Jurnal 4
Jurnal 4
Jurnal 4
Clinical Medicine
Review
Umbilical Endometriosis: A Systematic Literature Review and
Pathogenic Theory Proposal
Dhouha Dridi 1, * , Francesca Chiaffarino 1 , Fabio Parazzini 2 , Agnese Donati 1 , Laura Buggio 1 ,
Massimiliano Brambilla 3 , Giorgio Alberto Croci 4,5 and Paolo Vercellini 1,2
1 Gynecology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
francesca.chiaffarino@gmail.com (F.C.); agnese.do@tiscali.it (A.D.); buggiolaura@gmail.com (L.B.);
paolo.vercellini@unimi.it (P.V.)
2 Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
fabio.parazzini@unimi.it
3 Plastic Surgery Service, Gynecology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
20122 Milan, Italy; massimiliano.brambilla@policlinico.mi.it
4 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
giorgio.croci@unimi.it
5 Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
* Correspondence: dh.dridi2@gmail.com; Tel.: +39-02-5503-2318
Abstract: Umbilical endometriosis represents 30–40% of abdominal wall endometriosis and around
0.5–1.0% of all cases of endometriosis. The aim of this systematic review is to revisit the epidemiology,
signs, and symptoms and to formulate a pathogenic theory based on literature data. We performed
a systematic literature review using the PubMed and Embase databases from 1 January 1950 to
7 February 2021, according to the PRISMA guidelines. The review was registered at PROSPERO
(CRD42021239670). Studies were selected if they reported original data on umbilical endometriosis
nodule defined at histopathological examination and described as the presence of endometrial
Citation: Dridi, D.; Chiaffarino, F.; glands and/or stromal cells in the connective tissue. A total of 11 studies (10 retrospective and
Parazzini, F.; Donati, A.; Buggio, L.;
one prospective), and 14 case series were included in the present review. Overall, 232 umbilical
Brambilla, M.; Croci, G.A.; Vercellini,
endometriosis cases were reported, with the number per study ranging from 1 to 96. Umbilical
P. Umbilical Endometriosis: A
endometriosis was observed in 76 (20.9%; 95% CI 17.1–25.4) of the women included in studies
Systematic Literature Review and
reporting information on the total number of cases of abdominal wall endometriosis. Umbilical
Pathogenic Theory Proposal. J. Clin.
Med. 2022, 11, 995. https://doi.org/
endometriosis was considered a primary form in 68.4% (158/231, 95% CI 62.1–74.1) of cases. A history
10.3390/jcm11040995 of endometriosis and previous abdominal surgery were reported in 37.9% (25/66, 95% CI 27.2–49.9)
and 31.0% (72/232, 95% CI 25.4–37.3) of cases, respectively. Pain was described in 83% of the women
Academic Editor: Jacques Donnez
(137/165, 95% CI 76.6–88.0), followed by catamenial symptoms in 83.5% (142/170, 95% CI 77.2–88.4)
Received: 10 January 2022 and bleeding in 50.9% (89/175, 95% CI 43.5–58.2). In the 148 women followed for a period ranging
Accepted: 10 February 2022 from three to 92.5 months, seven (4.7%, 95% CI 2.3–9.4) recurrences were observed. The results
Published: 14 February 2022 of this analysis show that umbilical endometriosis represents about 20% of all the abdominal wall
Publisher’s Note: MDPI stays neutral
endometriotic lesions and that over two thirds of cases are primary umbilical endometriosis forms.
with regard to jurisdictional claims in Pain and catamenial symptoms are the most common complaints that suggest the diagnosis. Primary
published maps and institutional affil- umbilical endometriosis may originate from implantation of regurgitated endometrial cells conveyed
iations. by the clockwise peritoneal circulation up to the right hemidiaphragm and funneled toward the
umbilicus by the falciform and round liver ligaments.
sites, endometriosis of the abdominal wall (AWE) is the most common [7]. Umbilical
endometriosis (UE), or Villar’s nodule, as first described by Villar in 1886, is defined as the
presence of endometrial glands and/or stroma within the umbilicus. It is a rare form of
endometriosis with a frequency of around 0.4–4% of extragenital lesions [8,9] and around
0.5–1% of all cases of endometriosis [10–12], and it has been reported that it represents
30–40% of cases of abdominal wall endometriosis (AWE) [13]. Generally, UE presents with
a red, purple, or black umbilical nodule with a diameter ranging from 0.5 to 3 cm [14].
