Introduction
Endometriosis is a polygenic multi factorial disease. Incidence
of deep infiltrating endometriosis (DIE) involving the GI tract is
estimated at 8-12% [1,2] and commonly involves the rectosigmoid
colon. Endometriosis is one of the most common benign gynecologic
diseases. It causes pelvic pain and sub fertility, and is characterised
by the presence of ectopic endometrial tissue outside the uterus
[3]. Endometriosis is under-diagnosed and associated with a
mean latency of 6.7 years from onset of symptoms to definitive
diagnosis [4]. Most estimates of prevalence are made on the basis
of surgical cases or small samples, and are highly selective, ranging
between 5% and 10% in women of reproductive age, and up to
50% among infertile women [5-7]. Endometriosis has an important
socio-economic impact, because it greatly lowers quality of life
for a significant portion of the population, and is responsible for
substantial health expenditure, diagnosis, treatment, and loss of
economic performance. The cost of endometriosis to the US health
care system was $69.4 billion in 2009 [8]. Despite 150 years of
hypothesis-driven research, the cause of endometriosis remains
uncertain. Therapeutic options are therefore limited, often lacking
unanimous consensus. However, there is mounting evidence
that endometriosis is a complex multifactorial disease, with both
genetic and environmental components contributing to disease
susceptibility [7]. In 1980, Simpson et al. published the first formal
genetic study of endometriosis [9]. Studying 123 probands with
histologically proven endometriosis, they found that 5.9% of female
siblings over the age of 18 years had endometriosis; the mothers
were affected in 8.1% of cases.
However, only 1% of the patients’ husband’s first-degree
relatives (controls) had the disease. Women with an affected sibling
or parent were more likely to have a severe form of endometriosis
[10]. Severe endometriosis was present in 61% of probands who
had an affected first-degree relative, whereas it was only present
in 23% of the affected probands with no affected first-degree
relatives. One recent meta-analysis combining results from a
genome-wide association study and replication studies showed
that of the nine loci found to be associated with endometriosis
in at least one of the studies, six remained statistically significant
genome-wide, and two showed borderline statistically significant
Cite this article: Adel S, Fariba B W, Joseph M. Identical Ovarian and Deep Pelvic Endometriosis with Colorectal Involvement in Monozygotic
Twins: A Case Report and Review of the Literature. Biomed J Sci & Tech Res 1(6)- 2017. BJSTR. MS.ID.000505.
DOI : 10.26717/BJSTR.2017.01.000505
Abstract
Endometriosis is a common benign gynecologic disease characterised by the presence of ectopic endometrial tissue outside the uterus. We
present a brief review on the genetic factors underlying endometriosis, followed by a case report on concordant anatomical distribution of deep
infiltrating endometriosis (DIE) in a pair of monozygotic (MZ) twins. To our knowledge, this is one of the first reported cases of DIE in MZ twins.
The remarkable concordance and resemblance of deep disease involving the same anatomical sites, ovaries, pelvic floor and rectosigmoid colon
in our MZ twins reiterates the role and impact of genetic factors in the pathogenesis of endometriosis.
Keywords
Deep Infiltrating Endometriosis; Sigmoid Resection; Monozygotic Twins; Genetics
Abbreviations: MZ: Mono Zygotic; DZ: Di Zygotic; DIE : Deep Infiltrating Endometriosis; IVP: Intravenous Pyelogram; TVS: Transvaginal
Ultrasound; RES: Rectal Endoscopic Sonography; SMM: Smooth Muscle Metaplasia
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Joseph Miller. Biomed J Sci & Tech Res Volume 1- Issue 6 : 2017 1648
genome-wide association with moderate/severe disease [11]. In an
Australian twin-based study, a twofold increase in endometriosis
risk in monozygotic (MZ) compared with dizygotic (DZ) twin pairs
was reported [7], which suggests that the genetic component
contributing to phenotypic variability in endometriosis is about
52%. These data imply that endometriosis is a complex genetic
trait, and indicate that a number of genes interact with each other
to form disease susceptibility, with the phenotype emerging in
the presence of environmental risk factors which in themselves
account for 53% of disease liability. Environmental chemicals, as
well as food, have been discussed as possible contributing factors
[12-14]. However, there is no existing evidence as to the nature of
this environmental contribution. Only one study to date has used
quantitative analysis to examine the contribution of genetic and
environmental factors to endometriosis, using a small twin sample
[7]. A larger twin sample is expected to provide further clarification
on the role of genetic and environmental factors [12-14]. In this
report, we present a case of deep infiltrating endometriosis (DIE)
in a pair of monozygotic (MZ) twins.
