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Journal of

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.

Keywords: endometriosis; umbilical endometriosis; Villar’s nodule; symptoms; pain; frequency


Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
1. Introduction
conditions of the Creative Commons
Attribution (CC BY) license (https:// Endometriosis is a benign gynecological disorder that affects about 5% of reproductive-
creativecommons.org/licenses/by/ aged women [1–4]. The pelvic cavity is the most common location of endometriotic
4.0/). implants, but about 12% of lesions are extragenital [5,6] and, among the extra-pelvic

J. Clin. Med. 2022, 11, 995. https://doi.org/10.3390/jcm11040995 https://www.mdpi.com/journal/jcm


J. Clin. Med. 2022, 11, 995 2 of 16

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.

2. Materials and Methods


The present review was conducted according to the PRISMA guidelines (Table S1) [18]
and was registered at PROSPERO (CRD42021239670).
We performed a systematic literature search using the electronic databases PubMed
and Embase on 07 February 2021. The search term “endometriosis” was used as the medical
subject heading (MeSH PUBMED) or Embase subject headings (EMTREE EMBASE) term or
as free text in combination with the term “umbilical”. The search was limited to full-length
articles published in English, French, and Italian since 1 January 1950.
A PICOS (Patient, Intervention, Comparator, Outcome, Study) design structure was used
to develop the study questions and the inclusion/exclusion criteria (Supplementary File S1).
Studies were selected if they reported original data on UE nodule defined through
histopathological examination and described as the presence of endometrial glands and/or
stromal cells in the connective tissue. Studies published from 1950 were identified, with
no restriction regarding the age of women. Data presented exclusively as case reports,
abstracts in national and international meetings, or review articles that did not include
original findings were excluded.
Two authors (D.D. and A.D.) reviewed the papers and independently selected the
articles eligible for the systematic review. In the case of more than one publication with the
same study population and data, we considered only the more recent article or the one that
included the most details. Moreover, bibliographies of the retrieved papers were reviewed
to identify other potentially relevant studies. Disagreements were resolved by discussion.
From each publication we extracted the following information: author, year of publi-
cation, country, study design, number of patients with UE, number of women with AWE,
age of participants, UE classification (primary or secondary), clinical features, previous
J. Clin. Med. 2022, 11, 995 3 of 16

pregnancy, mode of delivery, history of endometriosis, previous surgery, concomitant


endometriosis if pelvic surgery was conducted concomitantly with umbilical nodule’s
excision, and rate of postoperative UE recurrences.
Information on the methodological quality of included studies was assessed based on
the Methodological Index for Non-Randomised Studies (MINORS), a validated instrument
which is designed for assessment of methodological quality of non-randomized studies
in surgery [19]. Briefly, the studies were evaluated on eight pre-defined items with a
maximum score of 16. The studies with MINORS scores under 6 were excluded.
For the purpose of this analysis, in the tables we have defined as “clinical series”
studies that have reported data on the total of AWE, and as “case series” studies that have
reported data on UE cases only. Moreover, we have defined as catamenial symptoms
the following complaints: swelling, color changes, consistency change, and tenesmus
associated with or worsening during menstruation.
For each study with binary outcomes, we calculated the 95% confidence intervals (CI)
of the estimated proportion.

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.

Figure 1. Flow diagram of study identification and selection.


Figure 1. Flow diagram of study identification and selection.

Table 1. Main characteristics of the selected studies.


Women with
Study Design ° Women with Age (Mean) of
Author, Year of Abdominal Wall Primary UE Secondary UE MINORS
Country Period of UE Women with
Publication (Ref) Endometriosis % (n) % (n) Score
J. Clin. Med. 2022, 11, 995 4 of 16

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. Main characteristics of the selected studies.