According to Hirata et al. (2020), the risk of malignant transformation of UE is about 3% [9].
Two types of UE have been described. Primary UE occurs in the absence of a surgical
history. Severe theories have been proposed, such as the migration of endometrial cells
through the abdominal cavity, the lymphatic system, or embryonic remnants in the umbili-
cal fold (e.g., the urachus and umbilical vessels); genetic predisposition; and immunologic
defects [14]. Romera-Barba et al., demonstrated that the disease occurs after prolonged
exposure to the metaplastic and environmental factors [15], whereas secondary UE arises
on scar tissue following abdominal procedures such as laparoscopy [9,14]. The distinc-
tion between primary and secondary development of UE appears to be important for the
understanding of the pathogenic mechanism of this disease form [16].
Hirata et al. [17] suggested guidelines for management of extragenital endometrio-
sis and claims for umbilical endometriosis that radical surgery with wide local excision
represents the primary treatment. Surgical excision is strongly recommended but with
weak supporting evidence because of unknown long-term efficacy and complications. In
contrast, medical treatment is weakly recommended due to limited supporting data and
lack of studies comparing medical and surgical treatment for umbilical endometriosis.
Due to the low frequency of the condition, limited data are available on the prevalence
of primary and secondary UE and on the associated symptoms. We conducted this sys-
tematic review of published studies and case series to define the epidemiological aspects,
revisit the signs and symptoms, and suggest a potential pathogenic theory of UE based
on anatomic-physiological considerations and the pattern of distribution of associated
endometriotic lesions.
3. Results
Database searching identified 1096 articles. After removing duplicates, 753 records
were screened and 43 were then considered for eligibility. Nine reports were excluded
for lack of features; six were excluded because, although not explicitly stated in the title
and abstracts, they were case reports. One clinical series [20] and two case series [12,21],
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 15
although eligible, were excluded for low MINORS scores. Eventually, we selected 10 retro-
spective studies [22–31] on recorded cases in a defined period, one prospective study [32],
and 14 cases series [9,33–45]. The flow diagram of the literature search results is shown
in Figure 1.
Table 1 shows the study design, number of women with AWE (data available only for
clinical series), number of women with UE, mean age of women, primary or secondary
origin of reported cases of UE, and MINORS score for each of the 25 papers considered in
this review.
Table 1. Cont.
The quality of the selected studies was sufficiently good according to the MINORS
criteria, with the score being nine or more in 15 out of 25 papers (Table S2). The num-
ber of UE cases reported in the considered papers ranged from 2 to 96, being less than
10 in 21 studies.
J. Clin. Med. 2022, 11, 995 6 of 16
Overall, 232 UE cases were described. Considering only the 11 studies reporting infor-
mation on the number of total cases of AWE (i.e., the “clinical series”), UE was reported in
76 women, corresponding to 20.9% of women with AWE (95% CI 17.1–25.4) (Table 1).
The mean age of women with UE was 37.9 years (weighted mean for the number of
cases of the studies) and ranged from 28.5 to 47.5 among the studies. Out of the 231 cases
for which the information was available, 158 had primary UE (68.4%, 95% CI 62.1–74.1).
Parity, history of cesarean section, abdominal surgery, history of endometriosis, and
concomitant pelvic endometriosis are considered in Table 2.
