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Human Reproduction vol.15 no.4 pp.

767–771, 2000

Smooth muscles are frequent components of


endometriotic lesions

V.Anaf1,3, Ph.Simon1, I.Fayt2 and J.-C.Noel2 tissue with sparse finger-like extensions of glandular and
stromal tissue. It is not surprising that, on descriptive grounds,
Departments of 1Gynaecology and 2Pathology, Hospital Erasme,
Universite Libre de Bruxelles (ULB), 808, Route de Lennik, 1070 the lesion was initially called adenomyosis. Recently it was
Brussels, Belgium proposed that peritoneal, ovarian and rectovaginal endome-
3To whom correspondence should be addressed
triosis represent separate entities with different pathogeneses
(Nisolle and Donnez, 1997). Red peritoneal endometriosis
Deep infiltrating endometriosis (deeper than 5 mm under represents early implantation of endometrial cells and stroma
the peritoneum) often takes the form of a nodular lesion while typical black lesions and white opacifications represent
(or ‘adenomyotic nodule’) consisting of smooth muscles distinctive steps in the evolutionary process of the disease.
and fibrosis with active glands and scanty stroma. Thus, Ovarian endometriomas result from the metaplasia of the
among endometriotic lesions, a certain distinction is drawn invaginated ovarian mesothelium into the ovarian cortex.
between musculo-glandular lesions and glandular lesions Rectovaginal endometriosis must be considered as an adenomy-
composed of endometrial-like epithelium surrounded by a otic nodule whose histopathogenesis is related to the metaplasia
cell-producing (cytogenous) stroma. The aim of this study of Müllerian remnants located in the rectovaginal septum
was to detect by immunohistochemistry, with a monoclonal (Nisolle and Donnez, 1997). Whether deep endometriosis
antibody against muscle-specific actin, the presence of actually represents adenomyosis or not, a certain distinction is
smooth muscles in 54 endometriotic lesions originating drawn between musculo-glandular lesions (deep infiltrating
from four different pelvic locations (peritoneum, ovary, endometriosis) and glandular lesions surrounded by a cytogenic
rectovaginal septum and uterosacral ligaments) and to stroma (peritoneal and ovarian endometriosis). In order to
quantify the smooth muscle content. Smooth muscles were clarify this issue, we investigated the presence and the abund-
frequent components of endometriotic lesions in pelvic ance of smooth muscles in 54 cases of endometriosis originating
locations. In addition, smooth muscles were significantly from four different pelvic locations and in unaffected tissues
(P < 0.001) more abundant in endometriotic lesions than from the same pelvic locations.
in their respective unaffected sites. This finding supports,
at least partially, the occurrence of a metaplastic phenom-
enon in the pathogenesis of endometriotic lesions. The Materials and methods
definition of distinct endometriotic entities based on the Fifty-four endometriotic lesions were obtained from 54 patients who
difference in the tissue composition of the lesions (endome- underwent laparoscopy (n ⫽ 49) or laparotomy (n ⫽ 5) for sterility
triotic nodules versus adenomyotic nodules) is inconsistent (n ⫽ 22), pelvic pain (n ⫽ 16: laparoscopy n ⫽ 11; laparotomy n ⫽
5) or both conditions (n ⫽ 16). In five patients, laparotomy was
with the very frequent presence of smooth muscle cells in
performed for chronic pelvic pain because of previous major abdom-
endometriosis irrespective of its localization. inal surgery (ileal resection: n ⫽ 3; total sigmoidectomy: n ⫽ 1;
Key words: adenomyosis/endometriosis/rectovaginal endome- partial hepatectomy for traumatic partial hepatic rupture: n ⫽ 1). All
triotic nodule/smooth muscle metaplasia patients were non-menopausal caucasian women. The mean age of
the patients was 28 years old (range: 20–43). None of the patients
had taken any hormonal treatment for at least 2 months before
surgery. All the lesions were excised in toto, immediately fixed in
Introduction 10% phosphate-buffered formalin for 12 h and then embedded in
Endometriosis is histologically defined as the presence of paraffin. Serial sections of 4 µm thick were cut and some were stained
endometrial-like glands and/or stroma outside the uterus. with haematoxylin and eosin; other sections were immunostained with
the monoclonal antibody against muscle-specific actin.
Deep infiltrating endometriosis is defined as the presence of
endometriosis more than 5 mm under the peritoneum (Cornillie Endometriotic lesions
et al., 1990) and is strongly associated with chronic pelvic Four different endometriotic lesions were studied: peritoneal endome-
pain. The uterosacral ligaments are one of the most frequent triosis (n ⫽ 21), ovarian endometriomas (n ⫽ 13), uterosacral
locations of deep endometriosis followed by the rectum and endometriotic nodules (n ⫽ 8) and rectovaginal septum endometriotic
the bladder (Cornillie et al., 1990). Deep endometriosis is a nodules (n ⫽ 12).
nodular lesion which is histologically characterized by dense Peritoneal endometriosis
tissue composed of fibrous and smooth muscle cells with Fourteen lesions were typical black implants and seven were red
islands or strands of glands and stroma. The major component lesions. The surface areas of the biopsies were between 0.5 and 1
of the nodular lesion is not endometrial tissue but fibromuscular cm2. The peritoneal lesions were excised in toto with the help of

