuse
types of adenomyosis may be present in the same speci-
men. One lesion related to adenomyoma is “polypoid
adenomyoma” which is a benign tumor commonly arising
from the lower uterine segment forming either a single
polypoid lesion or multiple polyps.42 Histologically, endo-
metrial glands are embedded in a fibromuscular or mus-
cular stroma. The glands are usually lined with
endometrioid cells and embedded by smooth muscle fas-
cicles.42,43 The endometrial stromal cells are not always
present, arguing that atypical polypoid adenomyoma is
related to conventional adenomyosis.
SIN, once considered to be a variant of adenomyosis, is
now mostly seen as an acquired fallopian tube lesion
analogous to adenomyosis of the uterus. Grossly, SIN
appears as a nodular protrusion on the tubal serosa and
is most often localized to the isthmic portion of the tube.
SIN can cause either infertility due to luminal obstruction or
tubal pregnancy due to the irregular and convoluted lumen
of the fallopian tubes. Adenomyosis and SIN may share
pathogenic mechanisms, as they have similar glandular
proliferation with an associated muscular hypertrophy
phenotype.
Pathology-Based Classification
Several classification systems based on histological features
of adenomyosis have been proposed: (1) depth of myome-
trium involvement, (2) location of adenomyotic lesions, and
(3) whether the myometrial involvement is diffuse or local-
ized. However, a standard and well-accepted system for
histological classification has not yet been established, in
part because studies attempting to correlate pathological
features with clinical presentations have not shown signifi-
cant or reproducible results. We believe that this is related to
how specimens are processed and examined. For example,
there is a direct correlation between the number of histologic
sections examined and the prevalence of adenomyosis. In a
study by Bird et al,17 the prevalence of adenomyosis in-
creased from 31 to 61.5% when additional histologic uterine
sections were obtained and examined. Despite this fact,
Seminars in Reproductive Medicine Vol. 38 No. 2-3/2020
there is no consensus among pathologists regarding sam-
pling hysterectomy specimens. Moreover, not all adenomy-
otic lesions are created equal. It is plausible that other than
conventional histopathology, adenomyosis can be classified
according to developmental patterns or the molecular alter-
ations. Molecular classification would be welcome but ap-
pear to be out of reach until we better understand the
pathogenesis of adenomyosis, and can correlate molecular
changes and clinical phenotypes.
Nevertheless, it is worth briefly reviewing classifications
that have been proposed in the past so that investigators can
design better studies for future classification of adenomyo-
sis. Since the depth of myometrial involvement is the most
obvious histopathological feature of adenomyosis, many
investigators have proposed classification systems based
on the depth of glands within the myometrium. This is
analogous to endometrial carcinoma in which the depth of
myometrial invasion by the cancer cells determines the FIGO
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stage, which is highly associated with clinical outcome.44,45
For example, one study46 proposed that superficial adeno-
myosis could be characterized as glands within 40% of the
myometrial thickness, intermediate adenomyosis when
glands were present in 40 to 80% of myometrial thickness,
and deep adenomyosis when glands were seen beyond 80%
of the myometrial thickness. Another study applied one-
third and two-third as the cut-off.47 Unfortunately, those
proposed cut-offs are arbitrary, lacking biological or clinical
grounds.
In general, significant conflicts are seen among results of
studies aimed at correlating disease symptoms with depth
of glands within the myometrium. In some studies, the two
most common symptoms of pain (dysmenorrhea, chronic
pelvic pain, or dyspareunia) and abnormal uterine bleeding
(AUB, or menorrhagia) were assessed.23 Some studies found
a positive correlation between depth of adenomyosis in-
volvement and dysmenorrhea,17,46,48 whereas others found
no correlation at all.49 Dysmenorrhea has been reported to
correlate with the number of glandular tissue foci seen
within the myometrium.46,48,49 Dyspareunia is also associ-
ated with the number of lesion foci but not with depth of
the lesion.49 Diffuse adenomyosis has been associated with
worse dysmenorrhea than focal disease, while the later has
been associated with infertility especially when located in
the outer myometrium.50,51 Conflicting data have been
reported concerning the relationship of AUB and histologic
features such as depth and glandular density. Most studies
have shown that there is no relationship between AUB and
glandular depth, but the numbers of adenomyotic foci per
slide show a strong correlation with the reported bleeding
volume. In one report, menorrhagia was found to be more
prevalent in women with deep adenomyosis than in those
with intermediate disease.46 Another study used the gross
appearance of uterus and tissue consistency at the time of
surgery was used to classify adenomyosis as either diffuse
type or as sclerotic type in which densely packed collagen
fibers surrounded the adenomyotic foci.28 Menorrhagia was
found to be more frequently present in the diffuse type than
in other types.