Materials and methods
A pair of monozygotic twins was referred to our office within the
same year, mainly due to severe chronic pelvic pain and infertility,
with the following pertinent clinical information.
a) Twin A : A 31-year-old nulliparous woman was admitted
to Farmanieh Hospital (Tehran, Iran) complaining of heavy
menstrual blood loss, progressive chronic severe pelvic pain
and dyspareunia for the past six years, painful defecation with
passage of narrow, occasionally blood-tinged stool, and history
of failed hormonal medical treatment on and off during the past
six years. The patient had been infertile for the past two years.
She had a history of hypothyroidism, thalassemia minor, cervical
spinal cord tumour surgery, rhinoplasty and eye surgery.
Transvaginal ultrasound detected a 25 x 22mm cyst in the right
ovary and two heterogeneous hypoechoic foci (32 x 21mm and
29 x 18mm respectively) in the left ovary; these observations
were compatible with endometrioma. Colonoscopy results
were negative. Hemoglobin level was 11.4g/dL, serum CA 125
level was 60.67U/mL, serum CA 19-9 level was 6.4 U/mL, and
AMH level was 5.7ng/mL. Intravenous pyelogram (IVP) results
were negative.Magnetic Resonance Imaging (MRI) revealed
two T1 foci in both ovaries (25 x 15mm and 20 x 10mm high
respectively), which was suggestive of a hemorrhagic cyst or,
more probably, a dermoid cyst. No other pathology was noted,
including for the intestinal tract.
b) Twin B: A 31-year-old nulliparous woman was
admitted to Farmanieh Hospital (Tehran, Iran) complaining
of menorrhagia, progressive severe pelvic pain with rectal
radiation for six years, painful defecation with occasional
blood-tinged stool, severe dyspareunia for the past two years
and failed hormonal medical treatment for the past six years.
She had a history of hypothyroidism, thalassemia minor, mitral
valve prolapse rhinoplasty and eye surgery. Two transvaginal
pelvic ultrasounds revealed a small anterior wall myoma;
there were no other findings. Hemoglobin level was 10.8g/dL,
serum CA 125 level was 21U/mL, serum CA 19-9 level was 9.4
U/mL, and AMG level was 7.4ng/mL. IVP results were within
normal limits. MRI of the pelvis detected three small myomas
(10-15mm) at the anterior uterine wall and a 20 mm follicle
in the left ovary. There were no other findings, including for
the bowel. Colonoscopy results were within normal limits. A
double-contrast barium enema detected segmental luminal
narrowing with upward displacement of the sigmoid area, with
mucosal thinning. These findings suggested extrinsic pressure,
mostly due to endometriosis, which seemed to have involved
the posterior wall of the sigmoid colon.
Results
Twin A
A laparoscopic segmental sigmoid resection was performed,
with staple re-anastomosis, resection of pelvic floor DIE, and
resection of a bilateral endometrioma. The procedure took 152
minutes. The patient was discharged after four days shown in
below Figure 1.
Figure 1: Laparoscopic images for Twin A.
(A) Anterior uterine myoma,
(B) Attached left adnexa to stenotic RS colon,
(C) Left adnexal colonic adhesion,
(D) Left ovarian endometrioma,
(E) Right ovarian endometrioma,
(F) Segmental resection of RS colon,
(G) Resected bowel with deep endometriosis,
(H) DIE pelvic floor,and
(I) DIE at peritoneal site of invagination.
Twin B
Twin B’s initial procedure was performed in the same
month as Twin A’s procedure. Laparoscopic adhesiolysis was
performed, with resection of pelvic floor DIE, resection of ovarian
endometrioma, and shaving of rectal deep endometriosis. Bowel
resection was deferred because of inadequate bowel preparation,
and laparoscopic sigmoid resection with staple anastomosis was
performed 8 weeks after the initial procedure (Figure 2).