© European Society of Human Reproduction and Embryology 767


V.Anaf et al.

scissors or a CO2 laser. The lower limit of the biopsies was the or by pathological tissue) did not exceed 0.9% per studied field (in
subperitoneal fat. In order to avoid sampling smooth muscles from the four different endometriotic locations for actin positive area
an organ lying under the endometriotic lesion, no biopsies were from evaluation and total lesion area evaluation as well as in the controls),
the uterine serosa, tubes or round ligaments. only the entirely filled grid squares were counted. It must be
Ovarian endometriosis emphasized that at ⫻400 high power field, the area of a myocyte is
Ovarian endometriotic lesions were ovarian endometriotic cysts of larger than that of a grid square, which means that partially filled
⬎3 cm diameter (n ⫽ 9) and ovaries containing endometriomas of squares represent less than the area of a smooth muscle cell. In order
the same diameter (n ⫽ 3). to perform precise measurements, the areas of the intersects on the
grid were measured on the monitor screen and taken into account in
Uterosacral and rectovaginal nodules
the evaluation of the area of actin-positive tissues, endometriotic
Uterosacral and rectovaginal lesions were nodular lesions felt at
lesions and the controls. The relative area occupied by smooth
physical examination and located deep in the uterosacral ligaments
muscles was measured in at least 10 non-overlapping randomly
and rectovaginal septum. These lesions were excised by laparoscopy
selected high power fields (⫻400) in each endometriotic lesion on
with a CO2 laser until no residual induration was felt in the
each slide and in each biopsy of the unaffected same pelvic location.
surrounding tissues.
Results are expressed as percentages (mean ⫾ SD) representing the
Controls relative areas occupied by smooth muscles in unaffected tissues and
Controls were obtained the eutopic endometrium (n ⫽ 10) of patients in endometriotic lesions.
with and without laparoscopically proven endometriosis. In both A computerized stereological method was not used in this study
groups, actin stainings were performed on endometrial tissues of the because there was not enough contrast between the haematoxylin-
early proliferative (n ⫽ 2) and secretory (n ⫽ 2) phases, mid stained tissue and the actin-stained tissue.
proliferative (n ⫽ 2) and secretory (n ⫽ 2) phases and premenstrual
phase (n ⫽ 2). Controls were also performed on the normal pelvic
Statistical analysis
peritoneum (n ⫽ 10), ovaries (n ⫽ 4) and uterosacral ligaments (n ⫽
6). To investigate the normal rectovaginal septum, actin stainings Comparison of the data was performed using the Student’s t-test
were performed on the rectovaginal septum of three female fetuses (two-tailed). Statistical significance was defined as P ⬍ 0.001.
of more than 30 weeks (pregnancy interruption for lethal fetal
cytomegalovirus infection) and on the rectovaginal septum of pelvec- Special stainings
tomy specimens (n ⫽ 2). In order to differentiate smooth muscle cells from myofibroblasts,
we performed silver stainings in the four different endometriotic
Immunohistochemistry locations. Silver stainings are able to reveal the external lamina
After deparaffinization in xylene and rehydration through graded basalis, composed of glycoproteins and collagen type 4, which is
concentrations of alcohol, the endogenous peroxidase activity was present in smooth muscle cells but not in myofibroblasts (Stevens
blocked in 0.3% H2O2 in methanol for 30 min. Then normal serum and Lowe, 1997).
was applied in order to minimize non-specific reactivities. The
