Title: The etiology differs regards to the locations of the lesion: a clinical experience of 1350
patients with adenomyosis confirmed by postoperative pathology
Version: 2 Date: 10 Feb 2025
Reviewer:  Takashi Matsushima
Reviewer's report:
This manuscript is a paper that examines the clinical characteristics of different subtypes of
adenomyosis (comparison of focal types and diffuse types, and comparison of anterior wall
localization and posterior wall localization). First of all, the research aim is vague and it is not
clear what is being attempted to be clarified. Therefore, It is also unclear whether the research
methods used in this study are correct for achieving the research objectives. In addition, the
study does not make it clear what it is trying to clarify, as it uses vague language such as “the
etiology of the disease remains enigmatic” in relation to adenomyosis.
As shown above, there are many problems with this manuscript, and it cannot be accepted unless
these are corrected.
There have been many reports on the clinical characteristics of each subtype of adenomyosis.
The authors should summarize these reports and clearly state in the introduction what are already
known, what are unknown, and what this study aims to clarify. In addition, although significant
differences were obtained for many items, there were no significant differences in the individual
values (e.g. age: diffuse type 46.8 years old, focal type 44.7 years old, etc.), and it seems that
the significant differences were obtained due to the large sample size. In clinical practice, is
a difference of 2 years useful for treatment? In other words, is the sample size of this study
appropriate? The theoretical and/or statistical basis for the sample size of this study should be
presented. Furthermore, all of the subjects were cases that had undergone surgery and received a
histological diagnosis, and cases of adenomyosis that did not require surgery were not included,
so these results do not apply to all patients with adenomyosis. In addition, cases of adenomyosis
combined with uterine fibroids are also included, so it is not possible to determine whether
the clinical symptoms (such as hypermenorrhea and dysmenorrhea) are due to adenomyosis. In
research investigating the symptoms of adenomyosis, cases with complications that present with
similar symptoms should normally be excluded. In other words, the limitations of this study
should be described in the #Discussion# section, and it should be stated that the bias of the data
obtained from this study should be taken into account when interpreting the data.
The following is a detailed discussion of each point.
1. Introduction, 3rd paragraph, lines 1-2, “the etiology of the disease remains enigmatic.”: Even
though it is shrouded in mystery, there are already some facts that have been reported. Authors
need to specifically state what has been clarified and what facts have yet to be clarified. Authors
should also state what benefits there will be when these things are clarified.
2. Introduction, 3rd paragraph, 6th line, “helped to estimate true prevalence better”: As the
subjects are cases diagnosed histologically as having adenomyosis, it is not possible to estimate
the true prevalence. Please revise the research objective.
3. Materials and Methods Population: Are there any exclusion criteria for the study cases? If
there are no exclusion criteria, this should be stated. Also, there is no description of the sample
size for this study. As mentioned above, the theoretical and/or statistical basis for the sample
size for this study should be presented.
4. Materials and Methods The criteria for classifying into each subtype are not described. In
other words, the definitions of focal type and diffuse type, as well as anterior wall group and
posterior wall group, are required. It should also be stated whether types that cannot be classified
into either group were excluded, whether circumferential types were excluded from the anterior
wall group and posterior wall group, or whether they were added to both groups.
5. Materials and Methods Data extraction: Items that are not listed in the “Results” section are
also listed here. Items that are not listed in the results should be deleted here.
6. Materials and Methods Statistical Analysis, Line 5, “Multivariate regression analyses”: The
abstract states that the analysis was conducted using “Logistic regression analysis”, but which
method was used? The method of analysis should be standardized.
7. Results, 6th paragraph, lines 1-4, “After excluding ~ ultrasound.”: This sentence should be
included in the Materials and Methods section.
8. Discussion: As I pointed out in the “introduction” section, it should be stated what is unknown,
what will be clarified in this research, and what is expected in terms of the treatment of this
disease as a result of this research.
The following is a description of what is known about adenomyosis that occurs in the anterior
and posterior walls of the uterus, as well as focal and diffuse types (including unproven
information).