 Pathology and Pathogenesis of Adenomyosis Antero et al. 113

Pathogenesis of Adenomyosis
The pathogenesis of adenomyosis, especially the steps through
which normal-appearing endometrial tissue is displaced to
myometrium, and the mechanisms by which adenomyotic foci
cause symptoms, remain largely unclear. Current evidence
from histopathological observations and recent molecular
genetic studies indicates that adenomyosis is derived from
invagination from the basal layer of endometrium into adja-
cent myometrium, a modern view resonant with what Cullen
proposed almost one century ago. Tissue sections of adenomy-
otic lesions that are prepared for pathology diagnosis almost
always show multiple irregularly shaped seemingly intercon-
nected endometrial glands embedded in stroma. This is one of
the salient morphological features of adenomyosis, and sug-
gests that the glands within adenomyosis are highly convolut-
ed, forming a labyrinth network, and do not display a simple
arrangement (►Fig. 4a). This architecture of adenomyosis
superficial myometrium (►Fig. 4b). Several studies argue that
this involves a true invasion process. If this is the case, it would be
different from that seen in carcinoma. If this were a bone fide
invasion, both glandular epithelium and stroma would have to
acquire a constellation of complex molecular and cellular
changes including expression of proteases that degrade the
extracellular matrix, enhanced motility, and the ability to
comigrate and dissect into remarkably cohesive smooth muscle
layers. These features are highly unusual for any adult normal-
appearing tissues. Moreover, adenomyosis does not exhibit a
classical stromal reaction (desmoplasia), which is one of the
hallmarks of tumor invasion under microscopic examination.
Rather, we propose that the genesis of adenomyosis derives
from an embryonic or an early postnatal invagination of the
basal endometrium followed by extension deep into myome-
trium, likely associated with a physiological or pathological
defect of the endometrial–myometrial junction. This is sup-
ported by reported cases of fetal and prepubescent adenomyosis

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resembles that in the basal layer of endometrium.
Comparison of eutopic endometrium between uteri with and
without adenomyosis may offer some clues. In hysterectomy
specimens showing adenomyosis, it is not uncommon to ob-
serve a more irregular endo-myometrial border with endome-
trial glands and stroma “attempting” to extend from basalis into
and endometriosis.52–54 It is also possible that the basal endo-
metrium can acquire access to myometrium in a gestational
uterus where the myometrium is relatively loosened due to
interstitial edema and focal disarray of the muscular layer.
Nevertheless, the eutopic endometrium of adenomyosis
patients may possess certain characteristics that differ from

Fig. 4 Adenomyosis originating from the basal layer of endometrium. (a) A schematic representation of the development of adenomyosis with
the focal extension of a single clonally distinct endometrial gland from the endometrial basalis into the myometrium. In the myometrium, the
incipient adenomyosis continues to clonally expand to form intricate and interconnected glandular foci which are similar to the endometrial
basalis layer. Together with the “invading” gland, stromal cells also migrate and clonally expand. Different color lines (glands) and dots (stroma)
represent clonally distinct subpopulations. (b) Immunostaining of cytokeratin suggesting the process of early adenomyosis development. The
adenomyotic tissue appears to descend from the basal endometrium through the endometrial myometrial interface (dashed red line) with the
vertical “invasion” of ectopic glandular and stromal tissue into myometrium. (20 magnification).