sections were then incubated at 4°C overnight with the specific
monoclonal primary antibody against muscle-specific actin (clone
HHF 35, dilution 1/50; Biogenex, San Ramon, CA, USA) able to
Results
recognize actin isotypes alpha and gamma of smooth muscle cells. Controls
This antibody does not recognize other muscle filament proteins and
Eutopic endometrium from endometria and non-endometriotic
it is non-reactive for other mesenchymal or epithelial cells except
myoepithelial cells. After rinsing with Tris-buffered saline (TBS), patients were negative (n ⫽ 10; 100%) for actin staining
biotinylated anti-mouse immunoglobulin (IgG) was applied for 30 irrespective of the cycle phase (early proliferative and secretory
min at room temperature. After rinsing again with TBS, preformed phase, mid-proliferative and secretory phase or premenstrual
avidin and biotinylated horseradish peroxidase macromolecular com- period). Actin stainings were negative both in the non-endome-
plex (Vectastain Elite ABC kit; Vector Laboratories, Inc., Burlingame, triotic peritoneum (n ⫽ 12) and in the rectovaginal septum
CA, USA) was applied for 30 min at room temperature. The antigen– (n ⫽ 5). The smooth muscle content was estimated at 2 ⫾
antibody reaction was visualized using diaminobenzidine. The sections 1% in the normal ovary, essentially located in the ovarian
were then slightly counterstained with Mayer’s haematoxylin, dehyd- stroma, and at 36 ⫾ 5.2% in the normal uterosacral ligament.
rated and coverslipped. Negative control sections were processed by
There was a significant difference (P ⬍ 0.001) in smooth
omitting the primary antibody. Positive controls consisted in uterine
leiomyomas and normal myometrium.
muscle content between the normal uterosacral ligament and
the ovary (Table I).
Quantification of the smooth muscle content in endometriotic lesions
and in unaffected tissues Endometriotic lesions
Using a microscope grid (at ⫻400) linked via a colour CCD video All endometriotic lesions (100%) were positive to various
camera (MW-F15-e, Panasonic; Matsushita Electrical Industrial Co. degrees for actin staining (Figures 1, 2 and 3). The smooth
Ltd, Osaka, Japan) to a large screen monitor (Panasonic Quintrix;
muscle content of all endometriotic lesions was significantly
Matsushita Electrical Co., Pentwyn, Cardiff, UK), we measured the
smooth muscle content in the four different endometriotic locations
greater (P ⬍ 0.001) than in their respective unaffected pelvic
and in their respective unaffected tissue by measuring the relative locations. Comparisons between the different locations are
area occupied by smooth muscle cells (stained area/area occupied by illustrated in Table I. The smooth muscle content of typical
unaffected tissue or by endometriotic lesion). Because the mean black peritoneal lesions was higher than in red lesions but this
number of grid squares only partially filled (by actin positive tissue difference was not found to be significant (Table II).
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Smooth muscles and endometriosis

Table I. Smooth muscle (SM) content of controls and endometriotic lesions in the four different locations

Controls

P (n ⫽ 12) OV (n ⫽ 7) USL (n ⫽ 6) RVS (n ⫽ 5)

Actin ⫹ 0/12 (0) 7/7 (100) 6/6 (100) 0/5 (100)


SM content (%) 0 2⫾1 36 ⫾ 5.2 0
(mean ⫾ SD)

Lesions

PE (n ⫽ 21) OVE (n ⫽ 13) USLE (n ⫽ 8) RVSE (n ⫽ 12)

Actin ⫹ 21/21 (100) 13/13 (100) 8/8 (100) 12/12 (100)


SM content 75.7 ⫾ 5.7a 23 ⫾ 6a 73.3 ⫾ 10.6a 78.7 ⫾ 7.1a
(mean ⫾ SD)

aSignificantlydifferent (P ⬍ 0.001) when compared with the unaffected pelvic location.