Clinical features of diffuse adenomyosis and focal adenomyosis
Diffuse adenomyosis and focal adenomyosis are conditions in which endometrial tissue is
ectopically present in the myometrium, but they have different clinical features.
Characteristics of diffuse adenomyosis
Diffuse adenomyosis is a condition in which endometrial tissue spreads throughout the
myometrium of the uterus. The main features are as follows:
· Symptoms: Dysmenorrhea and hypermenorrhea are common, and chronic pelvic pain may be
present.
· Imaging diagnosis: On MRI, diffuse thickening of the endometrial-muscular junction is seen,
usually 7-37 mm thick, with an average of around 16 mm(1).
· Biological differences: It has been shown that the expression of steroid receptors is lower than
in focal adenomyosis(2).
Characteristics of focal adenomyosis
Focal adenomyosis is a condition in which endometrial tissue is present in a specific area. The
main characteristics are as follows:
· Symptoms: The symptoms are similar to those of diffuse adenomyosis, but the localized pain
may be more severe.
· Imaging diagnosis: On MRI, it is often recognized as an isolated lesion with a clear boundary
with the surrounding muscle layer.
· Biological differences: Localized adenomyosis may respond differently to certain hormonal
treatments(2).
As you can see, diffuse adenomyosis and focal adenomyosis have different characteristics
in terms of symptoms, imaging diagnosis, and biological properties. Understanding these
differences is important for appropriate diagnosis and treatment.
Regarding the biological differences between diffuse and focal adenomyosis, it has been shown
that focal adenomyosis responds differently to hormonal treatment. Specifically, it has been
observed that the expression of estrogen receptors (ER) and progesterone receptors (PR) is
relatively lower in focal adenomyosis compared to myoma tissue(2). This may lead to a different
response to hormonal treatment, so it is important to consider these biological differences
when planning treatment strategies. Furthermore, in terms of diagnosis using MRI, localized
adenomyosis often appears as a low-signal-intensity round or oval mass with a diameter of 2-7
cm, and the boundary with the surrounding muscle layer is generally unclear(1)
Treatment
· Drug therapy: Hormone therapy and painkillers may be used for both types, but diffuse
adenomyosis is more severe and difficult to treat.
· Surgical therapy: In cases of severe symptoms, especially focal adenomyosis, surgical removal
may be considered.
(##Byun JY, Kim SE, Choi BG, Ko GY, Jung SE, Choi KH. Diffuse and focal
adenomyosis: MR imaging findings. Radiographics. 1999 Oct;19 Spec No:S161-70. doi:
10.1148/radiographics.19.suppl_1.g99oc03s161. PMID: 10517452.
(##Khan KN, Fujishita A, Koshiba A, Mori T, Kuroboshi H, Ogi H, Itoh K, Nakashima
M, Kitawaki J. Biological differences between focal and diffuse adenomyosis and response
to hormonal treatment. Reprod Biomed Online. 2019 Apr;38(4):634-646. doi: 10.1016/
j.rbmo.2018.12.015. Epub 2018 Dec 21. PMID: 30850322.
Comparison of the clinical features of adenomyosis of the anterior and posterior walls of the
uterus
Adenomyosis is a condition in which the endometrium grows ectopically within the
myometrium, and the anterior and posterior walls may show different clinical features.
Characteristics of anterior wall adenomyosis
· Symptoms: A mass is often formed on the anterior wall, and dysmenorrhea and hypermenorrhea
may be prominent.
· Imaging diagnosis: On MRI, the anterior wall myometrium is generally unevenly thickened,
and thickening of the junctional zone (JZ) is observed. In particular, signal changes on T1-
weighted and T2-weighted images are observed.
· Complications: Adenomyosis of the anterior wall is often complicated by uterine fibroids and
other lesions, making diagnosis difficult.
· Age of onset: Adenomyosis of the anterior wall is particularly common in women in their late
30s and 40s, and the risk is also increased in women who have given birth.