Seminars in Reproductive Medicine Vol. 38 No. 2-3/2020

114 Pathology and Pathogenesis of Adenomyosis Antero et al.
tissue of disease-free controls. Indeed, eutopic endometrium
in adenomyosis shows molecular changes which favor a
phenotype including increased angiogenesis and prolifera-
tion, decreased apoptosis, impaired immune function, and
altered hormone levels (increased estrogen production and
progesterone resistance).36,55–63 As a result, the basal layer
of eutopic endometrium has a propensity to migrate into
myometrium. If more comprehensive molecular studies are
able to confirm these findings, it may help explain the origins
and pathogenesis of adenomyosis.
Despite the histopathological evidence, the tissue origin
of adenomyosis from eutopic endometrium has only recently
received molecular validation; the identification of somatic
mutations using next-generation sequencing has provided
unequivocal evidence that adenomyosis develops from
eutopic endometrium.64 In many cases, the same somatic
mutations, including mutations in KRAS, could be detected in
both adenomyosis and corresponding eutopic endometrium,
suggesting that both ectopic and eutopic endometrium are
clonally related. In further separating glandular epithelium
from stroma of adenomyotic lesions using laser capture
microdissection, mutations were found to occur only in
the epithelial component of adenomyosis,64 a result similar
to a previous report showing that mutations in endometri-
osis are detected only in epithelium and not in stroma.65
Since adenomyosis may select cancer driver mutations
like KRAS, which is known to promote cell survival and
growth, thus confounding the clonality studies, we analyzed
selection-neutral mutations (synonymous and passenger
gene mutations) that do not confer any selection advantage
to cells in adenomyosis and matched basal layer samples of
eutopic endometrium. We found truncal mutations shared
by ectopic and eutopic endometrium, confirming that both
adenomyosis and associated eutopic endometrium are prog-
eny of the same endometrial epithelial progenitor cells
(Lihong Li, MD; unpublished data October 1, 2020). However,
the adenomyosis and eutopic endometrium also harbor
distinct mutations. It is thus possible that after leaving the
endometrium, these progenitor cells develop into adeno-
myosis in myometrium through the acquisition of private
mutations.
An interesting result from this recent study is that the
KRAS mutations identified in adenomyosis were associated
with increased risk of cooccurring endometriosis, and that
KRAS mutations were often shared between the two coex-
isting pathologies.64 Whether this is coincidental or biologi-
cally meaningful is uncertain. Among different types of
endometriotic lesions, ovarian endometriotic cysts (69%)
were more likely to cooccur in KRAS-mutated adenomyotic
lesions than in deeply infiltrating endometriosis (46%), or
peritoneal endometriosis (11.6%). The study also showed
that KRAS mutations were often shared by cooccurring
adenomyosis and endometriotic lesions. This finding
appears consistent with other studies that have shown
that deeply infiltrating endometriosis and ovarian endome-
triomas harbor a variety of somatic cancer driver mutations
in PIK3CA, ARID1A, PPP2R1A, and/or KRAS.66,67 Since the
number of cases that have been subjected to mutational
Seminars in Reproductive Medicine Vol. 38 No. 2-3/2020
analysis is limited, it remains to be confirmed if KRAS
mutations are important in the pathogenesis of adenomyosis
and endometriosis, or if the mutations merely represent
clonal markers without biological consequences.
Endometriosis is a common finding in patients with
adenomyosis and vice versa; both diseases cooccur in up
to 80% of patients.35,68–70 Among different types of endome-
triosis (►Fig. 1), deeply infiltrative endometriosis is more
commonly seen in women who have focal adenomyosis of
the outer myometrium.69 Like adenomyosis, deeply infiltra-
tive endometriosis is characterized by the ectopic presence
of normal-appearing endometrial glands and stroma in the
smooth muscle layers of peritoneal organs such as urinary
bladder and bowel wall. Imaging studies have also shown an
increased incidence of deeply infiltrative endometriosis and
ovarian endometriomas in women with adenomyosis, spe-
cifically in adenomyosis involving the outer portion of the
myometrium.71–73 This suggests that adenomyosis and cer-
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tain types of endometriosis may be biologically related.
Inoue et al. looked at the genetic landscape of the eutopic
endometrium in disease-free women and those with adeno-
myosis.64 As noted in other studies,74,75 the eutopic endo-
metria of disease-free women were found to have somatic
cancer driving mutations in genes such as KRAS and PIK3CA
at much higher variant allele frequencies. Whether the single
cancer driver mutation, as occurs in ectopic endometrium, is
sufficient to drive the disease phenotypes remains to be
determined. It is still not known if these somatic mutations
are present at birth or acquired later in life, and whether
there is a genetic basis for the development of adenomyosis.