Values in parentheses are percentages.
Actin ⫹: positive immunostaining with smooth muscle actin antibody.
SM content is expressed as mean percentage area of lesions occupied by smooth muscle cells.
P ⫽ peritoneum; OV ⫽ ovary; USL ⫽ uterosacral ligament; RVS ⫽ rectovaginal septum; PE ⫽ peritoneal
endometriosis; OVE ⫽ ovarian endometriosis; USLE ⫽ uterosacral ligament endometriosis; RVSE ⫽
rectovaginal septum endometriosis.

Figure 3. Section through a rectovaginal endometriotic nodule.


Figure 1. Peritoneal endometriosis: presence of smooth muscle
Presence of abundant smooth muscle cells around the lesion.
cells (stained brown) at the periphery of the stroma. Muscle-
Muscle-specific actin immunohistochemistry. Original magnification
specific actin immunohistochemistry. Original magnification ⫻100.
⫻10.

Table II. Comparison of the smooth muscle (SM) content of red and black
peritoneal lesions

Controls Red lesions Black lesions


(n ⫽ 12) (n ⫽ 7) (n ⫽ 14)

SM content (%) 0 73.4 ⫾ 5.5 78 ⫾ 5.9a


(mean ⫾ SD)

aNot significant when compared with the smooth muscle content of red
lesions.

Special stainings
Silver stainings showed the presence of the external lamina
Figure 2. Section through the wall of an ovarian endometriotic basalis in the peristromal actin positive areas in red and black
cyst. Presence of smooth muscle cells (stained brown) in the deep peritoneal endometriosis, ovarian endometriomas, uterosacral
layers of the stroma and at the periphery of the stroma. Muscle- endometriotic nodules and in rectovaginal endometriotic
specific actin immunohistochemistry. Original magnification ⫻400. nodules.
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V.Anaf et al.