· Treatment methods: Hormone therapy and surgical therapy are often chosen for adenomyosis of
the anterior wall, and selective removal surgery may be performed for patients who particularly
wish to preserve their uterus.
Characteristics of adenomyosis of the posterior wall
· Symptoms: Adenomyosis of the posterior wall can also cause dysmenorrhea and
hypermenorrhea, but the symptoms are often milder than those of adenomyosis of the anterior
wall.
· Imaging diagnosis: On MRI, the muscular layer of the posterior wall thickens, and low signal
intensity with indistinct borders may be seen. In particular, thickening of the posterior wall is
characteristic.
· Complications: Adenomyosis of the posterior wall may be associated with deep endometriosis,
which can complicate diagnosis.
· Age of onset: As with adenomyosis of the posterior wall, it is most common in women in their
late 30s and 40s, but the risk is particularly high in women who have given birth.
· Treatment: Hormone therapy and surgical treatment are also used for adenomyosis of the
posterior wall, but because adenomyosis of the posterior wall is often associated with deep
endometriosis, more complex treatment may be required.
Summary
Uterine adenomyosis of the anterior and posterior walls have different characteristics in terms
of symptoms and imaging findings. The anterior wall is characterized by prominent mass
formation, while the posterior wall is often seen as having indistinct thickening. Understanding
these differences will enable more accurate diagnosis and treatment.
9. Discussion: There is another classification method that divides endometriosis into intrinsic
and extrinsic types, and it is said that endometriosis is caused by the extrinsic type in particular.
The relationship between this classification method and the current classification method should
also be considered to some extent. It is said that this classification method makes it easier to
explain the pathophysiological mechanisms of the development of adenomyosis.
Extrinsic-type adenomyosis is closely related to endometriosis, and in particular, it is often found
in combination with deep invasive endometriosis (DIE). Research has shown that the detection
rate of DIE in patients with the extrinsic type can reach 90%(3). In addition, it has been observed
that the histological lesions of extrinsic adenomyosis and DIE are similar, and this has led to the
extrinsic adenomyosis being considered as “adenomyosis externa”(3).
On the other hand, the intrinsic type has a structure similar to that of the endometrium, as the
endometrial tissue infiltrates the muscular layer, and is considered to have little relationship
to DIE. As a result, patients with the intrinsic type often have a relatively simple approach to
treatment.
As you can see, the difference between the intrinsic and extrinsic types is an important factor in
clinical management and treatment strategy. In particular, patients with the extrinsic type require
treatment that takes into account the complications of DIE, and a more specialized approach
is required.
#3#Khan KN, Fujishita A, Koshiba A, Kuroboshi H, Mori T, Ogi H, Itoh K, Nakashima M,
Kitawaki J. Biological differences between intrinsic and extrinsic adenomyosis with coexisting
deep infiltrating endometriosis. Reprod Biomed Online. 2019 Aug;39(2):343-353. doi: 10.1016/
j.rbmo.2019.03.210. Epub 2019 Mar 27. PMID: 31160242.
10. Discussion: There is no mention of limitations. As mentioned above, all of the subjects in
this study had undergone surgery and had a histological diagnosis, so the results do not apply
to all cases of adenomyosis. Similarly, the study also included cases of adenomyosis combined
with uterine fibroids, so it is not possible to determine whether the clinical symptoms (such as
heavy menstrual bleeding and menstrual pain) were caused by the adenomyosis. In principle,
cases with complications should be excluded. In other words, the limitations of this study should
be described in the discussion, and it should be stated that the bias of the data obtained from this
study should be considered when interpreting the data.
11. Conclusion: The purpose of this study was to “to learn more about of the characteristics
of the disease and the pathophysiological mechanisms that may be occurring.”, but this is not
concluded. In particular, there is no conclusion drawn from the differences between the “diffuse
type and focal type”. Furthermore, it is too much of a leap to conclude from the results of this
study that “Patients with ultrasound evidence of posterior wall lesions should be treated in an
experienced tertiary center to reduce the risk of surgery”. These need to be revised.