A recent study reports the mutational landscape of the
normal endometrium, showing that while age positively
correlates with the mutational burden in the endometrium,
some KRAS and PIK3CA mutations arise as early as the first
decade of life.75 The fact that adenomyosis develops later in
life, usually in the fourth or fifth decade, would seem to favor
the theory that the mutations are acquired, and that the
disease is not genetically predetermined. However, there
have been reports of adenomyosis developing in adoles-
cents,24,76 and a case report of familial adenomyosis suggests
that the disease may have a genetic predisposition.77 Fur-
thermore, relatively late diagnosis of adenomyosis as com-
pared with endometriosis may be due to the diagnosis at
hysterectomy, which is uncommonly performed in young
women. Therefore, this interesting observation awaits con-
firmation in future studies.
Recently, differentially expressed genes were identified in
the eutopic endometrium of patients with adenomyosis.78
Using RNA sequencing followed by quantitative real-time
PCR and immunohistochemistry to validate findings, they
were able to identify 373 differentially expressed genes in
both ectopic and eutopic endometrium of adenomyosis
patients irrespective of menstrual cycle phases. Pathway
analysis of these differentially expressed genes identified
pathways responsible for regulating cellular proliferation
and growth, tissue morphology, and angiogenesis. Among
the identified differentially expressed genes was C/EBPβ, a
core node in the network analysis. The protein encoded by C/
 Pathology and Pathogenesis of Adenomyosis
EBPβ acts as a transcription factor regulating expression of
genes that control cellular proliferation, differentiation, and
metabolism. C/EBPβ is also a key regulator of human endo-
metrial stromal proliferation and differentiation.79,80 Other
pathways noted to be upregulated were IL-6, which has been
shown to be increased in adenomyotic stromal cells cocul-
tured with macrophages,59 and ERK/MAPK, which has been
associated with uterine smooth muscle proliferation in
women with adenomyosis.81
The aforementioned evidence supports that invagination
of the endometrial basalis into the myometrium is the
favored model for the genesis of adenomyosis, as both
epithelial and stromal progenitor cells residing in basalis
are responsible not only for regenerating the entire func-
tional layer after menstruation but can also promote adeno-
myosis development in the opposite direction. However, the
data should not be construed as supporting only this model
of the pathogenesis of adenomyosis. For example, it has also
been proposed that metaplasia of displaced embryonic plu-
ripotent Müllerian remnants or differentiation of adult en-
dometrial progenitor cells can also be the origin of
adenomyosis and its related lesion, endometriosis. Over
the last few years, it has been shown that stem cells present
in the endometrium basalis have the capacity to regenerate
and replace endometrium.82 This discovery has led to the
postulation that individual stem cells may disseminate lo-
cally or spread through the circulation to cause adenomyosis
if deposited in the myometrium and/or to cause endometri-
osis if deposited outside the uterus. Why are stem cells
present in the myometrium? A possible explanation is that
stem cells may be activated by tissue injury which favors
migration to the myometrium rather than the endometri-
um.83,84 However, this stem cell hypothesis faces a major
challenge, that is, how does an individual stem cell simulta-
neously could differentiate into both epithelium and stroma
which are present in all adenomyosis and endometriosis
lesions. If it does, both lesions should harbor the same
founder mutations, and future studies need to provide
such new evidence. From the standpoint of histopathology,
it is more likely that endometrial epithelial progenitor cells
reside in basal glands which may extend into the myome-
trium, where the progenitor cells and their glands accompa-
nied by presumed stromal progenitor cells codevelop into
adenomyosis.
Conclusions
Adenomyosis is a benign gynecological disorder which con-
sists of endometrial glands and stroma in the myometrium.