Previous
Abdominal History of
Parous Cesarean Section Endometriosis If Laparoscopy
(Women with a Surgery (Women
Author, Year of (Parae/Total with Previous (Women with Associated,
Women with UE) History of History of En- Concomitant
Publication (Ref) CS/Total Parae) Abdominal
% (n) Surgery/Total dometriosis/Total Endometriosis
% (n) Cases UE) % (n)
Cases with UE)
% (n) % (n)
Clinical
series
Steck and NR NR 25.0 (7/28) NR NR
Helwing, 1965 [31]
McKenna and
Wade-Evans, 100 (5/5) 0 0 40.0 (2/5) 20.0 (1/5)
1985 [30]
Zhao et al., NR NR 0 NR NR
2005 [29]
Agarwal et al.,
100 (2/2) 50.0 (1/2) 50.0 (1/2) 0 50.0 (1/2)
2008 [28]
Leite et al., 100 (2/2) 100 (2/2) 100 (2/2) NR NR
2009 [27]
Savelli et al., NR NR 75.0 (6/8) 75.0 (6/8) NR
2012 [26]
Ecker et al., 33.3 (3/9) 33.3 (1/3) 55.5 (5/9) NR NR
2014 [25]
Vellido-Cotelo NR
et al., 2015 [24] 50.0 (1/2) 100 (1/1) 100 (2/2) 50 (1/2)
Chrysostomou
NR NR 0 0 0
et al., 2017 [32]
Marras et al., NR NR 40.0 (4/10) 60.0 (6/10) 80.0 (8/10)
2019 [23]
Youssef, 2020 [22] NR NR 50.0 (1/2) NR 50.0 (1/2)
Total clinical
series 65.0 (13/20) 38.5 (5/13) 36.8 (28/76) 45.5 (15/33) 44.0 (11/25)
Al-Saad et al., 0 0 NR NR
66.7 (2/3)
2007 [35]
J. Clin. Med. 2022, 11, 995 7 of 16
Table 2. Cont.
Previous
Abdominal History of
Parous Cesarean Section Endometriosis If Laparoscopy
(Women with a Surgery (Women
Author, Year of (Parae/Total with Previous (Women with Associated,
Women with UE) History of History of En- Concomitant
Publication (Ref) CS/Total Parae) Abdominal
% (n) Surgery/Total dometriosis/Total Endometriosis
% (n) Cases UE) % (n)
Cases with UE)
% (n) % (n)
Dessy et al.,
75.0 (3/4) 66.7 (2/3) 50.0 (2/4) 0 NR
2008 [36]
Fedele et al., NR
14.3 (1/7) 42.8 (3/7) 71.4 (5/7) 28.6 (2/7)
2010 [37]
Abramowicz et al., NR NR 0 100 (3/3) 100 (3/3)
2011 [38]
Darouichi et al.,
66.7 (2/3) 50.0 (1/2) 33.3 (1/3) 33.3 (1/3) 33.3 (1/3)
2013 [39]
Saito et al., NR
28.6 (2/7) 28.6 (2/7) 14.3 (1/7) 14.3 (1/7)
2013 [40]
Chikazawa et al., 0
100 (3/3) 66.7 (2/3) 66.7 (2/3) 33.3 (1/3)
2014 [41]
Boesgaard-Kjer
20.0 (2/10) 0 0 NR 10.0 (1/10)
et al., 2017 [42]
Dos Santos Filho 100 (6/6) 0 0 0 NR
et al., 2018 [43]
Hirata et al., 63.5 (61/96) 18.0 (11/61) 32.3 (31/96) ◦ NR NR
2020 [9]
Makena et al., 60.0 (3/5) 33.3 (1/3) 20.0 (1/5) NR 40.0 (2/5)
2020 [44]
Total case series 57.3 (86/150) 22.2 (18/81) 28.2 (44/156) 30.3 (10/33) 29.5 (13/44)
95% Confidence 49.3–65.0 14.5–32.4 21.7–35.7 17.4–47.3 18.2–44.2
Interval
Total all studies 58.2 (99/170) 24.5 (23/94) 31.0 (72/232) 37.9 (25/66) 34.8 (24/69)
95% Confidence 50.7–65.4 16.9–34.1 25.4–37.3 27.2–49.9 24.6–46.6
Interval
Legend: * Patients with previous pelvic surgery or caesarean section who presented with scar or umbili-
cal endometriosis were excluded from the study; § woman with adenomyosis; ◦ one patient had unknown
surgical history.