Women with Age


Author, Year
Study Design ◦ Abdominal Women (Mean) Primary Secondary MINORS
of Country Period of Wall En- with UE of UE
Publication UE Score
Recruitment ◦◦ dometriosis (n) Women % (n) % (n)
(Ref) (n) with UE
Clinical
series
Steck and Retrospective
Helwing, 75.0
USA study on 70 28 NR 25.0 (7/28) 8
(21/28)
1965 [31] recorded cases
Retrospective
McKenna and study on
Wade-Evans, UK recorded cases 25 5 47.5 100 (5/5) 0 8
1985 [30] between
1951–1980
Retrospective
study on
Zhao et al., China 62 2 NR 0 10
2005 [29] recorded cases 100 (2/2)
between
1951–1980
Retrospective
Agarwal et al., study on
Singapore recorded cases 8 2 42 50.0 (1/2) 50.0 (1/2) 9
2008 [28]
between
2000–2007
Retrospective
Leite et al., Brazil 31 2 NR 0 100 (2/2) 10
2009 [27] study
2001–2007
Retrospective
Savelli et al., Italy 19 8 NR 25.0 (2/8) 75.0 (6/8) 8
2012 [26] study
2001–2007
Retrospective
Ecker et al., USA 63 9 NR 8
study 44.4 (4/9) 55.6 (5/9)
2014 [25]
2001–2013
Vellido- Retrospective
Cotelo et al., Spain study 15 2 37 0 100 (2/2) 8
2015 [24] 2000–2012
Chrysostomou Prospective
South 14 6 31.1 100 (6/6) 0 13
et al., 2017 Africa study
[32] 2010–2016
Retrospective
Marras et al., 60.0
Switzerland study 35 10 NR 40.0 (4/10) 11
2019 [23] (6/10)
2007–2017
Retrospective
Youssef, 2020 Egypt 21 2 NR 9
[22] study 50.0 (1/2) 50.0 (1/2) §
2016–2019
Total clinical 63.2 36.8
363 76
series (48/76) (28/76)
95%
Confidence 51.9–73.1 26.9–48.1
Interval
Case series
J. Clin. Med. 2022, 11, 995 5 of 16

Table 1. Cont.

Women with Age


Author, Year
Study Design ◦ Abdominal Women (Mean) Primary Secondary MINORS
of Country Period of Wall En- with UE of UE
Publication UE Score
Recruitment ◦◦ dometriosis (n) Women % (n) % (n)
(Ref) (n) with UE
Rabinovitch
et al., 1952 USA NR 3 36 100 (3/3) 0 6
[46]
Pathak and
Hayes, 1968 Jamaica NR 3 42 66.7 (2/3) 33.3 (1/3) 10
[33]
Lattuneddu
et al., 2002 Italy 2000–2001 3 43.6 33.3 (1/3) 66.7 (2/3) 9
[34]
Kingdom
Al-Saad et al., 2002–2005 3 42.3 0 11
of 100 (3/3)
2007 [35]
Bahrain
Dessy et al.,
Italy 2003–2006 4 37 50.0 (2/4) 50.0 (2/4) 11
2008 [36]
Fedele et al., Italy 2001–2003 7 37 57.1 (4/7) 42.9 (3/7) 9
2010 [37]
Abramowicz
et al., 2011 France NR 3 29 100 (3/3) 0 9
[38]
Darouichi
et al., 2013 Switzerland NR 3 37.3 66.7 (2/3) 33.3 (1/3) 7
[39]
Saito et al., Japan 1999–2011 7 35.7 71.4 (5/7) 28.6 (2/7) 11
2013 [40]
Chikazawa
et al., 2014 Japan NR 3 37 33.3 (1/3) 66.7 (2/3) 7
[41]
Boesgaard-
100
Kjer et al., Denmark 2011–2014 10 28.5 (10/10)
0 9
2017 [42]
Dos Santos
Filho et al., Brazil 2014–2017 6 33 100 (6/6) 0 11
2018 [43]
Hirata et al., Japan 2006–2016 96 40 66.7 32.3 11
2020 [9] (64/96) * (31/96) *
Makena et al., Kenya 2015–2019 5 40 10
80.0 (4/5) 20.0 (1/5)
2020 [44]
Total case 71.0 29.0
156
series (110/155) (45/155)
95%
Confidence 63.4–77.5 22.5–36.6
Interval
Total all 68.4 31.6
232
studies (158/231) (73/231)
95%
Confidence 62.1–74.1 26.0–37.9
Interval
Legend: ◦ for clinical series; ◦ ◦ if available; NR: not reported; § woman with a previous hysterosonography; * one
patient had unknown surgical history.