Discussion Sampson’s transplantation theory (Sampson, 1927), the absence


This is the first study on pelvic endometriosis with a monoclonal of actin positive cells in the eutopic endometrium of patients
antibody against smooth muscle-specific actin. One of the with and without laparoscopically proven endometriosis and
most intriguing findings of this study is the presence of smooth its very frequent presence in endometriotic lesions suggests
muscles in peritoneal lesions and their absence in the unaffected that regurgitated endometrium undergoes some smooth muscle
peritoneum and in the eutopic endometrium of women with metaplasia under the influence of peritoneal fluid or that
and without pelvic endometriosis. This absence of muscular implanted endometrium causes a metaplastic response in the
tissue in the unaffected peritoneum and in the eutopic endomet- underlying tissue. There are numerous arguments to consider
rium suggests a metaplastic phenomenon. This metaplastic that the endometrium of patients with endometriosis differs
phenomenon refers to the induction theory (Levander, 1955; from that of disease-free patients. These range from gross
reviewed by Ridley, 1968, and van der Linden, 1996). It has morphological changes such as the polypoid appearance of the
been demonstrated that smooth muscle metaplasia can occur endometrium at hysterosalpingography (McBean et al., 1996),
in the peritoneum. According to some authors, metaplasia of to changes in immunocytochemistry such as aberrant integrin
the subcoelomic mesenchyme in the direction of smooth expression (Lessey et al., 1994), and biochemical changes
muscles underlies the pathogenesis of leiomyomatosis periton- such as overexpression of plasminogen activator receptor
ealis disseminata (Fujii et al., 1980, 1981; Parmley et al., (Sillem et al., 1997) and abnormal endothelial, epithelial and
1987). The term ‘secondary Müllerian system’ has been applied stromal proliferation (Wingfield et al., 1995). P-450 aromatase,
to the pelvic and lower abdomen mesothelium and underlying which converts androgens into oestrone and oestradiol, is not
mesenchyme of females, on the basis of its close embryological expressed in the endometrium of patients without endometriosis
relationship with the Müllerian ducts (Lauchlan, 1972). The (Prefontaine et al., 1990; Noble et al., 1996; Kitawaki et al.,
potentiality of this tissue is manifested by the existence in the 1997) but its expression has been demonstrated in the eutopic
peritoneal cavity and most often in the pelvic region of a large endometrium of patients with endometriosis and in the stroma
variety of metaplastic and neoplastic lesions that are analogous of endometriotic lesions (Yamamoto et al., 1993; Noble et al.,
in all regards to those more commonly found in the ovary, 1996, 1997; Kitawaki et al., 1997). This may result in an
uterus, or other organs of the female genital tract (Thor increased local concentration of oestrogens in the endometriotic
et al., 1991). In Rosai’s classification of peritoneal lesions, lesion. Although actin positive cells were absent in the endo-
endometriosis, endosalpingiosis, endocervicosis, ectopic decid- metrium of patients with endometriosis in this study, such
ual reaction and leiomyomatosis peritonealis disseminata are differences between the endometrium of patients with endome-
considered as metaplastic lesions of the secondary Müllerian triosis and disease-free patients may result in microenviron-
system (Rosai, 1996). The smooth muscle component of mental conditions that could favour smooth muscle metaplasia
endometriosis may thus result from the totipotential capacity within the regurgitated tissue or within the underlying tissue.
of the secondary Müllerian system to differentiate not only into Among these differences, angiogenic factors and in particular
endometrial glands and stroma but also into smooth muscles. vascular endothelial growth factor (VEGF) seem to play an
Another possibility is that peristromal smooth muscles result important role in the evolution of the lesion after the first stage
from the differentiation of the stromal cells into smooth muscle of implantation (Donnez et al., 1998; Healy et al., 1998). It
cells. Red peritoneal lesions are often considered as early has been shown that the VEGF content is higher in red
implantation of endometrial tissue while typical black lesions peritoneal lesions than in black peritoneal lesions. Lower
and white opacifications represent distinctive steps in the VEGF concentrations in black lesions may explain the decrease
evolutionary process of the disease (Nisolle and Donnez, in both stromal and epithelial vascularization, followed by
1997). If this is correct, we would expect to find some smooth fibrosis and inactivation of the implant (Donnez et al., 1998).
muscle differentiation in the eutopic endometrium of women The smooth muscle content of peritoneal lesions does not
with endometriosis, at least in the premenstrual tissue. How- seem to be correlated with the age of the lesion. Indeed, as
ever, actin stainings performed in the eutopic endometrium we have shown here, black lesions contained a similar amount
were all negative. In fact, smooth muscle metaplasia of the of muscle to red lesions. Nevertheless, it has been demonstrated
endometrial stroma is a rare event. Indeed, in the eutopic that the amount of fibrotic tissue was more important in the
endometrium, smooth muscle metaplasia occasionally represent stroma of black than in red lesions (Matsuzaki et al., 1999).
small foci of typical benign smooth muscles within the Interestingly, a recent immunohistological study on pleuro-
endometrium called ‘intra-endometrial leiomyomatosis’. In pulmonary endometriosis and pulmonary ectopic deciduosis
addition, only 1–2% of endometrial polyps show the presence also showed the presence of smooth muscle actin positive
of smooth muscle in their stroma (Silverberg and Kurman, cells in most stromal cells of all endometriotic and ectopic
1991). decidual lesions (Flieder et al., 1998). It is postulated that
According to Leyendecker, endometriosis is a disease of viable endometrial tissue regurgitated through the Fallopian
the endometrial–subendometrial unit also called archimetra tubes enters the thorax through right diaphragmatic fenestra-
(Leyendecker, 1998). This model postulates that endometriosis tions (Sampson, 1927). However, it must also be emphasized
results from hyperperistalsis, dysperistalsis of the archimetra that the pleural and peritoneal cavity are both of mesodermal
and increased intrauterine pressure causing increased transtubal embryologic origin and that factors able to induce metaplasia
transport. In agreement with Leyendecker’s model but also could also pass through these diaphragmatic defects and
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Smooth muscles and endometriosis

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Received on August 6, 1999; accepted on January 5, 2000
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