The proportion of parous women ranged from 20% to 100% among studies. Ninety-
nine of the 170 women for which the obstetrical history was available were parae (58.2%,
95% CI 50.7–65.4). The mode of delivery was reported in 94 women and 23 of them (24.5%,
95% CI 16.9–34.1) underwent a cesarean section. A history of abdominal surgery was
reported in 31.0% of UE patients (72/232, 95% CI 25.4–37.3). Finally, considering only
women for which the information was reported, around one third of women with UE
received a previous diagnosis of endometriosis (25/66, 37.9%; 95% CI 27.2–49.9) and, when
pelvic surgery was conducted at the same time as umbilical nodule excision, concomitant
pelvic endometriosis was observed in 34.8% of the UE cases (24/69, 95%CI 24.6–46.6).
Despite the variability due to random fluctuation, these findings were largely consistent in
the considered studies.
The clinical features are considered in Table 3. Pain was the most common symptom,
being reported in 83% of women (137/165, 95% CI 76.6–88.0), followed by previously
defined catamenial symptoms in 83.5% of cases (142/170, 95%CI 77.2–88.4). Bleeding was
recorded in 89 of 175 patients (50.9%, 95%CI 43.5–58.2).
J. Clin. Med. 2022, 11, 995 8 of 16
Duration of
Time to
Author, Year of Publication Cases of UE Follow Up (Mean Recurrence
Treatment Recurrence
(Ref) (n) in Months and % (n)
(Mean in Months)
Range)
Clinical series
Agarwal et al., 2008 [28] 2 surgery 20.5 0
Leite et al., 2009 [27] 2 surgery NR 100 (2/2) NR
Chrysostomou et al., 2017 [32] 6 surgery 36 (6–72) 0
Marras et al., 2019 [23] 10 surgery 62.4 ± 39.6 § 10.0(1/10) 24
Case series
24 (2 cases)
Pathak and Hayes, 1968 [33] 3 surgery 33.3 (1/3) 22
NR (1 case)
Lattuneddu et al., 2002 [34] 3 surgery 24 0
Al-Saad et al., 2007 [35] 3 surgery 28 0
Dessy et al., 2008 [36] 4 surgery 13 0
Fedele et al., 2010 [37] 7 surgery 92.5 0
Abramowicz et al., 2011 [38] 3 surgery 3 0
Saito et al., 2013 [40] 7 1 surgery ** 58.3 0
Dos Santos Filho et al., 2018
6 surgery NR 0
[43]
Recurrence
occurred in
3 women, at 3, 8,
Hirata et al., 2020 [9] 87 * surgery 6870 3.4 (3/87) and 12 months
after excision
without
peritoneum. ◦
Makena et al., 2020 [44] 5 surgery NR 0
Total 148 7
Legend: § information based on all the cases of abdominal wall endometriosis; * 9 cases are not considered in
the analysis of recurrence; ** 1/7 underwent radical resection of umbilical nodule, 2/7 underwent expectant
management, 4/7 took estrogen-progestogen hormone therapy or Dienogest; ◦ % cumulative recurrence rate:
6 months—1.34, 12 months—6.35, 60 months—6.35.
The size of the umbilical nodule was reported only in two clinical series [24,28], while
it was cited in all case series except two with a mean of 21.2 ± 7.9 mm (data not reported
in Table 4) [9,34].