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.

Table 2. Reproductive and endometriosis history of women with UE.

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)

95% Confidence 43.3–81.9 17.7–64.5 26.9–48.1 29.8–62.0 26.7–62.9


Interval
Case series
Rabinovitch et al., NR NR 0 NR NR
1952 [46]
Pathak and Hayes,
0 0 33.3 (1/3) NR 33.3 (1/3) §
1968 [33]
Lattuneddu et al., NR
2002 [34] 33.3 (1/3) 100 (1/1) 33.3 (1/3) 33.3 (1/3)

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

Table 3. Clinical symptoms of UE.

Pain Bleeding Catamenial Symptoms *


Author, Year of Publication (Ref)
% (n) % (n) % (n)
Clinical
series
Steck and Helwing, 1965 [31] NR NR NR
McKenna and Wade-Evans, 1985 [30] NR NR 80.0 (4/5)
Zhao et al., 2005 [29] NR NR NR
Agarwal et al., 2008 [28] 50.0 (1/2) 100 (2/2) 100 (1/2)
Leite et al., 2009 [27] NR 50.0 (1/2) NR
Savelli et al., 2012 [26] NR NR NR
Ecker et al., 2014 [25] 55.5 (5/9) NR NR
Vellido-Cotelo et al., 2015 [24] NR NR 100 (2/2)
Chrysostomou et al., 2017 [32] 100 (6/6) 50.0 (3/6) 0
Marras et al., 2019 [23] NR 40.0 (4/10) NR
Youssef, 2020 [22] 100 (2/2) 50.0 (1/2) 100 (2/2)
Total clinical series 73.7 (14/19) 50.0 (11/22) 52.9 (9/17)
95% Confidence Interval 51.2–88.2 30.7–69.3 31.0–73.8
Case series
Rabinovitch et al., 1952 [46] 100 (3/3) 0 (0/3) 100 (3/3)
Pathak and Hayes, 1968 [33] 100 (3/3) 0 (0/3) 66.6 (2/3)
Lattuneddu et al., 2002 [34] 100 (3/3) NR NR
Al-Saad et al., 2007 [35] 100 (3/3) 100 (3/3) 100 (3/3)
Dessy et al., 2008 [36] 50.0 (2/4) 25.0 (1/4) 100 (4/4)
Fedele et al., 2010 [37] 100 (7/7) 57.0 (4/7) 100 (7/7)
Abramowicz et al., 2011 [38] 66.6 (2/3) 33.3 (1/3) 66.6 (2/3)
Darouichi et al., 2013 [39] 66.6 (2/3) 33.3 (1/3) 33.3 (1/3)
Saito et al., 2013 [40] 100 (7/7) 57.0 (4/7) 86.0 (6/7)
Chikazawa et al., 2014 [41] 100 (3/3) 0 (0/3) 33.3 (1/3)
Boesgaard-Kjer et al., 2017 [42] NR 100 (10/10) 100 (10/10)
Dos Santos Filho et al., 2018 [43] 100 (6/6) 100 (6/6) 100 (6/6)
Hirata et al., 2020 [9] 81.0 (78/96) 44.8 (43/96) 86.5 (83/96)
Makena et al., 2020 [44] 80.0 (4/5) 100 (5/5) 100 (5/5)
Total case series 84.2 (123/146) 51.0 (78/153) 86.9 (133/153)
95% Confidence Interval 77.5–89.3 43.1–58.8 80.7–91.4
Total all studies 83.0 (137/165) 50.9 (89/175) 83.5 (142/170)
95% Confidence Interval 76.6–88.0 43.5–58.2 77.2–88.4
Legend: * catamenial symptoms: swelling, color change, consistency change, and tenesmus.

Information on the frequency or UE recurrence was detailed in 14 studies (Table 4).


J. Clin. Med. 2022, 11, 995 9 of 16

Table 4. Frequency of recurrence of UE.