Discussion
Anatomical involvement of the relevant pelvic organ in
this pair of identical twins was nearly identical. The twins had
grown up in the same environment all their lives, both worked as
secretaries at the same institution, and both were experiencing
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Joseph Miller. Biomed J Sci & Tech Res
Volume 1- Issue 6 : 2017
1649
not only the symptoms of DIE, but also signs and symptoms of
intestinal involvement. The ultrasound and MRI for both patients
was reported negative, which clearly indicates the importance of
experienced radiologists for the detection of deep endometriosis
[15], and reiterates the importance of bimanual exam by clinicians,
particularly at the time of menstruation, to achieve an accurate
diagnosis,. In fact, available data clearly indicates that the accuracy
of good physical examination (PE) is not much different from that
of transvaginal ultrasound (TVS), rectal endoscopic sonography
(RES) and MRI, all within the 80% range [16]. Twin A was managed
by laparoscopic segmental sigmoid resection and staple re-
anastomosis, along with global resection of DIE from the pelvic floor
and endometriomas. We were intending to do the same for Twin B,
but in OR the lack of adequate bowel preparation was noted; thus
bowel resection was postponed and was performed 8 weeks later
under adequate bowel preparation.
Figure 2: Laparoscopic images for Twin B.
(A) Myoma at anterior uterine wall,
(B) Left ovarian endometrioma severely attached to
sigmoid colon,
(C) Ovarian attachment to sigmoid colon,
(D) Left ovarian endometriosis,
(E) Right ovarian endometriosis,
(F) Shaving DIE off rectal surface,
(G) Defect at rectal surface,
(H) DIE pelvic floor with rectal involvement,
(I) DIE peritoneal site on invagination, right side,
(J) Segmental resection of RS colon,
(K) Resected bowel with undivided DIE nodule and
(L) Resected bowel with divided DIE nodule.
However, after resection of endometriomas and pelvic floor
deep lesions, larger DIE at the posterior cervix with extension to
the rectum was managed by laparoscopic shaving, and the defect
was closed in two layers. No intraoperative or postoperative
complications were encountered in either twin. In many instances,
the culprit for DIE is endometrioma, which starts from its peritoneal
site of invagination (Figure 3). By extension medially, it involves
the parametrium, rectum, recto-vaginal space, and, by deeper
extension, the ureter and hypogastric nerve may also be involved.
Thus, timely and proper surgical management of endometrioma
and excision of its dependent peritoneal site could serve not only to
manage patients’ pain, but also to conceivably prevent a significant
percentage of DIE. In one study focusing exclusively on patients with
rectosigmoid lesions, 48% and 84% had ovarian endometriosis and
retrocervical lesions, respectively [17] (Figure 3).
Figure 3: Endometrioma and the peritoneal site of
invagination.
Both superficial peritoneal and ovarian endometriomas may
be found in association with DIE in variable percentages, thus
contributing to the intensity of painful stimuli, as well as to infertility
[18]. Thisraises the question of whether DIE is an independent
form of the disease, or whether it represents its most severe clinical
representation [19]. Nisolle and Donnez have argued that peritoneal
endometriosis, ovarian endometriosis and adenomyotic nodules
of the rectovaginal septum are three different entities [20]. In a
retrospective observational study by Kamergorodsky [21]. Involving
176 patients and 271 biopsies, the histologic differentiation in
superficial endometriosis, DIE and ovarian endometriomas was
evaluated. Results showed a predominance of the undifferentiated
glandular pattern (33.5%) and mixed glandular pattern (46.9%)
in deeply infiltrating endometriosis lesions, whereas the well-
differentiated glandular pattern (41.8%) was most frequently seen
in superficial endometriosis lesions, and in ovarian endometriomas
a predominance of both the undifferentiated (40.5%) and mixed
patterns (37.8%) was observed. There was no significant histologic
difference between infiltrative endometriosis of the uteroscacral
ligaments, recto-vaginal endometriosis, or bowel endometriosis.
There was a predominance of the well-differentiated pattern in
more superficial lesions and the undifferentiated pattern in deeper
lesions, suggesting a similar mechanism to explain the invasive
potential of endometriosis.
Recently, Sapkota [22] analysed genetic risk scores derived
from two large European genome-wide association (GWA) datasets
from a previous multi-ethnic GWA meta-analysis of endometriosis.
They found that genetic factors contributing to minimal disease
might differ from those contributing to more severe endometriosis,
and that more severe endometriosis cases exhibit greater genetic
loading than minimal or mild disease. The genetic burden generally
increased from less severe (minimal) to more severe disease,
consistent with disease progression. Considering the fact that
endometriotic lesions undergo repeated cyclic bleeding (injury)
and repair like other organs leading to fibrosis [23], it has been
suggested that endometriotic lesions are fundamentally wounds
with repeated tissue injury resulting in smooth muscle metaplasia
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Joseph Miller. Biomed J Sci & Tech Res Volume 1- Issue 6 : 2017 1650
(SMM) and ultimately fibrosis, which somehow do not heal like an
ordinary wound [24]. This points to the complex microenvironment
and cross-reaction of endometrioc lesions with other cells, i.e.
platelets and macrophages, their gradual but progressive evolution
to SMM and fibrosis and, on occasion, to malignancy and the new
traits/phenotypes they may acquire while losing old ones. This
dynamic feature of endometriotic lesions may explain the reason
for some conflicting results in this area of research, including the
fact that development of biomarkers for the diagnosis or prognosis
of endometriosis has posed a challenge, at least until now.