Overall, these studies included 148 women (range 2–87). The follow-up period ranged
from three to 92.5 months. A total of seven (4.7%, 95%CI 2.3–9.4) recurrences after the index
surgery were reported. Hirata et al., therefore, concluded that there was no statistically sig-
nificant difference between the risk of recurrence after excision with or without peritoneum
or with medical treatment after surgery [9].
4. Discussion
The results of this analysis show that UE represents about 21% of all the AWE cases:
Most lesions were primary UE (about 70%); a history of endometriosis was reported in
almost one third of women of UE; pelvic lesions co-existed in about 35% of the patients;
and pain and catamenial symptoms were the most commonly reported complaints.
Before discussing the results of this analysis, potential limitations should be considered.
The selected studies reported large differences in the number of UE cases, with less than
J. Clin. Med. 2022, 11, 995 10 of 16
10 cases included in most of the studies. However, effect of random fluctuation aside, the
results of this analysis are largely consistent among different studies, particularly among
the largest ones.
Although, when planning the systematic literature search, articles published in three
languages were potentially considered, eventually the selected papers were almost all
published in English, and only two in French [38,39] and one in Italian [34]. Authors
may be more prone to publish in an international, English language journal if results are
“newer”. Further, studies published before the year 1950 were excluded, as papers were
sparse, frequently lacking histological diagnosis, and differed in diagnostic criteria.
The results of this systematic review are consistent with the findings of previous
literature reviews. For example, in a review published in 2007 and including 122 patients
with documented UE from 1966 to 2007 and 109 cases reported before 1953, the mean age
of the study population was 37.7 years, and 27% of cases had a history of endometriosis [8].
Concerning symptoms, Calagna et al. [5] showed that intermittent pain in the umbilical
area was the most common complaint reported by 66.0% of the study women, whereas
cyclic bleeding from the umbilical site was described by 43.3% of them. Our findings are
consistent but slightly higher than their results.
The data emerging from our review show that the post-operative recurrence rate of
the UE is very low. In fact, a total of 7/148 (4.7%, 95%CI 2.3–9.4) recurrences were observed
during a follow-up period ranging from three to 92.5 months. This suggests that surgery is
an effective treatment for this endometriotic lesion type.
An interesting finding of the present review is the fact that primary UE was the most
common form; secondary was the iatrogenic form, representing 31.6% of cases. A history
of endometriosis was reported by 37.9% of women. In a literature review published in
2015 (Calagna et al.) [5], the authors estimated that about 20% of cases of primary UE had a
diagnosis of pelvic endometriosis. In the present review, this figure is substantially higher,
as concomitant endometriotic lesions were observed in over one third of women who
underwent pelvic visualization. This observation offers some insights in the pathogenesis
of UE. Primary endometriosis is obviously the disease form of interest here, as the origin of
secondary endometriosis is mainly iatrogenic.
In cases of isolated umbilical endometriosis, the disease might arise from metaplastic
changes of urachal remnants [45]. Otherwise, in consideration of the frequency of UE
among cases of AWE (21% in our review), it can be hypothesized that endometrial cells may
stem from the umbilical cord at birth. According to Calagna et al. (2015) [5], inflammation
of the tissues around endometriotic pelvic implant may favor the shedding of endometriotic
cells which may be transported through the venous vessels to the umbilicus.
However, when primary UE is associated with endometriosis at other, mainly pelvic,
sites, the metastatic hypothesis appears also plausible. Of note, the prevalence of en-
dometriotic pelvic lesions co-existent with primary UE was much higher than the usual
estimates observed in the general premenopausal population [1–4]. This finding supports
the possibility of a common etiological mechanism for the two disease locations because, if
a separate pathogenesis exists for UE, the unusually high frequency of concomitant pelvic
lesions would be difficult to explain.
If transtubal menstrual reflux is the origin of endometriosis, once in the pelvis en-
dometrial cells might reach the umbilicus and implant directly on its parietal peritoneal
surface without necessarily entering the vascular or lymphatic vessels. Indeed, a large body
of evidence supports the notion that intra-abdominal endometriotic lesion distribution is
determined to a large extent by physiological and anatomical factors that favor endometrial
cell implantation [47].