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

higher prevalence of right-sided diaphragmatic, hepatic, and pleural endometriosis lesions


compared with left-sided ones and could also elucidate the origin of UE.
In fact, once stuck by the falciform ligament, the peritoneal fluid containing free-
floating endometriotic glands could be funneled by this crescentic peritoneal fold and by
the hepatic round ligament toward the intra-abdominal aspect of the umbilicus, where
endometriotic cells may eventually implant and infiltrate the overlying connective tissue.
The presence of a small peritoneal concavity creates a sort of niche that would further
facilitate endometrial cells implantation. This is also supported by reports of UE in women
affected by umbilical hernia [27,40,53].
Even in the hypothesis of peritoneal fluid ascending directly from the pelvis along
the anterior abdominal wall, endometrial cells would be channeled by the peritoneal folds
created by the medial umbilical ligaments (obliterated umbilical arteries) and the median
umbilical ligament (obliterated uracus), which create two anatomic preferential routes
converging toward the umbilicus [54].
The pattern of dissemination of ovarian epithelial cancer cells might constitute a
similar pathogenic model here. Both hematogenous and lymphatic spread have been
suggested as the physio-pathological mechanism to explain umbilical metastases, the so-
called Sister Mary Joseph’s nodules, from gynecologic cancers [10,55]. However, according
to Hugen et al. (2021) [56], a local direct extension of cancer cells from the peritoneal
aspect to the skin is possible, as the umbilicus is a deep structure directly connected to the
extraperitoneal tissue.
Indeed, a contiguous extension of ovarian cancer cells from the peritoneal surface to
the umbilical skin has been demonstrated [57]. Moreover, in a recent nationwide review
of pathology records of umbilical metastases diagnosed in the Netherlands between 1979
and 2015, almost three fourths of the 806 study patients were females and, in these cases,
umbilical metastases most frequently originated from the ovaries [56].
The peritoneal fluid conveyance hypothesis would be in line with evidence on en-
dometriosis affecting the liver, diaphragm, and pleura [47,58,59], and would add further
support to the unifying mechanistic theory of endometriosis as a disease originating from
menstrual reflux and subsequent abdominopelvic distribution of lesions according to
specific local characteristics that facilitates implantation [60]. If this is the case, primary
UE should be considered part of the “right hypochondrium complex” [47]. Of note, this
hypothesis would explain primary UE even in the absence of co-existent pelvic implants,
as the origin of ectopic umbilical endometriotic glands would be the retrograde menstrual
flow per se, independently of already extant pelvic localizations of the disease.
The sine qua non for the validity of this theory is the demonstration of a contin-
uum of endometriotic infiltration through the entire thickness of the umbilical scar with
involvement of the parietal peritoneal layer, as shown in Figures 2–4.
Future studies on UE should focus on detailed histopathology findings of those women
who undergo en-bloc omphalectomy. In addition, when laparoscopy is also indicated, a
careful visual inspection of the diaphragm after liver retraction by means of a blunt probe
should be performed to identify concomitant endometriotic implants [61]. These measures
would both help clarify whether UE originates from inside the abdominal cavity or is a
purely skin condition with a separate pathogenesis.
should
J. Clin. Med. 2022, bePEER
11, x FOR considered
part of the “right hypochondrium complex” [47]. Of note, this hy-11 of 15
REVIEW
pothesis would explain primary UE even in the absence of co-existent pelvic implants, as
the origin of ectopic umbilical endometriotic glands would be the retrograde menstrual
flow per se, independently of already
should be considered partextant
of thepelvic
“right localizations
hypochondrium of complex”
the disease.
[47]. Of note, this hy-
pothesis
The sine qua would
non for the explain
validityprimary
of this UE evenis
theory inthe
the demonstration
absence of co-existent pelvic implants, as
of a continuum
J. Clin. Med. 2022, 11, 995 theinfiltration
origin of ectopic umbilical endometriotic glands would be the retrograde12 of 16
menstrual
of endometriotic through the entire thickness of the umbilical scar with in-
volvement of theflow per se, peritoneal
parietal independently of already
layer, as shownextant pelvic localizations
in Figures 2–4. of the disease.
The sine qua non for the validity of this theory is the demonstration of a continuum
of endometriotic infiltration through the entire thickness of the umbilical scar with in-
volvement of the parietal peritoneal layer, as shown in Figures 2–4.

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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