Endometriosis appears to be a progressive disease, as evidenced
by longitudinal laparoscopies in female baboons [25]. There are at
least eight studies reported (with a total of 162 patients) on repeat
laparoscopy in women assigned to placebo treatment. The results
indicate nearly equal distribution among women whose disease
stage deteriorated (31%), was unchanged (32%), or improved
(38%). In fact, all but one study noted that 23% of placebo patients
had complete regression of the disease over intervals of 4 to 39
months, meaning that in over two thirds of women the disease
will either persist or progress [26-33]. The clinical presentation of
the disease followed a similar trend and evolution in both of our
cases. Each twin had undergone a long history of slowly progressive
pelvic pain from the point of intensity, developing bowel symptoms
and dyschesia as time passed, with dyspareunia and change in stool
diameter to the point of bowel stenosis and impending obstruction.
All of this is consistent with the progressive nature of the disease
reported in the existing literature.
Deep infiltrating endometriosis, contrary to being an estrogen-
dependent disease, usually does not respond well to hormonal
suppressive therapy. Adequate surgical excision of the lesions
provides the best long-term results and symptomatic relief [31-
34] but surgical treatment of colorectal endometriosis has been
quite controversial, and there is no consensus on whether the
treatment should be conservative (shaving or discoid resection)
or radical (segmental bowel resection and anastomosis) [35].
Lately, there has been a great deal of effort to advocate shaving
as the treatment of choice, mainly because of higher early and
late complications in segmental colorectal resection [36]. The
efficacy of segmental colorectal resection is very debatable; data in
this regard is controversial and, to a great deal, dependent upon
the surgeon’s experience [37,38]. Findings from histopathologic
analysis of specimens from segmental bowel resection indicates
that in 50% of cases there is a satellite lesion independent of
the primary deep nodule.The deepest layer of the bowel wall
containing endometrioticfoci at the primary lesion is in the
submucosal layer in 70% of cases and the internal circular muscle
layer in 30%. Furthermore, persistent lesions are present in 50% of
patients treated with discoid or shaving resection [39]. The latest
systematic review of different surgical approaches to bowel and
rectovaginal endometriosis showed that the complication rate is
variable for conservative and radical treatment. Recurrence rate for
shaving was reported at 22.2%, for discoid resection 5.17%, and in
segmental resection 2.19%; these rates were significantly different
[37]. Positive bowel resection margins as well as age <31 years and
body mass index ≥23kg/m2 appear to be important independent
predictors of disease recurrence [40].
Our patients were managed according to the extent of their
pathology, intensity of pelvic pain, and future fertility, thus
minimising the chance of recurrence. Most importantly, patients’
wishes and decisions regarding the type of clinical management
to be pursued were incorporated, following proper counselling
and explanation. It is crucial to keep in mind that there is currently
no scientifically proven best treatment technique for bowel
endometriosis, and comparison of different currently practised
techniques is not possible. According to our current knowledge
regarding the nature of disease pathology and its progression,
recurrence should be as much a source of concern as complications
for any given surgical technique. Resection of DIE should be
global, not local, and limited to the bowel. Operations should be
performed by an experienced surgeon and a well-organised team,
in a multidisciplinary fashion. In summary, we present a case of
advanced DIE in monozygotic twins; one of the first such cases to
our knowledge. Our findings reiterate the importance of genetic
factors in the aetiology of endometriosis. These cases also reinforce
the importance of the following considerations for surgeons
considering conservative treatment for colorectal endometriosis:
a) The extent of lesions cannot be assessed macroscopically
with certainty.
b) Assessment of the depth of infiltration of endometriosis
foci in the bowel requires an expert radiologist.
c) In the majority of rectal endometriosis nodules, the
fibrosis which is the landmark for shaving does not surround,
but follows behind the glandular epithelium and stroma.
d) More than 2cm of bowel tissue must be removed from the
main lesion to obtain clear margins in two thirds of patients.
e) Low rectal lesions (<5–8cm from the anal verge) are
associated with a higher risk of complications.
f) A great majority of patients have been through previous
surgeries and have a good chance of recovering and becoming
pain-free.
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