Although adenomyosis is related to endometriosis, both
lesions are thought to develop through different mecha-
nisms. Results of recent molecular genetic studies imply
that adenomyosis is clonally derived from the basal endo-
metrium, a result in resonance to the original Cullen’s
hypothesis that adenomyosis is the “invasion” of endometri-
al tissue into myometrium. Despite this fact, adenomyosis
develops its own progeny during development, and can be
molecularly distinguished from proximal eutopic endome-
Antero et al. 115
trium. Several studies have also suggested that the eutopic
endometrium is inherently different in women with versus
without adenomyosis. However, the data on this are not
conclusive, and more rigorous research employing new
technologies with a larger case cohort will be needed to
validate these conclusions.
Future Directions
Despite new progress in our understanding of the pathology
and pathogenesis of adenomyosis, several fundamental
questions remain unanswered. Future pathology research
is needed to classify adenomyosis, and there is a pressing
need to understand the molecular and genetic underpin-
nings of this disease to facilitate new diagnostic and thera-
peutic paradigms.
Classification. Foremost is that a standardized classifica-
tion system is developed in pathology to accurately docu-
Downloaded by: World Health Organization ( WHO). Copyrighted material.
ment and report the disease and for a consistency in
designing basic and clinical studies for meaningful interpre-
tation in future adenomyosis research. With the advent of
molecular technologies, we believe that a model integrating
clinical–pathological findings and molecular data such as
somatic mutation load, cancer driver mutation landscape,
and methylation profiles can be developed to correlate with
clinical phenotypes. This knowledge will be essential for a
better understanding of the pathogenesis of the disease.
Diagnosis. Development of practical diagnostic tools with
high accuracy is desirable to guide diagnosis and clinical
management. While MRI and ultrasound in the past two
decades have provided a noninvasive diagnostic tool for
adenomyosis, correlation of these with pathological findings
is warranting. As molecular signatures may likely differ in
eutopic endometrium of women with versus without adeno-
myosis, it is envisioned that adenomyosis could be reliably
predicted based on an endometrial molecular “adenomyosis
signature,” ideally including imaging results in a risk-predict-
ing algorithm. Equally important is to develop blood-based
biomarkers that can help diagnose a woman with adenomyosis
with high sensitivity and specificity. This will be made possible
after a better understanding of the aberrant adenomyosis-
specific secretome including exosome, miRNA species, and
unique protein biomarkers and their combinations.
Disease mechanisms. It is important for future directions
in studying the pathology of adenomyosis to focus on under-
standing molecular and genetic changes present in both
eutopic and ectopic lesions to determine their roles in the
development of adenomyosis and how they relate to specific
disease phenotypes. More studies are needed to determine
phylogenetic trajectories in the development of adenomyo-
sis from eutopic endometrium. Future studies also need to
integrate the somatic mutation data to the theory of endo-
metrial progenitor (stem cell-like) cells. While truncal muta-
tions are shared by progenitor cells and their progeny,
indicating a clonal derivation of the latter from the former,
it remains unclear where those progenitor cells are physi-
cally located and how many they are in eutopic and ectopic
endometrium.
Seminars in Reproductive Medicine Vol. 38 No. 2-3/2020
116 Pathology and Pathogenesis of Adenomyosis Antero et al.
Moreover, experimental designs of molecular studies
warrant revisiting. Historically bulk tissue analyses of the
lesions as a whole (combining epithelium and stroma) or
only on epithelium were conducted. Given the critical roles
of the stromal components in codeveloping adenomyosis
with glandular epithelium, it will be necessary to study
stroma alongside glandular epithelium by careful separation
of glands and stroma using laser-capture microdissection
before sequencing analysis and genome-wide profiling.
Finally, recent technological developments have greatly
helped advance our understanding of many human diseases,
especially in the fields of cancer and immunology. Tools such as
multiplexed imaging analysis, single cell profiling, and epige-
netic and epigenomic methods all offer unprecedented oppor-
tunities to accelerate discovery of altered genetic and
molecular pathways in adenomyosis and associated eutopic
endometrium. The new knowledge will, in turn, inform clinical
studies for the development of improved diagnosis and treat-
ments, which may be more patient centered, potentially
curative, and fertility sparing. This task is long overdue.
Funding
This study is supported by an NIH grant RO1HD096147
and by the Richard W. TeLinde Endowment, Department of
Gynecology and Obstetrics, Johns Hopkins University.
Conflict of Interest
None declared.
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