Large bowel peristalsis combined with diaphragmatic respiratory movements, i.e.,
a physiologic factor, originate hydrostatic pressure variations that convey the peritoneal
fluid from the pelvis along the right peritoneal gutter to the retro-hepatic and sub-phrenic
area [48–50]. The falciform ligament, i.e., an anatomical factor, hampers the transit across
the midline from the right to the left sub-phrenic space [51,52]. This explains the much
J. Clin. Med. 2022, 11, 995 11 of 16
Figure2.
Figure Endometriosis
2.Endometriosis infiltrating
Figure 2.infiltrating
Endometriosis theinfiltrating
the entire skin
entire skin aspect
aspect
the of
entireof theaspect
the
skin umbilicus.
umbilicus.
of the umbilicus.
(a) (b)
Figure 3. The umbilical peduncle is dissected down to the parietal peritoneum, which is included in
(a)
the resected (b) of umbilical endometriosis from the
tissue (a). Anatomical specimen of en-bloc resection
skin aspect to the parietal peritoneum (b).
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 12 of 15
J. Clin. Med. 2022, 11, 995 Figure 3. The umbilical peduncle is dissected down to the parietal peritoneum, which is included in
13 of 16
the resected tissue (a). Anatomical specimen of en-bloc resection of umbilical endometriosis from
the skin aspect to the parietal peritoneum (b).
(a)
(b)
Figure 4. Pathology specimen after full-thickness omphalectomy for umbilical endometriosis. At
Figure 4. Pathology specimen after full-thickness omphalectomy for umbilical endometriosis. At
scanning magnification ((a), hematoxylin-eosin, 10×), foci of endometriosis are apparent, spanning
scanning magnification ((a), hematoxylin-eosin, 10×), foci of endometriosis are apparent, spanning
from the deeper tissues of the abdominal wall throughout the dermal layer (left to right). At higher
from the deeper
magnification ((b),tissues of the abdominal
hematoxylin-eosin, 100×),wall throughout
endometrial theare
glands dermal layerin(left
identified to right).
the stroma At
under-
higher magnification
lying the ((b), hematoxylin-eosin,
parietal peritoneal ×), endometrial glands are identified in the stroma
100(arrows).
mesothelial surface
underlying the parietal peritoneal mesothelial surface (arrows).
Future studies on UE should focus on detailed histopathology findings of those
women who undergo en-bloc omphalectomy. In addition, when laparoscopy is also indi-
Supplementary Materials: The following supporting information can be downloaded at: https:
cated, a careful visual inspection of the diaphragm after liver retraction by means of a
//www.mdpi.com/article/10.3390/jcm11040995/s1, Supplementary File S1: PICO (Patient, Interven-
blunt probe should be performed to identify concomitant endometriotic implants [61].
tion, Comparator, Outcome, Study) design structure; Table S1: MINORS (Methodological Index for
Non-Randomised Studies) score; Table S2: PRISMA 2020 Checklist.
Author Contributions: Conceptualization, P.V., D.D. and F.P.; methodology, P.V., D.D., F.C., F.P. and
A.D.; software, F.C.; validation, D.D., F.C., F.P., A.D., L.B., M.B., G.A.C. and P.V.; formal analysis
J. Clin. Med. 2022, 11, 995 14 of 16
and data curation, F.C., D.D. and A.D.; writing—original draft preparation, D.D., P.V., F.P. and F.C.;
writing—review and editing, D.D., P.V., F.P., G.A.C., M.B. and L.B. All authors have read and agreed
to the published version of the manuscript.
Funding: This research was not funded.
Institutional Review Board Statement: Since only published data were considered, the current
research project was exempt from institutional review board approval.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data generated or analyzed during this study are included in this
published article.
Conflicts of Interest: The authors report no conflict of interest.
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